Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:42])[C@H:4]([OH:41])[CH2:5][NH:6][C:7](=[O:40])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:28]2[CH:33]=[CH:32][C:31]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:30][CH:29]=2)[C:16]([NH:18][C@H:19]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH3:20])=[O:17])=[CH:10][CH:9]=1.Cl>C1COCC1.CO.[OH-].[Na+]>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C@@H:19]([NH:18][C:16](=[O:17])[N:15]([CH2:14][C:11]2[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][C@@H:4]([OH:41])[C:3]([OH:42])=[O:2])=[O:40])=[CH:13][CH:12]=2)[C:28]2[CH:29]=[CH:30][C:31]([CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]3)=[CH:32][CH:33]=2)[CH3:20])=[CH:26][CH:25]=1
Reactant: COC(=O)[C@H](O)CNC(=O)c1ccc(CN(C(=O)N[C@@H](C)c2ccc(Cl)cc2)c2ccc(C3CCCCC3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](NC(=O)N(Cc1ccc(C(=O)NC[C@@H](O)C(=O)O)cc1)c1ccc(C2CCCCC2)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-{4-[3-[1(S)-(4-Chlorophenyl)ethyl]-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2(R)-hydroxypropionic acid methyl ester (280 mg, 0.473 mmol) was dissolved in a mixture of THF (2.5 mL) and methanol (2.5 mL) and 4 N aqueous sodium hydroxide (0.355 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The pH was adjusted to 3.0 by addition of 1 N hydrochloric acid. Solvent was removed by rotary evaporation in vacuo and the residue re-dissolved in ethyl acetate (10 mL). The organic phase was washed twice with water and once with brine, and then concentrated to dryness in vacuo leaving the title compound as a powder. Yield: 168 mg (89%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][N:5]2[C:6](=[O:8])[CH:7]=1.C1C=C[NH+]=CC=1.[Br:22][Br-]Br>N1C=CC=CC=1>[Br:22][C:7]1[C:6](=[O:8])[N:5]2[CH:9]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[S:11][C:4]2=[N:3][C:2]=1[CH3:1]
Reactant: COC(=O)c1cn2c(=O)cc(C)nc2s1
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Product: COC(=O)c1cn2c(=O)c(Br)c(C)nc2s1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 71.8 %

Procedure:
7-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, methyl ester (3.4 g), prepared according to Example 1, was reacted with pyridinium bromide perbromide (5.31 g) in anhydrous pyridine (80 ml) under stirring at room temperature for 40 minutes. The reaction mixture was poured in ice water and the precipitate was filtered and washed with water until neutral. The crude compound was purified over a SiO2 column, using chloroform:ethyl acetate 100:5 as eluent, so obtaining 3.3 g of 6-bromo-7-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, methyl ester, m.p. 199°-201° C., which was reacted with benzaldehyde (2.3 g) in methanol (90 ml) in the presence of sodium methoxide (0.75 g) under stirring at reflux temperature for 48 hours. The precipitate was filtered and dissolved in a mixture of dimethylformamide and formic acid: the solution was diluted with ice water and the precipitate was filtered and washed with water until neutral. Crystallization from methanol gave 2.4 g of 6-bromo-7-trans-(2-phenyl-ethenyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, m.p. 281°-285° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9](=[O:18])[N:10]([CH3:17])[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)(C)(C)C.[C:20]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:21]>>[F:23][C:22]([F:25])([F:24])[C:20]([OH:26])=[O:21].[NH2:7][CH2:8][C:9]([N:10]([CH3:17])[C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1)=[O:18]
Reactant: CN(C(=O)CNC(=O)OC(C)(C)C)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)CN)c1ccncc1
Reaction time: 1 h

Procedure:
[(Methyl-pyridin-4-yl-carbamoyl)-methyl]carbamic acid tert-butyl ester (181) (7 g, 28.1mmol) was dissolved in TFA (35mL) at rt. The reaction had to be cooled to prevent excessive heat being released. Once the reaction had settled, it was left for 1 hr. TFA was evaporated and the residue co-evaporated with toluene (3×1000 mL) and dried under vacuum to afford compound (182).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:12]([NH:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(COC)OC.O>[C:2]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:12]([NH:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(Nc2nc(C)ccc2S(=O)(=O)c2ccc(Br)cc2)c(C)c1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: COCCOC
Product: Cc1cc(C)c(Nc2nc(C)ccc2S(=O)(=O)c2ccc(-c3ccccc3)cc2)c(C)c1
Yield: 47 %

Procedure:
[3-(4-Bromobenzenesulfonyl)-6-methylpyridin-2-yl]-(2,4,6-trimethylphenyl)-amine, prepared as described in Example 46, (100 mg, 0.225 mmol), phenylboronic acid (32.9 mg, 0.269 mmol), Pd(PPh3)2Cl2 (7.7 mg, 0.011 mmol) and Ba(OH)2.8H2O (84.6 mg, 0.269 mmol) were heated at reflux in 1:1 dimethoxyethane/water (2 mL) for 20 h. The reaction was partitioned between EtOAc (100 mL) and water (20 mL) and the organic extract was washed with brine, dried, and stripped in vacuo. The residue was purified by silica gel chromatography (10% EtOAc/hexanes eluent) to give the title compound as a solid (47 mg, 47% yield), mp 140–141° C. mass spec. (AP+): m/z 443 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:20]C(=O)OC(C)(C)C)[S:9][C:10]=1[C:11]([C:13]1[C:14]([CH3:19])=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:12]>FC(F)(F)C(O)=O>[CH3:19][C:14]1[C:13]([C:11]([C:10]2[S:9][C:8]([NH2:20])=[N:7][C:6]=2[C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:12])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Cc1ncccc1C(=O)c1sc(NC(=O)OC(C)(C)C)nc1-c1ccco1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncccc1C(=O)c1sc(N)nc1-c1ccco1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
Compound 308 (83.0 mg, 0.215 mmol) was dissolved in trifluoroacetic acid (1 mL), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate were added to the resulting residue, and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:4) to afford the entitled Compound 309 (60.0 mg, 99%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1B(O)O>>[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1
Reactant: Cc1cccc(Br)c1
Reactant: OB(O)c1ccc(F)cc1F
Product: Cc1cccc(-c2ccc(F)cc2F)c1

Procedure:
Using a method analogous to Method B, using 3-bromotoluene and 2,4-difluorobenzene boronic acid, the title compound was obtained as a clear oil.
Reaction SMILES: [CH:1]([C:4]([C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)=[O:5])([CH3:3])[CH3:2].[C:17](O)(=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[O:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:7]1[N:8]=[C:9]([NH:11][C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[O:24])[S:10][C:6]=1[C:4](=[O:5])[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)C(=O)c1sc(N)nc1-c1ccco1
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(=O)c1sc(NC(=O)c2ccncc2)nc1-c1ccco1
Temperature: 60 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
Compound 392 (100 mg, 0.424 mmol) was dissolved in DMF (5 mL), and isonicotinic acid (205 mg, 1.68 mmol), EDC hydrochloride (324 mg, 1.69 mmol) and 1-hydroxybenzotriazole monohydrate (259 mg, 1.69 mmol) were added thereto, followed by stirring at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was recrystallized from ethanol to afford the entitled Compound 393 (103 mg, 71%) as a pale green solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1([N:16]([CH3:18])[CH3:17])[CH2:15][CH2:14][C:9]2(OCC[O:10]2)[CH2:8][CH2:7]1.Cl>O>[CH3:18][N:16]([CH3:17])[C:6]1([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH2:7][CH2:8][C:9](=[O:10])[CH2:14][CH2:15]1
Reactant: COCCCC1(N(C)C)CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Product: COCCCC1(N(C)C)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
[8-(3-methoxypropyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-dimethylamine (8.11 g, 31.5 mmole) was dissolved in water (12 ml), conc. HCl (19.5 ml) was added while cooling with ice, and the reaction mixture was stirred for 3 days at room temperature. The reaction mixture was washed with ether (2×75 ml). The solution was then made alkaline with 5N NaOH and extracted with dichloromethane (3×75 ml). The combined organic phases were washed with water (75 ml), dried over Na2SO4, filtered, and the solvent was removed in vacuo.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([NH2:33])=[O:32])[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:18][N:17]=1)[CH3:2].C=O.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH2:1]([C:3]1[CH:8]=[C:7]([CH:9]2[CH2:10][CH2:11][N:12]([CH3:40])[CH2:13][CH2:14]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([NH2:33])=[O:32])[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:18][N:17]=1)[CH3:2]
Reactant: CCc1cc(C2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CCc1cc(C2CCN(C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
2-(2-(2-(2-((2-Ethyl-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (8) (84 mg, 0.16 mmol) was dissolved in methanol (8 mL), 37% formaldehyde solution (53 μl., 0.66 mmol) was added and the mixture stirred for ten minutes at room temperature. Sodium tris(acetoxy)borohydride (174 mg, 0.821 mmol) was added, and after two hours the mixture was concentrated. The residue was diluted with 10% sodium hydroxide (15 mL) and brine (15 mL), and the mixture extracted with ethyl acetate (4×25 mL). The combined ethyl acetate phases were washed with brine, dried over sodium sulfate, evaporated and the residue evaporated from DCM to give the title compound (9) (72 mg, 84% yield) as a white solid; 1H NMR (400 MHz, d6-DMSO) δ 9.46 (s, 1H), 8.49 (s, 1H), 7.36 (s, 1H), 7.21 (t, J=4.6 Hz, 2H), 7.18-7.10 (m, 4H), 7.06 (dd, J=8.2, 1.6 Hz, 1H), 6.88 (s, 1H), 3.44 (s, 2H), 3.07-2.90 (m, 4H), 2.86 (d, J=11.3 Hz, 2H), 2.57 (q, J=7.5 Hz, 2H), 2.48-2.37 (m, 1H), 2.19 (s, 3H), 2.02-1.89 (m, 2H), 1.79-1.59 (m, 4H), 1.09 (t, J=7.5 Hz, 3H). LCMS Method C: rt 5.04 min; m/z 526.2 [M+H]+; m/z 524.2 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:41])[C:12](=[CH:15][C:16]3[N:17]=[CH:18][N:19]([C:22]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:20]=3[CH3:21])[CH2:13][CH2:14][C:3]=12>[Pd].CN(C)C=O.C(O)C>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:41])[CH:12]([CH2:15][C:16]3[N:17]=[CH:18][N:19]([C:22]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:20]=3[CH3:21])[CH2:13][CH2:14][C:3]=12
Reactant: Cc1c2n(c3ccccc13)C(=O)C(=Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1c2n(c3ccccc13)C(=O)C(Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Reaction time: 6 h

Procedure:
A mixture of 8,9-dihydro-10-methyl-7-[(5-methyl-1 -trityl-1H-imidazol-4-yl)methylene]pyrido[1,2-a]indol-6(7H)-one (2.0 g) and 10% palladium on carbon (0.4 g) in N,N-dimethylformamide-ethanol (6:1, 49 ml) was hydrogenated at an atmospheric pressure for 6 hours. After filtration of the catalyst, the filtrate was evaporated in vacuo to give 8,9-dihydro-10-methyl-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]-indol-6(7H)-one as an oil, which was used in the next reaction without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH2:12]Br)[CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([CH2:34][OH:35])[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1.[H-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[CH2:12][O:35][CH2:34][C:21]1([C:18]2[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=2)[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]1
Reactant: FC(F)(F)c1cc(Br)cc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(C(F)(F)F)c2)(c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-Bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (1.2 g, 3.78 mmol) and tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.96 g, 3.2 mmol) were combined in dimethylformamide (10 mL) and cooled to 0° C. The reaction was treated with sodium hydride (151 mg, 6.3 mmol), stirred at 0° C. for 1 h, and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (15% ethyl acetate/hexanes) gave 1.1 g (61%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.61 (s, 1H), 7.35 (s, 1H), 7.30-7.31 (m, 2H), 7.26 (s, 1H), 7.03-7.07 (m, 2H), 4.36 (s, 2H), 3.72-3.75 (m, 2H), 3.38 (s, 2H), 3.01-3.06 (m, 2H), 2.13-2.16 (m, 2H), 1.81-1.87 (m, 2H), 1.43 (s, 9H). 13C-NMR (CDCl3, 126 MHz) δ 161.6 (d, J=245.7 Hz), 152.0, 141.9, 138.3, 133.3, 132.4 (q, J=32.6 Hz), 128.8, 127.5 123.2 (q, J=273.5 Hz), 122.8, 122.4, 115.5, 115.3, 79.7, 79.5, 71.7, 68.0, 41.4, 32.2, 28.5, 25.7. Mass spec.: 548.16 (MH)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:32]=[CH:33][CH:34]=1)[CH2:7][NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:28][C:29]([NH2:31])=[O:30])([O-:3])=[O:2].Cl.Cl[CH2:37][CH2:38][N:39]([CH2:42][CH3:43])[CH2:40][CH3:41].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:38]([N:39]([CH2:42][CH3:43])[CH2:40][CH2:41][N:25]1[CH2:24][CH2:23][N:22]([C:19]2[CH:20]=[CH:21][C:16]([NH:15][C:13]3[N:12]=[CH:11][C:10]([CH2:28][C:29]([NH2:31])=[O:30])=[C:9]([NH:8][CH2:7][C:6]4[CH:32]=[CH:33][CH:34]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)[CH:14]=3)=[CH:17][CH:18]=2)[CH2:27][CH2:26]1)[CH3:37]
Reactant: CCN(CC)CCCl
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCNCC3)cc2)cc1NCc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCN1CCN(c2ccc(Nc3cc(NCc4cccc([N+](=O)[O-])c4)c(CC(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
40 mg of 4-[(3-nitrobenzyl)amino]-6-{[4-(piperazin-1-yl)phenyl]amino}pyridine-3-carboxyamide (the compound of Example 224) was dissolved in 0.3 mL of N,N-dimethylformamide, to which 18.5 mg of 2-chloro-N,N-diethylethylamine hydrochloride and 25 mg of potassium carbonate were added, and stirred at room temperature for 3 hours. Water was added to the reaction mixture, extracted with chloroform, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:ammonia methanol=10:1) to obtain 43 mg (88%) of the title compound as an orange crystalline powder.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:10])[CH2:8][OH:9])(=[O:3])[CH3:2].O>CN(C)C=O>[C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:10])[CH:8]=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC=C(C)CO
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCC=C(C)C=O
Yield: 91.2 %

Procedure:
To a solution of 4-acetoxy-2-methyl-2-buten-1-ol (6.69 g, 46.4 mmol) in dimethylformamide (40 ml) were added 2,2,6,6-tetramethyl-piperidine-1-oxy (0.39 g, 2.32 mmol, 5 mol %) and cuprous chloride (0.48 g, 4.64 mmol, 10 mol %). The mixture was subjected to reaction at 40° C. for 8 hours while bubbling oxygen at a rate of about 100 ml/min. After completion of the reaction, the reaction mixture was poured into ice-cooled water (30 ml) and extracted with ether (100 ml) three times. The extract was dried over anhydrous magnesium sulfate. Evaporation of the ether followed by purification by column chromatography (ethyl acetate-hexane (=1:3)) gave 4-acetoxy-2-methyl-2-buten-1-al (6.02 g, 42.3 mmol; Yield: 91.2%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:21][C@@H:22]1[C:38](=[O:39])[N:24]2[C:25]([C:30]([O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=[O:31])=[C:26]([CH3:29])[CH2:27][S:28][C@H:23]12>CC(N(C)C)=O.C(#N)C>[CH3:29][C:26]1[CH2:27][S:28][C@@H:23]2[C@H:22]([NH:21][C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3])[C:38](=[O:39])[N:24]2[C:25]=1[C:30]([O:32][CH2:33][C:34]([Cl:35])([Cl:37])[Cl:36])=[O:31]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](NC(=O)OCC(Cl)(Cl)Cl)[C@H]2SC1
Reaction time: 0.5 h

Procedure:
2,2,2-Trichloroethyl chloroformate (3.15 ml, 22 mmole) was added to a suspension of 2,2,2-trichloroethyl 7β-amino-3-methylceph-3-em-4-carboxylate hydrogen p-toluenesulphonate (10.36 g, 20 mmole) in a mixture of dimethylacetamide (25 ml) and acetonitrile (100 ml.) The mixture was stirred at ca. 25° for 30 minutes, the acetonitrile was evaporated and ethyl acetate (80 ml) was added. The solution was washed with saturated sodium hydrogen carbonate solution (80 ml), dried and evaporated to an oil which could not be crystallised. The oil was taken up in chloroform (50 ml), washed with water (3 × 50 ml) and re-evaporated to an orange foam which on trituration with methanol (20 ml) gave the title ester as an off-white solid, λmax. 262 nm (E1cm1% 113.5). Crystallisation from ethanol gave an analytical sample, m.p. 179° to 181.5°, [α]D + 70°, λmax. 262 nm (ε 6,000), νmax (CHBr3) 3410 (NH), 1780 (azetidin-2-one), 1740 and 1520 (NHCO2R) and 1740 cm-1 (CO2R), τ(CDCl3) 3.98 (1H,d,J 9.5 Hz; NH), 4.34 (1H,dd,J 9.5 Hz; C7 -H) 4.91 (1 H,d J 5 Hz; C6 -H), 4.91, 5.08 (2H, AB-q, J 12 Hz; CO2CH2CCl3), 5.17 (2H, s; NHCO2CH2CCl3), 6.34, 6.73 (2H, AB-q, J 18 Hz; C2 -H2), 7.74 (3H,s; C3 -CH3) (Found: C, 30.3; H, 2.4; Cl, 40.2; N, 5.3; S, 6.5. C13H12Cl6N2O5S (521.1) requires C, 30.0; H, 2.3; Cl, 40.8; N, 5.3; S, 6.2%
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:24]=[C:13]3[C:14]4[C:19]([CH2:20][CH2:21][N:12]3[C:11](=[O:25])[N:10]=2)=[CH:18][C:17]([O:22][CH3:23])=[CH:16][CH:15]=4)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Br:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38]>C1COCC1>[Br:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[CH:24]=[C:13]3[C:14]4[C:19]([CH2:20][CH2:21][N:12]3[C:11](=[O:25])[N:10]=2)=[CH:18][C:17]([O:22][CH3:23])=[CH:16][CH:15]=4)[CH:3]=1)=[O:38]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: COc1ccc2c(c1)CCn1c-2cc(Nc2cccc(N)c2)nc1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2cccc(NC(=O)c3cccc(Br)c3)c2)nc1=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
To a mixture of 2-(3-amino-phenylamino)-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (§) (20.0 mg, 0.06 mmol) in THF (2 mL), triethylamine (13 μL, 0.09 mmol) and 3-bromobenzoylchloride (10 μL, 0.07 mmol) was added and stirred at 50° C. for 2 hrs. The mixture was quenched with concentrated HCl and purified on BondElut® SCX (Varian Incorporated). Formed solid was washed with CH2Cl2 to give the title compound (25.3 mg, 81%). 1H-NMR (400 MHz, d6-DMSO) δ 10.43 (s, 1H), 9.68 (s, 1H), 8.15 (t, 1H), 8.08 (s, 1H), 7.97 (dt, 1H), 7.81 (ddd, 1H), 7.75 (brd, 1H), 7.70 (d, 1H), 7.51 (t, 1H), 7.36 (dt, 1H), 7.31 (t, 1H), 7.05-6.98 (2H), 6.42 (s, 1H), 3.99 (t, 2H), 3.84 (s, 3H) and 2.97 (t, 2H); MS (ESI) (M+H)+ 517, 519.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CN(C=O)C>[OH:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:4][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: Oc1ccccc1O
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccccc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
To a solution of pyrocatechol (5.51 g, 50 mmol) in dry DMF (30 mL) was slowly added sodium hydride (1.2 g, 50 mmol) at 0° C. After stirring at 25° C. for 4 hours, the reaction mixture was heated at 65-70° C. for 1 hour followed by an addition of ethyl 4-bromobutyrate (10.7 mL, 75 mmol). The reaction mixture was then left stirring at this temperature for 6 hours. Upon quenching with water, extraction with dichloromethane, and evaporation gave the crude product which was purified by column chromatography, eluting with 87% hexane:10% CH2Cl2:3% EtOAc. Crystallization with hexane afforded a white solid in 55% yield (6.17 g, mp. 37.2-38.4° C.). 1H NMR (400 MHz, CDCl3): 1.26 (3H, t, J=7.1 Hz), 2.17 (2H, m), 2.52 (2H, t, J=7.0 Hz), 4.09 (2H, t, J=6.0 Hz), 4.16 (2H, q, J=7.1 Hz), 6.81-6.89 (3H, m), 6.92-6.94 (1H, m).
Reaction SMILES: C1C=CC=CC=1.CCN(CCO[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=C[CH:20]=1)CC.Cl.CCCCCCCCCCCC.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(I)C=CC=CC=1>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.COCCOC>[C:22]1([C:21]2[CH:20]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCN(CC)CCOc1ccc(Cc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: c1ccccc1
Solvent: Ic1ccccc1
Solvent: CCCCCCCCCCCC
Product: c1ccc(-c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 85.7 %

Procedure:
Closed system: To a J. Young NMR tube, in a glove box, was added benzene (437 mg, 5.60 mmol), Ir(COD)(indenyl) (3.0 mg, 0.0070 mmol), dppe (2.8 mg, 0.0070 mmol), dodecane (internal standard, 11.5 mg, 0.0675 mmol), and HBPin (45 mg, 0.352 mmol). The tube was sealed, removed from the box, and stirred at 100° C. for 18 h. The tube was allowed to cool to room temperature and Pd(PPh3)4 (8.1 mg, 0.007 mmol), K3PO4 (112 mg, 0.528 mmol), PhI (72.7 mg, 0.356 mmol), and DME (2 mL) were added. A GC-trace of the reaction mixture revealed PhBPin in 85.7% yield. Three freeze-pump-thaw cycles were performed to remove residual O2 and the reaction mixture was heated at 80° C. for 2 days. GC analysis showed biphenyl (81.8% GC-yield), iodobenzene (7.9.7% GC-conversion), and PhBPin (79.1% GC-conversion).