Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:11]([CH2:17][N:18](C(OCC2C=CC=CC=2)=O)[C:19](=[O:26])[C@H:20]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH2:21])[O:10]C1(C)C)=O)(C)(C)C.FC(F)(F)C(O)=O.[ClH:46].[H][H]>ClCCl.[Pd].O.C(O)(=O)C>[ClH:46].[ClH:46].[NH2:8][C@@H:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C@H:11]([OH:10])[CH2:17][NH:18][C:19](=[O:26])[C@H:20]([CH2:22][CH:23]([CH3:24])[CH3:25])[NH2:21]
Reactant: [H][H]
Reactant: CC(C)C[C@H](N)C(=O)N(CC1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](N)C(=O)NC[C@@H](O)[C@@H](N)CC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
A solution of 250 mg (0.47 mmol) of N-[[(4S)-3-[(t-butyloxy)carbonyl]-2,2-dimethyl-4-(2-methylpropyl)-5-oxazolidinyl]methyl]-N-[(phenylmethoxy)carbonyl]-L-leucinamide in 3 ml of dry dichloromethane was cooled in an ice bath under nitrogen, and treated with 1.5 ml of distilled trifluoroacetic acid. The reaction was stirred at ambient temperature. After 1 hour, the solvent was removed in vacuo, the residue dissovled in 1.7 ml of distilled tetrahydrofuran, treated with 1.0 ml (1 mmol) of 1N hydrochloric acid, and stirred at ambient temperature. After three hours, the reaction was concentrated in vacuo, and the residue was stored in the freezer overnight. The next morning a solution of 259 mg of the free amine hydrochloride from above in 6 ml of a 3:1; acetic acid:water mixture was treated with 1.4 ml (1.4 mmol) of 1N hydrochloric acid, and 150 mg of 10% palladium on charcoal. It was reduced with a steady stream of hydrogen at 1 atmosphere pressure. After 4 hours, filtration of the reaction mixture followed by concentration of the filtrate afforded 242 mg of crude product. The compound was purified by chromatography on a 40 ml column of HP-20 resin, eluted with a gradient from 250 ml of 96:3:1 to 250 ml of 18:2:80, water:1N hydrochloric acid:methanol. The product containing fractions were pooled and concentrated in vacuo then lyophilized from water to obtain 112 mg of the title compound as a 1.3 mole water solvate.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1.[NH2:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26]>ClCCl>[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26])=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1
Reactant: CC(C)(O)CN
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
Triethylamine (17.35 mL, 124 mmol) was added to a solution of 7-bromo-4-chloro-3-nitroquinoline (29.84 g, 104 mmol) in dichloromethane (253 mL), and the reaction was cooled to 0° C. 1-Amino-2-methylpropan-2-ol (10.17 g, 114 mmol) was added dropwise, and then the reaction was allowed to warm to ambient temperature and stirred overnight. A precipitate formed and was isolated by filtration and washed with water. The crude solid was recrystallized from a mixture of isopropanol and acetonitrile to provide 27.78 g of 1-(7-bromo-3-nitroquinolin-4-ylamino)-2-methylpropan-2-ol as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:6]=1[CH3:19])=[O:4].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:6]=1[CH2:19][Br:20])=[O:4]
Reactant: CCC(CC)Cn1c(C)c(C(=O)OC)cc(Br)c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(CC)Cn1c(CBr)c(C(=O)OC)cc(Br)c1=O
Yield: 69.2 %

Procedure:
A mixture of 5-bromo-1-(2-ethyl-butyl)-2-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (5.72 g, 17.3 mmol), N-bromosuccinimide (3.39 g, 19.1 mmol), and benzoyl peroxide (0.42 g, 1.73 mmol) in CCl4 (170 mL) was refluxed for 16 h. The resulting suspension was filtered, and the filtrate was evaporated in vacuo. The residue was purified by silica gel chromatography (0-20% EtOAc/hexanes) to give 4.9 g of the title compound as a yellow viscous oil. MS: (+) m/z 432.10 (M+Na).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26](Br)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[Br-].[O:67]1[CH2:71][CH2:70][O:69][CH:68]1[CH2:72][CH2:73][Zn+]>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:67]1[CH2:71][CH2:70][O:69][CH:68]1[CH2:72][CH2:73][C:26]1[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[N:28][C:23]([N:20]2[CH2:19][CH2:18][C:17]3[C:22](=[C:13]([C:11](=[O:12])[NH:10][C:2]4[S:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)[CH:14]=[CH:15][CH:16]=3)[CH2:21]2)=[CH:24][CH:25]=1
Reactant: [Zn+]CCC1OCCO1
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1CCC1OCCO1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.3 %

Procedure:
A mixture of compound 94B (8.0 g, 14.15 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (1.162 g, 2.83 mmol) and palladium acetate (0.318 g, 1.415 mmol) in THF (60 mL) was stirred at room temperature for 5 min. To this solution was added 0.5 M (2-(1,3-dioxolan-2-yl)ethyl)zinc(II) bromide (56.6 mL, 28.3 mmol) via an additional funnel drop wise at room temperature. The reaction was stirred overnight. The solvent was removed, and residue was loaded on a silica column and eluted with 7:3/hexanes: EtOAc to give 7.58 g of desired product 96A: APCI (+)LC/MS: 587 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[CH2:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O)[CH3:14].[F-].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O1CCOCC1.CC(OC)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH2:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12])[CH3:14]
Reactant: CCc1ccccc1B(O)O
Reactant: COC(=O)c1ccc(Br)c(O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Solvent: COC(C)(C)C
Product: CCc1ccccc1-c1ccc(C(=O)OC)cc1O

Procedure:
A mixture of methyl 4-bromo-3-hydroxybenzoate (Combi-Blocks CA-4189, 3.00 g, 13.0 mmol), 2-ethylphenylboronic acid (2.92 g, 19.5 mmol), cesium fluoride (5.92 g, 39.0 mmol; 3.00), palladium acetate (58 mg, 0.26 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (320 mg, 0.78 mmol) was prepared in dioxane (30 mL) and water (15 mL) and heated at 90° C. for 2 hours. Additional amounts of 2-ethylphenylboronic acid (1.46 g, 9.7 mmol), palladium acetate (58 mg, 0.26 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (320 mg, 0.78 mmol) were added, and the mixture was stirred for 2 additional hours. Additional amounts of 2-ethylphenylboronic acid (0.73 g, 4.9 mmol), palladium acetate (29 mg, 0.13 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (160 mg, 0.39 mmol) were added, and the mixture was stirred for 2 additional hours. The reaction mixture was diluted with MTBE (150 mL), and then washed with water (50 mL) and brine (50 mL). The aqueous layers were extracted with MTBE (75 mL). The organic layers were combined, dried (MgSO4) and concentrated under vacuum. After purification by flash chromatography (silica, heptane/EtOAc), the title compound was obtained as a yellow oil (3.13 g, 94%). HPLC (Method A) Rt 4.5 min (Purity: 99.2%). LC/MS (Method B): 255.1 (M−H)−.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][N:13]1[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[S:20][C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2.CC(O)C.S(=O)(=O)(O)O.[OH-].[Na+]>O>[CH:25]1[C:26]2[N:13]([CH2:12][CH2:11][O:10][CH2:9][CH2:8][OH:7])[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:20][C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc2c(c1)Sc1ccccc1N2CCOCCOC1CCCCO1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: OCCOCCN1c2ccccc2Sc2ccccc21
Reaction time: 8 h
Yield: 52.2 %

Procedure:
A mixture of crude 10-(2-(2-((tetrahydro-2-pyranyl)oxy)ethoxy)ethyl)-10H-phenothiazine (3.8 g, 10 mmol), 2-propanol (50 ml) and a 4 M aqueous sulfuric acid solution (8 ml) was heated at 60° C. for 3 h and then left overnight at room temperature. The reaction mixture was poured into a mixture of water (500 ml) and a 4 N sodium hydroxide solution (17 ml). The mixture was extracted with diethyl ether (150 ml) and the organic extract was washed with brine and dried over sodium sulphate. The solvent was evaporated in vacuo to give 1.5 g of crude 2-(2-(10H-phenothiazin-10-yl)ethoxy)ethanol. TLC: rf=0.52 (SiO2 ; dichloromethane/methanol=19:1).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.[OH:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:27][CH3:28])[C:25]=1[OH:26])[C:20](O)=[O:21].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C>[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH:14][C:20](=[O:21])[C:19]3[CH:23]=[C:24]([O:27][CH3:28])[C:25]([OH:26])=[C:17]([OH:16])[CH:18]=3)[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1
Reactant: COc1cc(C(=O)O)cc(O)c1O
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1cc(C(=O)Nc2cnn(Cc3c(C)noc3C)c2)cc(O)c1O
Reaction time: 0.08 h

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (example 4-1a) (228 mg, 1 mmol), 3,4-dihydroxy-5-methoxybenzoic acid (184 mg, 1 mmol), HOBt (135 mg, 1 mmol), and EDC (191 mg, 1 mmol) were dissolved in 2 mL DMF in a microwave vial followed by the addition of triethylamine (101 mg, 1 mmol). The reaction was placed in a microwave reactor at 165° C. for 5 minutes. The crude product was purified directly using Varian HPLC (10%-95% ACN in H2O:25 minute gradient). The pure fractions were combined and concentrated to afford N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-3,4-dihydroxy-5-methoxybenzamide. (280 mg, 70%). LC/MS; [M+H] calculated for C,17;H,18;N,4;O,5; expected 359.1; found 359.1.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]=[C:8](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[O:9][CH:10]=1)(=O)C.[OH-].[Na+].O>CS(C)=O>[OH:4][CH2:5][C:6]1[N:7]=[C:8](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[O:9][CH:10]=1
Reactant: CC(=O)OCc1coc(/C=C/c2ccc(C(F)(F)F)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: OCc1coc(/C=C/c2ccc(C(F)(F)F)cc2)n1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
4-(Acetoxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole (20.0 g, 64.3 mmol) was dissolved in dimethyl sulfoxide (200 ml), and 2N-aqueous sodium hydroxide solution (35 mL 70.0 mmol) was added at 50° C. The mixture was stirred at about 40° C. for 15 min. Water (200 ml) was added at the same temperature. After allowing to cool to room temperature and stirring, the mixture was stirred at the same temperature for 1 hour. The precipitated crystals were collected by filtration, washed with water (60 ml) and dried under reduced pressure to give 4-(hydroxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole (16.4 g, 61.1 mmol, yield 95%).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:5]#[C:6][C:7]([N:10]1[Si](C)(C)CC[Si]1(C)C)([CH3:9])[CH3:8])[CH3:4].[ClH:19]>>[ClH:19].[NH2:10][C:7]([CH3:9])([CH3:8])[C:6]#[C:5][CH:3]([O:2][CH3:1])[CH3:4]
Reactant: COC(C)C#CC(C)(C)N1[Si](C)(C)CC[Si]1(C)C
Agent: Cl
Product: COC(C)C#CC(C)(C)N

Procedure:
(2-Methoxy-5-methylhex-3-yn-5-yl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane (1.2 g) was stirred with dilute aqueous hydrochloric acid (12 ml) for 0.25 hours. The aqueous phase was washed with diethyl ether (twice) and the evaporated under reduced pressure. The residue was evaporated with toluene (twice) to remove residual water to give 5-amino-2-methoxy-5-methylhex-3-yne hydrochloride, 0.54 g, as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)[C@H]1CCCC[C@@H]1N.Br[C:35]1[S:36][CH:37]=[C:38]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[N:39]=1>C1(C)C=C(C)C=C(C)C=1.[Cu](I)I.O>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:35]3[S:36][CH:37]=[C:38]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[N:39]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2n[nH]c3ccccc23)cc1
Reactant: CCOC(=O)c1csc(Br)n1
Agent: I[Cu]I
Agent: CN(C)[C@H]1CCCC[C@@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1cc(C)cc(C)c1
Product: CCOC(=O)c1csc(-n2nc(-c3ccccc3)c3ccccc32)n1
Temperature: 180 °C
Yield: 46.7 %

Procedure:
To a solution of 3-phenyl-1H-indazole (689 mg) synthesized according to the literature (T. Edward C., et al., Tetrahedron, 1991, 47, 9599-9620) in mesitylene (5 mL, manufactured by Kanto Chemical Co., Inc.), potassium phosphate (2.38 g, manufactured by Wako Pure Chemical Industries, Ltd.), (1S,2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (50 mg, manufactured by Tokyo Chemical Industry Co., Ltd.), copper iodide (34 mg, manufactured by Kanto Chemical Co., Inc.), and ethyl 2-bromo-4-thiazolecarboxylate (840 mg) synthesized according to the literature (T. R. Kelly, et al., J. Org. Chem., 1996, 61, 4623-4633) were added, and the mixture was heated overnight at 180° C. The reaction solution was cooled to room temperature, and then water (20 mL) was added thereto. Ethyl acetate was extracted (3×20 mL), washed with brine (20 mL), and dried (MgSO4), and then the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1), to give 579 mg of the title compound. LC-MS: HPLC retention time 6.80 minutes, m/z 350 (M+H), condition B-1.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.C1C=CC=CC=1>O>[N:8]1([C:4]2[CH2:5][CH2:6][S:1][CH2:2][CH:3]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C1CCNC1
Reactant: O=C1CCSCC1
Solvent: c1ccccc1
Solvent: O
Product: C1=C(N2CCCC2)CCSC1

Procedure:
A solution of 103 g (0.89 mole) of tetrahydrothiopyran-4-one, 95 g (1.33 moles) of pyrrolidine, and one l. of anhydrous benzene is heated under reflux in a nitrogen atmosphere for 2 hours until the theoretical amount of water has collected in a Dean-Stark trap. The solvent is distilled, and the residue is fractionated under reduced pressure to provide 5,6-dihydro-4-(1-pyrrolidinyl)-2H-thiopyran as a colorless liquid, b.p. 124° (0.01 mm).
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([O:15][CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[C:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:6]=1)[OH:4])#[CH:2].I[C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1.C(N(CC)CC)C>O.C(OCC)C.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.[Cu](I)I>[OH:4][CH:3]([C:5]1[CH:6]=[C:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:8]([O:15][CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:23])[CH3:22])=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)[C:1]#[C:2][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1
Reactant: C#CC(O)c1cc(C(C)(C)C)c(OCOCC[Si](C)(C)C)c(C(C)(C)C)c1
Reactant: COC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)c1ccc(C#CC(O)c2cc(C(C)(C)C)c(OCOCC[Si](C)(C)C)c(C(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6 g (15.4 mmol) of α-ethynyl-3,5-di-tert-butyl-4-(2-trimethylsilylethoxymethoxy)benzenemethanol, 4.1 g (15.4 mmol) of methyl 4-iodobenzoate and 50 ml of triethylamine are introduced into a three-necked flask. The reaction medium is degassed with nitrogen for 30 minutes and 820 mg (1.2 mmol) of bis(triphenylphosphine)palladium(II) chloride and 360 mg (1.9 mmol) of copper iodide are then added successively. The reaction medium is stirred at room temperature for four hours and evaporated to dryness, and the residue obtained is taken up in water and ethyl ether. The organic phase is separated out after settling has taken place, dried over magnesium sulphate and then evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of dichloromethane and heptane (80/20% by volume); 6.7 g (84%) of methyl 4-{3-hydroxy-3-[3,5-di-tert-butyl-4-(2-trimethylsilylethoxymethoxy)phenyl]-1-propynyl}benzoate are collected, with a melting point of 91-2° C.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:3]=1[O:4][C:5]1[C:13]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[O:28][CH2:29][CH2:30][OH:31].[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[Cl:1][C:2]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:3]=1[O:4][C:5]1[C:13]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][CH:19]=2)(=[O:16])=[O:17])=[CH:12][C:8]([C:9]([NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:11])=[CH:7][C:6]=1[O:28][CH2:29][CH2:30][OH:31]
Reactant: COc1ccc(Cl)c(Oc2c(NS(=O)(=O)c3ccc(C(F)(F)F)cc3)cc(C(=O)O)cc2OCCO)c1
Reactant: Nc1ccccc1
Product: COc1ccc(Cl)c(Oc2c(NS(=O)(=O)c3ccc(C(F)(F)F)cc3)cc(C(=O)Nc3ccccc3)cc2OCCO)c1

Procedure:
Analogously to Example 74, by condensing 4-(2-chloro-5-methoxy-phenoxy)-3-(2-hydroxy-ethoxy)-5-(4-trifluoromethyl-benzenesulphonylamino)-benzoic acid with aniline there was obtained 4-(2-chloro-5-methoxy-phenoxy)-3-(2-hydroxy-ethoxy)-N-phenyl-5-(4-trifluoromethyl-benzenesulphonylamino)-benzamide.
Reaction SMILES: [PH2](O)=O.N([O-])=O.[Na+].N[C:9]1[C:18]2[C:19](=[O:26])[CH:20]=[C:21]([C:23]([OH:25])=[O:24])[O:22][C:17]=2[C:16]([CH2:27][CH2:28][CH3:29])=[C:15]2[C:10]=1[C:11]([Cl:33])=[CH:12][C:13]([C:30]([OH:32])=[O:31])=[N:14]2>S(=O)(=O)(O)O.O.C(O)(=O)C>[Cl:33][C:11]1[C:10]2[C:15](=[C:16]([CH2:27][CH2:28][CH3:29])[C:17]3[O:22][C:21]([C:23]([OH:25])=[O:24])=[CH:20][C:19](=[O:26])[C:18]=3[CH:9]=2)[N:14]=[C:13]([C:30]([OH:32])=[O:31])[CH:12]=1
Reactant: CCCc1c2nc(C(=O)O)cc(Cl)c2c(N)c2c(=O)cc(C(=O)O)oc12
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: O=[PH2]O
Solvent: O
Solvent: CC(=O)O
Product: CCCc1c2nc(C(=O)O)cc(Cl)c2cc2c(=O)cc(C(=O)O)oc12
Temperature: 5 °C
Yield: 59.5 %

Procedure:
Cold hypophosphorous acid (50%, 20 ml) was added slowly to a solution of sodium nitrite (3.7 g) in sulphuric acid (100 ml) diluted with water (50 ml), maintaining the temperature from -5° to -10°. The reaction mixture was cooled to -15°, and a cooled solution containing 5-amino-6-chloro-4-oxo-10-propyl-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylic acid (0.753 g) in acetic acid (200 ml), added over two hours maintaining the temperature between -10° and -15°. When the addition was complete, the slurry was stirred for an hour, and the mixture allowed to warm to 5° C. The mixture was stored in a refrigerator overnight, with the evolution of nitrogen and oxides of nitrogen. Filtration of the reaction mixture, and recrystallisation from ethyl acetate, gave 0.43 g of the title compound, mp 338°-340° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1.[CH3:29][C:30]1([CH3:36])[CH2:34][NH:33][C:32](=[O:35])[CH2:31]1.N[C@@H]1CCCC[C@H]1N.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(O)=O.[Na+]>O1CCOCC1.[Cu]I>[CH3:29][C:30]1([CH3:36])[CH2:34][N:33]([C:6]2[CH:5]=[CH:4][C:3]([N:9]3[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]4[N:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[N:21]=[CH:20][CH:19]=4)=[N:10]3)=[C:2]([F:1])[CH:7]=2)[C:32](=[O:35])[CH2:31]1
Reactant: CC1(C)CNC(=O)C1
Reactant: COc1cn(-c2ccc(I)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: COc1cn(-c2ccc(N3CC(C)(C)CC3=O)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 110 °C
Yield: 60.3 %

Procedure:
A suspension of 1-(2-fluoro-4-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (244 mg, 0.500 mmol), 4,4-dimethyl-2-pyrrolidinone (67.9 mg, 0.600 mmol), trans-1,2-diaminocyclohexane (0.012 mL, 0.10 mmol), CuI (9.5 mg, 0.050 mmol), and K3PO4 (212 mg, 1.00 mmol) in 1,4-dioxane (2.0 mL) was stirred at 110° C. under Ar atmosphere. The reaction mixture was poured into 5% NaHCO3 aqueous solution (20 mL) and extracted with AcOEt (20 mL×3). The combined organic phase was washed with brine (40 mL), dried with MgSO4, and evaporated. The residue was purified by basic silica gel column chromatography (AcOEt/hexane=50%-100%) and silica gel column chromatography (AcOEt/hexane=50%-100%) to give the title compound (142.8 mg, 60% yield): NMR (300 MHz, DMSO-d6): δ ppm 1.16 (6H, s), 2.39-2.44 (2H, m), 3.58-3.63 (2H, m), 3.77 (3H, s), 6.94-6.98 (1H, m), 6.98-7.08 (1H, m), 7.29-7.35 (2H, m), 7.35-7.49 (4H, m), 7.68-7.88 (2H, m), 8.37-8.55 (1H, m). LC-MS (ESI) m/z 474 [M+H]+. Anal. Calcd for C26H24FN5O3.0.2H2O: C, 65.45; H, 5.16; N, 14.68. Found: C, 65.17; H, 5.16; N, 14.55.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:18]3[N:25]([CH2:26][C:27]4[O:31][C:30]([C:32]([O:34]CC)=[O:33])=[CH:29][CH:28]=4)[CH:24]=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:18]3[N:25]([CH2:26][C:27]4[O:31][C:30]([C:32]([OH:34])=[O:33])=[CH:29][CH:28]=4)[CH:24]=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CCOC(=O)c1ccc(Cn2ccc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c32)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(Cn2ccc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c32)o1
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.6 %

Procedure:
To a solution of ethyl 5-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]-2-furoate (440 mg) in a mixed solvent of tetrahydrofuran (2.0 mL) and ethanol (2.0 mL) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at room temperature for 5 hrs. 1N Hydrochloric acid (2.0 mL) and water (25 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The resultant precipitate was collected by filtration, washed with water (10 mL×3) and diisopropyl ether (10 mL×3), and dried under reduced pressure (80° C.) to give the title compound (310 mg) as white powder crystals.