Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:14][N:13]([C@@H](C3C=CC=CC=3)C)[CH2:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.ClC(OC(Cl)C)=O.CO>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:14][NH:13][CH2:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](c1ccccc1)N1CCCOC(c2cccc(Br)c2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CO
Product: Brc1cccc(C2CNCCCO2)c1
Temperature: 25 °C
Yield: 111 %

Procedure:
To a solution of diastereomerically pure 2-(3-bromophenyl)-4-((R)-1-phenylethyl)-[1,4]oxazepane (8.92 g, 24.8 mmol) in 1,2-dichloroethane (42 ml) was added 1-chloroethyl chloroformate (8.85 g, 61.9 mmol) at room temperature. The mixture was refluxed for 5 hours and cooled to room temperature. After methanol (20 ml) was added, the solution was refluxed for another 5 hours. The mixture was concentrated under reduced pressure to afford the crude product. This crude product was washed with ether, dried under reduced pressure to yield 2-(3-bromophenyl)-[1,4]oxazepane as white solid (7.05 g, 97%). An analytical sample for X-ray was obtained by crystallization from ethanol, and the absolute configuration of this compound was found to be the (R)-configuration by a method using a Flack parameter. The absolute configuration was determined by X-ray crystallography of a sample crystallized from ethanol.
Reaction SMILES: [CH3:1][C:2]([S:21]([CH3:24])(=[O:23])=[O:22])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:3](O)=[O:4].O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[O:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH:44]1[O:49][NH2:50]>C(Cl)Cl.O>[CH3:1][C:2]([S:21]([CH3:24])(=[O:23])=[O:22])([CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)[C:3]([NH:50][O:49][CH:44]1[CH2:45][CH2:46][CH2:47][CH2:48][O:43]1)=[O:4]
Reactant: CC(CCc1ccc(Oc2ccccc2)cc1)(C(=O)O)S(C)(=O)=O
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(CCc1ccc(Oc2ccccc2)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-methyl-2-(methylsulfonyl)-4-(4-phenoxyphenyl)butanoic acid (285 mg, 0.818 mmol) in methylene chloride (8.18 mL) at ambient temperature was added 1,(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (220 mg, 1.1 mmol), 1-hydroxy benzotriazole monohydrate (230 mg, 1.5 mmol), triethylamine (0.2 mL, 1.4 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (140 mg, 1.2 mmol). The resulting mixture was stirred at ambient temperature overnight. The mixture was diluted with methylene chloride and water. The phases were separated and the aqueous layer extracted with methylene chloride two times. The organic extracts were combined and dried over magnesium sulfate, filtered and concentrated in vacuo to a crude residue. The crude residue was purified via silica gel chromatography eluting with methylene chloride and methanol. The fractions containing the desired product were combined and concentrated in vacuo to afford 2-methyl-2-(methylsulfonyl)-4-(4-phenoxyphenyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide as a solid. 247.2 mg
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:36]C)=[O:35])=[CH:29][CH:28]=3)[CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:38]([F:41])([F:40])[F:39])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].[CH:44](O)=[O:45]>C(OC(=O)C)(=O)C>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([N:25]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][C:34]([OH:36])=[O:35])=[CH:29][CH:28]=3)[CH:44]=[O:45])[CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:38]([F:39])([F:40])[F:41])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Reactant: O=CO
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: O=CN(Cc1ccc(CC(=O)O)cc1)c1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
A mixture of methyl {4-[({3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amino)methyl]phenyl}acetate (0.05 g, 0.09 mmol) in 5 mL of 96% of formic acid and 1 mL of acetic anhydride was heated under reflux for 1 h. Removal of solvent under reduced pressure gave a crude product that was used for the LiOH hydrolysis as described in Example 66. 35 Mg (68%) of the title compound was obtained as a pale yellow solid. MS (ESI) m/z 569; HRMS: calcd for C33H23F3N2O4, 568.1610; found (ESI, [M−H]−), 567.1543.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.IC.[BH4-].[Na+].[C:22](=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]1[CH2:13][CH2:14][N:15]([CH3:22])[CH2:16][CH:17]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1ccncc1
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CCO
Solvent: CC(C)=O
Product: COc1ccc([N+](=O)[O-])cc1C1=CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(2-methoxy-5-nitrophenyl)pyridine (D36) (3.4 g, 14.8 mmol) in acetone (150 ml) was treated with excess iodomethane (5 ml) and the mixture stirred at room temperature overnight. The precipitated quaternary salt was filtered off, washed with acetone and dried, giving 5.02 g. This was dissolved in 1:1 ethanol: water (230 ml) and treated portionwise at room temperature, under argon, with sodium borohydride (1.23 g, 32.4 mmol). The mixture was stirred for 1 h at room temperature then potassium carbonate (10 g) was added and the organic layer was separated from the aqueous phase, which was back-extracted with ethyl acetate. The organic phases were combined and dried (Na2SO4) and evaporated under reduced pressure to give the title compound (D37) as an orange oil, which slowly crystallised (3.05 g, 91%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([C:15]([NH2:17])=[O:16])=[C:13]([NH:18][C:19]([N:21]3[CH2:25][CH2:24][CH2:23][C:22]3=[O:26])=[O:20])[S:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[OH-:28].[Na+]>>[NH2:17][C:15]([C:14]1[C:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[N:11][S:12][C:13]=1[NH:18][C:19]([NH:21][CH2:25][CH2:24][CH2:23][C:22]([OH:28])=[O:26])=[O:20])=[O:16]
Reactant: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)nsc1NC(=O)N1CCCC1=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)nsc1NC(=O)NCCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(4-Nitro-phenyl)-5-[(2-oxo-pyrrolidine-1-carbonyl)-amino]-isothiazole-4-carboxylic acid amide (12.5 g) added to 1 N sodium hydroxide (250 mL) at ambient temperature. The resulting mixture was stirred at ambient temperature for overnight (reaction mixture clear solution). Reaction mixture acidified with 2 N HCl. The solid which formed was collected by filtration and washed with water then dried in vacuo to give the title compound as off white solid (11.5 g, 88%).
Reaction SMILES: [CH3:1][O:2][P:3]([O:21]C)([N:5]1[CH2:8][C@H:7]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]1=[O:20])=[O:4].[NH2:23][C:24]([NH2:26])=[S:25]>C(#N)C>[O:20]=[C:6]1[C@@H:7]([NH:9][C:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:19])[CH2:8][N:5]1[P:3](=[O:4])([O-:21])[O:2][CH3:1].[C:24]([NH2:26])([NH2:23])=[S:25]
Reactant: COP(=O)(OC)N1C[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: NC(N)=S
Solvent: CC#N
Product: COP(=O)([O-])N1C[C@H](NC(=O)OCc2ccccc2)C1=O

Procedure:
(S)-[1-(Dimethoxyphosphinyl)-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester (100 mg; see example 1) was dissolved in 2 ml of acetonitrile, thiourea (23 mg) was added, and the mixture was refluxed under a nitrogen atmosphere for 20 hours. Solvent was then removed in vacuo and the residue was worked into a hygroscopic powder by triturating several times with anhydrous ether yielding (S)-[2-oxo-3-[[(phenylmethoxy)carbonyl]amino]-1-azetidinyl]phosphonic acid, methyl ester, thiuronium salt.
Reaction SMILES: OO.[CH3:3][O:4][C:5]1[C:6]([OH:11])=[N:7][CH:8]=[CH:9][CH:10]=1.S([O-])([O-])(=O)=S.[Na+].[Na+].[Br:19]Br.C(=O)([O-])[O-].[Na+].[Na+]>Br>[Br:19][C:8]1[N:7]=[C:6]([OH:11])[C:5]([O:4][CH3:3])=[CH:10][CH:9]=1
Reactant: COc1cccnc1O
Reactant: BrBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Product: COc1ccc(Br)nc1O
Temperature: 25 °C

Procedure:
45 ml of hydrogen peroxide (15% strength) are added dropwise to a stirred solution of 152.5 mmol of 3-methoxypyridin-2-ol [20928-63-6] in 152 ml of hydrobromic acid (48% strength) at 70° C. over the course of one hour so that the temperature remains at 70° C. The mixture is stirred at this temperature for a further hour. It is then cooled to room temperature, and 1M sodium thiosulphate solution is added to the reaction solution until excess bromine is completely reduced (decolorization). Saturated sodium carbonate solution is then added to the resulting solution until the pH is 4. A solid precipitates and is filtered off. Further saturated sodium carbonate solution is added to the clear filtrate until the pH reaches 11. It is extracted with dichloromethane (3×), and the combined organic phases are dried with sodium sulphate and evaporated. The title compound is identified by means of the Rf from the residue by flash chromatography (SiO2 60 F).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>N1C=CC=CC=1>[C:17]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(-c2nc3ccccc3s2)cc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1ccc(-c2nc3ccccc3s2)cc1)c1ccccc1
Yield: 82.2 %

Procedure:
A mixture of 2-(4'-aminophenyl)benzothiazole (0.3 g, 1.32 mmol) and benzoyl chloride (0.3 ml) in pyridine (8 ml) was stirred at reflux for 2 hours, then cooled and poured into water (100 ml). The precipitate formed was filtered off, washed with water and dissolved in hot dichloromethane (12 ml). The resulting solution was cooled in an ice-bath and the solid was filtered off. The filtrate was evaporated and the residue was recrystallised from dichloromethane-methanol to give a white powder (0.36 g, 82.2%), m.p. 227.1-228.5° C.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[C:39]([CH3:46])[C:40]([O:43][CH2:44][CH3:45])=[N:41][CH:42]=1>>[CH2:44]([O:43][C:40]1[N:41]=[CH:42][C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)=[CH:38][C:39]=1[CH3:46])[CH3:45]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CCOc1ncc(Br)cc1C
Product: CCOc1ncc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc1C

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 5-bromo-2-ethoxy-3-methylpyridine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.314 min, m/z=489; 1H NMR (CDCl3) 1.04 (s, 3H), 1.11 (s, 3H), 1.34 (t, 3H), 1.47 (d, 3H), 2.13-2.24 (m, 7H), 2.32 (m, 1H), 2.81 (m, 1H), 4.34 (q, 2H), 5.62 (q, 1H), 6.93 (d, 2H), 7.17-7.27 (m, 7H), 7.42 (s, 1H), 8.02 (s, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][C@H:3]1[OH:15].Cl[C:17]1[C:18]2[CH:25]=[C:24]([CH2:26][C:27]([F:30])([F:29])[F:28])[S:23][C:19]=2[N:20]=[CH:21][N:22]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH2:8]([N:5]1[CH2:6][CH2:7][C@@H:2]([NH:1][C:17]2[C:18]3[CH:25]=[C:24]([CH2:26][C:27]([F:30])([F:29])[F:28])[S:23][C:19]=3[N:20]=[CH:21][N:22]=2)[C@H:3]([OH:15])[CH2:4]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: FC(F)(F)Cc1cc2c(Cl)ncnc2s1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C[C@H]1O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1CN(Cc2ccccc2)CC[C@H]1Nc1ncnc2sc(CC(F)(F)F)cc12

Procedure:
The mixture of 36.7 mg of trans-4-amino-1-benzylpiperidin-3-ol (0.18 mmol), 30 mg of 4-chloro-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine (0.12 mmol) and 46 mg of N,N-diisopropylethylamine (0.36 mmol) was refluxed in 0.75 mL of isopropanol for 18 hs. Then reaction mixture was concentrated and purified on silica gel column eluting with DCM:MeOH 20:1 to afford 45 mf of trans-1-benzyl-4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-3-ol (Compound 165). Its monohydrochloride salt was obtained by adding 1 equivalent of 1N HCl solution in diethyl ether to a solution of compound in ethanol. 1H NMR (600 MHz, CD3OD) of HCl salt, signals are all broadened because of intramolecular H-bond: δ 8.37 (1H), 7.51-7.60 (6H), 4.43 (4H), 4.12 (1H), 3.85 (2H), 3.55 (2H), 3.21 (1H), 2.99 (1H), 2.06 (1H). 13C NMR (150 MHz, CD3OD): δC 165.78, 158.45, 153.97, 132.59, 131.46, 130.51, 130.18, 127.45, 125.62, 122.09, 118.50, 68.02, 61.86, 56.88, 54.15, 52.38, 35.81 (q, J=31.5 Hz), 28.14. ESI MS [MH+]: 423.1458.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([CH2:15][OH:16])=[C:13]([CH3:17])[O:12][N:11]=2)=[CH:6][CH:5]=1.Cl[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:14]([CH2:15][O:16][C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=3)=[C:13]([CH3:17])[O:12][N:11]=2)=[CH:8][CH:9]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1CO
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C#N)cn1
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 7.9 g, 181 mmol, 1.5 eq.) in THF (65 mL) was added within 30 minutes at room temperature a solution of [3-(4-Fluorophenyl)-5-methyl-isoxazol-4-yl]-methanol (25.0 g, 121 mmol) and 6-chloronicotinonitrile (16.7 g, 121 mmol) in THF (120 mL) and the resulting mixture was stirred for one hour. A solution of citric acid (18.5 g, 96.5 mmol) in water (185 mL) was added to the reaction mixture within 30 minutes. From the resulting THF/water mixture THF was distilled off under reduced pressure at a jacket temperature of 60° C. and replaced by ethanol. In total 284 g of ethanol were added. The resulting suspension was stirred for one hour at room temperature. The crystals were filtered off, washed with a mixture of ethanol (60 mL) and water (60 mL) and subsequently dried at 50° C./<25 mbar to afford 36.5 g (91% corrected yield) of the title nitrile as an off-white solid with an assay of 93% (w/w).
Reaction SMILES: I.I[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[C:12]([CH3:24])[CH:11]=2)[C:4]=1[NH2:25].[C:26]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)#[CH:27]>C(#N)C.C(N(CC)CC)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>[NH2:32][C:31]1[CH:33]=[CH:34][C:28]([C:26]#[C:27][C:3]2[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]4[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=4)=[C:12]([CH3:24])[CH:11]=3)[C:4]=2[NH2:25])=[CH:29][CH:30]=1
Reactant: C#Cc1ccc(N)cc1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc(I)c3N)cc2C)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(Oc2ccc(Nc3ncnc(C#Cc4ccc(N)cc4)c3N)cc2C)cn1
Yield: 65.9 %

Procedure:
6-Iodo-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diamine hydroiodide (270 mg) was dissolved in a mixed solvent of acetonitrile (10.3 mL)/triethylamine (7.72 mL), and 4-ethynylaniline (80.3 mg), trans-dichlorobis(triphenylphosphine)palladium(II) (20.8 mg) and copper(I) iodide (7.16 mg) were sequentially added. The title compound (134 mg) was obtained as a powder by the reaction in the same manner as in Example 9 (iv).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:12])(=O)[CH3:2].Cl>[OH-].[K+]>[CH3:2][C:1]1[C:4]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:10][C:11](=[O:12])[C:13]=1[CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CC(=O)c1ccccc1NC(=O)CCCC(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Cc1c(CCC(=O)O)c(=O)[nH]c2ccccc12
Yield: 50 %

Procedure:
4-(N-(2-acetylphenyl)carbamoyl)butanoic acid (4.87 g) was dissolved in 2% aqueous potassium hydroxide solution (100 ml), and the resulting solution was heated to reflux overnight. Concentrated hydrochloric acid was added to the reaction solution and the precipitated solids were recrystallized from methanol/chloroform/ethyl acetate to obtain 2.26 g of 3-(4-methyl-2-oxo-3-hydroquinolyl)propanoic acid as colorless crystals. Yield: 50%.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[N:3]=1.[H-].[Na+].Br[CH:24]([CH3:26])[CH3:25].O>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:24]([CH3:26])[CH3:25])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc(Nc2nc(Cl)nc3[nH]cnc23)c1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1cnc2c(Nc3cccc([N+](=O)[O-])c3)nc(Cl)nc21
Reaction time: 1 h
Yield: 90.7 %

Procedure:
(2-Chloro-9H-purin-6-yl)-(3-nitro-phenyl)-amine (872 mg, 3 mmol) was dissolved in dry DMF (10 mL). NaH (122 mg, 5.1 mmol) was added in portions and the resulting mixture was stirred for 1 h. 2-Bromopropane (480 mg, 3.9 mmol) was then added and the reaction was stirred overnight at 80° C. under N2. After cooling, H2O (50 mL) was added slowly with stirring and cooling. After 1 h, precipitated product was filtered, washed with more cold H2O, and dried in vacuo to afford the title compound as a lemon-yellow powder (905 mg, 90.7%). TLC (95:5 CH2Cl2/MeOH): RF=0.46.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=2[N:7]=1.[CH3:28][NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)(=[O:32])=[O:31].C(=O)(O)[O-].[Na+].O>COCCOC.O.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>[CH3:25][C:24]1[CH:23]=[C:22]([CH3:26])[NH:21][C:20](=[O:27])[C:19]=1[CH2:18][NH:17][C:15]([C:4]1[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=2[N:7]=[C:2]([C:36]2[CH:35]=[CH:34][C:33]([S:30]([NH:29][CH3:28])(=[O:31])=[O:32])=[CH:38][CH:37]=2)[CH:3]=1)=[O:16]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2c(C)nn3C(C)C)c(=O)[nH]1
Reactant: CNS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CNS(=O)(=O)c1ccc(-c2cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c3c(C)nn(C(C)C)c3n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (80 mg, 0.21 mmol), {4-[(methylamino)sulfonyl]phenyl}boronic acid (66.5 mg, 0.31 mmol) and bis(triphenylphosphine)palladium(II) chloride (8.4 mg, 0.01 mmol) were suspended in DME/water (4 mL, 3:1) and stirred for 10 min under nitrogen at room temperature. Sodium bicarbonate (52 mg, 0.62 mmol) was added and the heterogenous mixture was irradiated (microwave) at 150° C. for 30 min. After cooling to room temperature, water was added to the black mixture, and the contents were vacuum filtered. The crude product was dissolved in DCM/MeOH (1:1) and preabsorbed onto silica gel. The product was purified by silica gel chromatography (eluent: DCM/MeOH/NH4OH, gradient of 0 to 90:10:1). The light beige solid that was collected was suspended in EtOH, sonicated, and filtered. The solid was then air-dried for 15 min, and then in vacuum oven overnight. The final product was collected as 77 mg (70%). LCMS E-S (M+H)=523.2 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (br. s., 1H) 8.78 (t, J=5.05 Hz, 1H) 8.43 (m, J=8.59 Hz, 2H) 7.93 (m, J=8.59 Hz, 2H) 7.78 (s, 1H) 7.58 (br. s., 1H) 5.89 (s, 1H) 5.29 (quin, J=6.63 Hz, 1H) 4.40 (d, J=4.80 Hz, 2H) 2.46 (d, J=1.26 Hz, 6H) 2.25 (s, 3H) 2.12 (s, 3H) 1.52 (s, 3H) 1.51 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([F:16])=[C:4]([F:15])[C:5]([F:14])=[C:6](C(O)=O)[C:7]=1[C:8]([OH:10])=[O:9].[OH-].[Ca+2].[OH-]>O>[F:1][C:2]1[C:3]([F:16])=[C:4]([F:15])[C:5]([F:14])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1C(=O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(F)c(F)c(F)c1F
Temperature: 70 °C
Reaction time: 18 h

Procedure:
In a flask of an inner volume of 1 liter, 200 g (1.0 mole) of 3,4,5,6-tetrafluorophthalonitrile, 459 g of sulfuric acid, and 391 g of water were placed and heated and stirred for reaction under reflux for 17 hours. After completion of the reaction, the reactant was cooled. The precipitate of 3,4,5,6-tetrafluorophthalic acid consequently formed was separated by filtration. The cake, on analysis, was found to contain 5.0% by weight of sulfuric acid, 2.0% by weight of ammonium sulfate, and 7.2% by weight of water in addition to 3,4,5,6-tetrafluorophthalic acid. In an autoclave having an inner volume of 1 liter, 175 g (150 g as tetrafluorophthalic acid) of a total of 263 g of the cake, 14.0 (0.189 mole) of calcium hydroxide, and 500 g of water were placed and heated and stirred for decarboxylation at 160 ° C. for 18 hours [pH 1.90 at 70° C. at the time of charging]. The reaction mixture was then treated thereafter by following the procedure of Example 1, to produce white 2,3,4,5-tetrafluorobenzoic acid. By the same calculation as in Example 1, this example was found to have produced 2,3,4,5-tetrafluorobenzoic acid in a yield of 96.4 mole % based on 3,4,5,6-tetrafluorophthalic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[S:34]>>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[S:34]
Reactant: S=C=Nc1ccccc1Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Product: O=C1CC(=O)N(c2ccc(NC(=S)Nc3ccccc3Cl)cc2)c2ccc3ccccc3c2N1
Yield: 43.5 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (190 mg, 0.60 mmol) obtained in Example 1, (3), and 2-chlorophenyl isothiocyanate (196 μL, 1.50 mmol), the title compound (127 mg, yield 44%) was obtained in the same manner as that of Example 20.