Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:32]=[C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([C:24]5[CH:25]=[C:26]([CH2:30]O)[CH:27]=[CH:28][CH:29]=5)[N:18]4[N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CS([Cl:44])(=O)=O>ClCCl>[Cl:44][CH2:30][C:26]1[CH:25]=[C:24]([C:23]2[N:18]3[N:17]=[C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[CH:10][CH:11]=4)[N:32]=[C:19]3[CH:20]=[CH:21][CH:22]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: OCc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ClCc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(3-{2-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-phenyl)-methanol (0.35 g, 0.815 mmol) was dissolved in dichloromethane (20 mL). Triethylamine (508 uμL, 3.670 mmol) was added and the mixture cooled to 0° C., then methanesulfonyl chloride (252 μL, 3.260 mmol) was added dropwise and the reaction was allowed to warm to room temperature and stirred overnight. A small sample of the desired product was purified by preparatory HPLC. RT: 2.56 min, MI: 448 and 450.18, Method: 2.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(C(C)C)C(C)C)C.[NH2:60][CH:61]([C:67]1[CH:72]=[CH:71][C:70]([Cl:73])=[CH:69][CH:68]=1)[CH2:62][NH:63][C:64](=[O:66])[CH3:65]>CN1C(=O)CCC1>[C:64]([NH:63][CH2:62][CH:61]([NH:60][C:48]([C:33]1([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:34][CH2:35][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:37][CH2:38]1)=[O:50])[C:67]1[CH:68]=[CH:69][C:70]([Cl:73])=[CH:71][CH:72]=1)(=[O:66])[CH3:65]
Reactant: CC(=O)NCC(N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 65 h
Yield: 81.7 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (89 mg, 0.23 mmol) was added in one portion to a stirred solution of 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (80 mg, 0.22 mmol) and N-ethyldiisopropylamine (0.046 mL, 0.27 mmol) in NMP (3 mL). The mixture was treated with N-(2-amino-2-(4-chlorophenyl)ethyl)acetamide (Intermediate 83) (52 mg, 0.24 mmol). The solution was stirred for 65 hours at room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed twice with water. The organic solution was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica using gradient elution (1% methanol/DCM to 15% methanol/DCM). Product containing fractions were combined to give tert-butyl 4-(2-acetamido-1-(4-chlorophenyl)ethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (100 mg, 81%) as colourless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[OH:29][C:30]1([C:33]([OH:35])=O)[CH2:32][CH2:31]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:26][CH3:27])[C:33]([C:30]2([OH:29])[CH2:32][CH2:31]2)=[O:35])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(O)C1(O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)C2(O)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2′-Ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.240 g, 0.61 mmol), 1-hydroxy-1-cyclopropanecarboxylic acid (0.074 g, 0.73 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.175 g, 0.92 mmol), 1-hydroxybenzotriazole (0.124 g, 0.92 mmol), and triethylamine (0.21 mL, 1.53 mmol) were combined in CH2Cl2 (2 mL) and stirred at room temperature for 2 hours. The mixture was concentrated, and the residue was purified by silica gel chromatography (20-90% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:7][CH2:6][O:5][C:3]1=[O:4].[OH-:9].[K+].Cl>O>[OH:5][CH2:6][CH2:7][C:2]([CH3:8])([CH3:1])[C:3]([OH:9])=[O:4]
Reactant: CC1(C)CCOC1=O
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(C)(CCO)C(=O)O
Temperature: 25 °C

Procedure:
A mixture of 2,2-dimethylbutyrolactone (6.84 g, 60 mmol) and KOH (3.36 g) in H2O (60 mL) was heated at reflux for 2 h. The solution was cooled to room temperature and acidified to pH 5 with aqueous HCl solution. The mixture was then extracted with ethyl acetate 3 times. The combined organic layers were washed with brine, dried over Na2SO4, concentrated under reduced pressure to give 4-hydroxy-2,2-dimethyl-butanoic acid compound 54-B (4 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.S(Cl)([Cl:12])=O>>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([Cl:12])=[O:9])[CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CCOCC1
Product: O=C(Cl)C1CCOCC1

Procedure:
The tetrahydropyran-4-carboxylic esters II required for the novel reaction can be obtained from diethyl tetrahydropyran-4,4-dicarboxylate (i. Chem. Soc. (1952), page 2268). The tetrahydropyran-4-carboxylic esters of the formula II can be obtained from the diethyl ester by hydrolysis using potassium hydroxide to give tetrahydropyran-4,4-dicarboxylic acid, subsequent thermal decarboxylation to give tetrahydropyran-4-carboxylic acid, subsequent reaction with thionyl chloride to give tetrahydropyran-4-carbonyl chloride and subsequent esterification with alcohols (J. Chem. Soc. (1930), p. 2525).
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[N+:8]([C:16]1[S:12][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:15]=1)([O-:11])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1cccs1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1ccc([N+](=O)[O-])s1
Reaction time: 1 h

Procedure:
To 160 ml. of acetic anhydride cooled to -5° in an ice-salt bath is added 34 ml. of 90% nitric acid dropwise so that the temperature does not rise above 0°. To this mixture is added 62.7 g. of ethyl 2-thiophenecarboxylate dropwise so that the temperature remains below -5°. Reaction is stirred for 1 hour and poured onto ice. The product is filtered, dried, and recrystallized from hexane.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[O:16][C:15]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])=[N:14][C:13]=2[CH2:23][CH2:24][CH2:25][C:26](OCC)=[O:27])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[O:16][C:15]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])=[N:14][C:13]=2[CH2:23][CH2:24][CH2:25][CH2:26][OH:27])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCc1nc(-n2ccnc2C)oc1-c1ccc(F)c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nccn1-c1nc(CCCCO)c(-c2ccc(F)c3ccccc23)o1
Reaction time: 1 h

Procedure:
Ethyl 5-(4-fluoro-1-naphthyl)-2-(2-methyl-1-imidazolyl)-4-oxazolebutanoate (401 mg) was dissolved in 10 ml of tetrahydrofuran, to which was added gradually lithium aluminum hydride (50 mg) under ice-cooling, and the mixture was stirred for 1 hour. Water (0.1 ml) was carefully added to the reaction mixture, which was filtered. The residue on the filter paper was washed with ethyl acetate. The filtrate was concentrated to give crystals of 5-(4-fluoro-1-naphthyl)-2-(2-methyl-1-imidazolyl)-4-oxazolebutanol. Recrystallization from acetone-diethyl ether gave colorless prisms (294 mg, 82%). Melting point 107-109° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](Br)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1)=[O:11]>CO>[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1)(=[O:11])[CH3:9]
Reactant: CC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: Fc1ccc(I)cc1
Solvent: CO
Product: CC(=O)c1ccc(-c2ccc(F)cc2)c([N+](=O)[O-])c1

Procedure:
4-fluoroiodobenzene and 4-bromo-3-nitroacetophenone were reacted under Ullmann conditions to give 4-acetyl-4'-fluoro-2-nitrobiphenyl, m.p. 88°-90° C. (from methanol). This compound was reduced with stannous chloride in concentrated hydrochloric acid to give 4-acetyl-2-amino-4'-fluorobiphenyl, m.p. 88°-91° C. (from methanol). The amino group in this compound was converted to methoxy in the following way:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[Cl:12][Sn]Cl>Cl>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:11])=[C:4]([Cl:12])[N:3]=1
Reactant: Nc1ncc(Cl)cc1[N+](=O)[O-]
Reactant: Cl[Sn]Cl
Agent: Cl
Product: Nc1cc(Cl)c(Cl)nc1N

Procedure:
The compounds of the present invention may be prepared as follows. It has been reported that reduction of 2-amino-5-chloro-3-nitropyridine (2) by SnCl2 in concentrated HCl resulted in both reduction of the nitro group to an amino group as well as chlorination of the pyridine ring to give 2,3-diamino-5,6-dichloropyridine (4) as the only isolated product (Israel & Day, J. Org. Chem. 24:1455-1460 (1959)). We found that reduction of 2 under identical conditions as reported gave a mixture of 2,3-diamino-5-chloropyridine (3) and 2,3-diamino-5,6-dichloropyridine (4) in a ratio of 4:1. The mixture could not be separated by crystallization in water. It could be separated by preparative TLC and chromatography. Cyclization of 3 with oxalic acid gave 8-NQX 5 and cyclization of 4 with oxalic acid gave 8-NQX 6. 6,7-dichloro-8-NQX 6 was found to have a Ki of about 200 nM, which is similar to the corresponding 6,7-dichloro-QX. 6-Chloro-8-NQX 5 also was found to be about as active as the corresponding 6-chloro-QX. 6-Bromo-7-methyl-8-NQX (8) was found to have a Ki of about 200 nM. 6-NQX 11 and 6,8-diN-QX 13 also were found to be about as active as QX. ##STR8##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2B(O)O)=[CH:4][CH:3]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1-c1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Product: NS(=O)(=O)c1ccc(-c2ccccc2-c2ccc(Cl)cc2)cc1
Yield: 67 %

Procedure:
Following the general procedure outlined in Synthetic Scheme IX, 1.6 g (6.9 mmol) of 2-(4-chlorophenyl)phenylboronic acid (Step 2) was reacted with 1.8 g (7.6 mmol) of 4-bromobenzenesulfonamide. Purification by silica gel chromatography (Waters LC-2000) with ethyl acetate/hexane (3:7) and subsequent recrystallization from ethyl acetate/hexane gave 1.59 g (67%) of 4-[2-(4-chlorophenyl)phenyl]benzenesulfonamide as a colorless solid: mp 206.2°-207.0° C.; NMR (CDCl3) δ 4.77 (s, 2H), 7.04 (d, J=9 Hz, 2H), 7.16-7.31 (m, 4H), 7.36-7.51 (m, 4H), 7.80(d, J=9 Hz, 2H). MS (EI): m/e (rel intensity) 343 (100), 308 (13), 262 (21), 228 (82); HRMS Calc'd for C18H14ClNO2S: 343.0434. Found: 343.0434.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)#[N:24]>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)=[CH:3][C:2]=1[C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([C:23]#[N:24])[CH:30]=1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: N#Cc1cccc(B(O)O)c1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cccc(C#N)c4)c3)cnc2c1F
Yield: 79.9 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol (100 mg, 0.36 mmol) and 3-cyanophenylboronic acid (79 mg, 0.54 mmol) were coupled using the procedure in Example 30 to afford 2′-fluoro-5′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]biphenyl-3-carbonitrile (112 mg, 80%) as a white solid: δH (360 MHz, CDCl3) 1.74 (6H, s), 2.02 (1H, s), 7.20 (1H, dd, J 7 and 7), 7.37 (1H, dd, J 9 and 9), 7.54-7.63 (3H, m), 7.70-7.73 (2H, m), 7.82 (1H, d, J 9), 7.89 (1H, s), 8.04 (1H, d, J 7); m/z (ES+) 390 (100%, [MH]+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1.C([N:16](CC)CC)C.[OH-].[NH4+].O>O1CCCC1>[NH2:16][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1
Reactant: CCN(CC)CC
Reactant: CCOC(=S)c1cnc(C)nc1Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=S)c1cnc(C)nc1N
Reaction time: 4 h
Yield: 95 %

Procedure:
A solution of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (25.4 g, 106 mmol, Aldrich Chemical Co., Milwaukee, Wis., USA) in 300 mL of tetrahydrofuran was treated with 50 mL of triethylamine and 40 mL of aqueous ammonium hydroxide. After stirring for 4 hours, 300 mL of water was added and the phases were separated. The organic layer was washed with 300 mL of brine, concentrated in vacuo, dissolved in methylene chloride, dried over sodium sulfate, filtered and concentrated in vacuo to give 16.5 g (95%) of ethyl 4-amino-2-methylthiopyrimidine-5-carboxylate as a white solid.
Reaction SMILES: NC(N)=O.[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([OH:13])[C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][S:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>>[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:32]([NH:31][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([Cl:30])[C:24]=2[Cl:23])=[O:33])=[C:8]([OH:13])[C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][S:20][CH2:19][CH2:18]1)(=[O:15])=[O:16]
Reactant: Nc1ccc(Cl)c(S(=O)(=O)N2CCSCC2)c1O
Reactant: O=C=Nc1cccc(Cl)c1Cl
Agent: NC(N)=O
Product: O=C(Nc1ccc(Cl)c(S(=O)(=O)N2CCSCC2)c1O)Nc1cccc(Cl)c1Cl
Yield: 28 %

Procedure:
Following the general procedure for urea formation outlined in example 15, 4-chloro-2-hydroxy-3-(4-thiomorpholinylsufonyl)aniline (120 mg, 0.36 mmol) and 2,3-dichlorophenylisocyanate(68 mg, 0.36 mmol) were coupled to form the desired urea (50 mg, 28%). 1H NMR (MeOD-d4): δ 8.31 (m, 1H), 8.05 (m, 1H), 7.26 (m, 2H), 7.08 (m, 1H), 3.61 (m, 4H), 2.69 (m, 4H).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8](OC)=[O:9])=[CH:6][CH:5]=[C:4]([C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[NH:3]1.[CH3:18][NH2:19].Cl>>[CH3:18][NH:19][C:8]([C:7]1[C:2](=[O:1])[NH:3][C:4]([C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])=[CH:5][CH:6]=1)=[O:9]
Reactant: CN
Reactant: COC(=O)c1ccc(C(F)(F)C(F)F)[nH]c1=O
Agent: Cl
Product: CNC(=O)c1ccc(C(F)(F)C(F)F)[nH]c1=O

Procedure:
At room temperature, 300 mg (1.19 mmol) of methyl 2-oxo-6-(1,1,2,2-tetrafluoroethyl)-1,2-dihydropyridine-3-carboxylate were stirred in 3.3 ml of a 40% strength aqueous methylamine solution for 14 h. The pH was then adjusted to 2 by addition of 1N hydrochloric acid, and the mixture was extracted with dichloromethane. Drying and concentration of the extract gave 230 mg (77% of theory) of the product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:17]=[N:18][C:19]([NH:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:20][CH:21]=1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]>>[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:17]=[N:18][C:19]([NH:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:20][CH:21]=2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(NCCN(C)C)nc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(NCCN(C)C)nc1
Yield: 33.2 %

Procedure:
Following general procedure D, 1-(6-bromo-4-(6-(2-(dimethylamino)ethylamino)pyridine-3-ylamino)quinolin-3-yl)ethanone (100 mg, 0.23 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (101 mg, 0.35 mmol) to afford the desired product (39 mg, 33%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.28 (s, 1H), 8.26-8.17 (m, 2H), 8.04-7.99 (m, 2H), 7.67 (dd, J=9.0, 2.7 Hz, 1H), 7.28 (s, 2H), 6.93 (d, J=9.0 Hz, 1H), 3.86-3.82 (m, 2H), 3.44-3.36 (m, 2H), 2.96 (s, 6H), 2.81 (s, 3H); ESI MS m/z 510 [C26H25Cl2N5O2+H]+; HPLC 96.6% (AUC), tR=10.74 min.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.Br[C:8]1[N:33]=[C:11]2[CH:12]=[C:13]([NH:16][C:17]([C:19]3[N:23]([CH3:24])[N:22]=[CH:21][C:20]=3[C:25]3[S:26][CH:27]=[C:28]([CH:30]([F:32])[F:31])[N:29]=3)=[O:18])[CH:14]=[CH:15][N:10]2[N:9]=1>C(OCC)(=O)C>[F:32][CH:30]([F:31])[C:28]1[N:29]=[C:25]([C:20]2[CH:21]=[N:22][N:23]([CH3:24])[C:19]=2[C:17]([NH:16][C:13]2[CH:14]=[CH:15][N:10]3[N:9]=[C:8]([N:3]4[CH2:4][CH2:5][CH2:6][C@@H:2]4[CH3:1])[N:33]=[C:11]3[CH:12]=2)=[O:18])[S:26][CH:27]=1
Reactant: Cn1ncc(-c2nc(C(F)F)cs2)c1C(=O)Nc1ccn2nc(Br)nc2c1
Reactant: C[C@H]1CCCN1
Solvent: CCOC(C)=O
Product: C[C@H]1CCCN1c1nc2cc(NC(=O)c3c(-c4nc(C(F)F)cs4)cnn3C)ccn2n1
Temperature: 150 °C

Procedure:
An (S)-2-methylpyrrolidine (0.5 ml) solution of the N-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-(4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (30 mg) synthesized in (Example 3.15) <Step 6> was stirred under microwave heating at 150° C. for 1 hour. Thereafter, ethyl acetate (20 ml) was added to the reaction solution, and the mixed solution was successively washed with water (15 ml) twice and with a saturated saline (10 ml) once, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (silica gel: eluent; heptane:ethyl acetate=40:60), so as to obtain the title compound (13 mg) in the form of a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][C:17]1=O.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:17]3[CH2:18][CH2:19][CH2:20][N:16]=3)[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)Nc1ccccc1O2
Reactant: O=C1CCCN1
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccc2c(c1)N(C1=NCCC1)c1ccccc1O2

Procedure:
Reaction of 2-chlorophenoxazine, 2-pyrrolidinone, and phosphorus oxychloride according to the procedure of Example 1 provides the free base 2-CHLORO-10-(1-PYRROLIN-2-YL)PHENOXAZINE as a distillable oil, b.p. 150-165° C. at 0.1 mm Hg. Conversion of the free base to the hydrochloride salt affords 2-CHLORO-10-(1-PYRROLIN-2-YL)-PHENOXAZINE HYDROCHLORIDE, m.p. 209.5-213.5° C. (corr.), in a 40% overall yield.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][C:11]1[O:15][N:14]=[C:13]([C:16](Cl)=[O:17])[CH:12]=1>>[CH3:10][C:11]1[O:15][N:14]=[C:13]([C:16]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([NH2:1])=[CH:3][CH:4]=2)=[O:17])[CH:12]=1
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: NCc1ccc(N)cc1
Product: Cc1cc(C(=O)NCc2ccc(N)cc2)no1

Procedure:
4-Aminobenzylamine (265 mg, 2.17 mmol) and 5-methyl-3-isoxazoyl chloride (316 mg, 2.17 mmol) were converted to the title compound by the procedure of Preparation 1 except that a 2:1 mixture of mono to bis acylated products resulted which were separated by partitioning the mixture in 100 mL of ethyl acetate and 100 mL of 1N aqueous hydrochloric acid. The organic was extracted an additional two times with the acid and the combined acid extracts were made basic (about pH 8) with saturated aqueous sodium bicarbonate. This basic solution was extracted with ethyl acetate and the organic extracts were dried over magnesium sulfate, filtered, and concentrated to yield 94 mg of the monoacylated title compound. (18.7%). MS(FD) m/z 231 (M+). IR(KBr) υ=3334, 1646, 1551, 1519, 1459 cm−1.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.[Cl:9][CH2:10][C:11](=O)[CH2:12][C:13](OCC)=[O:14]>>[Cl:9][CH2:10][C:11]1[N:1]=[C:2]2[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]2[C:13](=[O:14])[CH:12]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Cc1nc(N)sc1C
Product: Cc1sc2nc(CCl)cc(=O)n2c1C
Yield: 144 %

Procedure:
This compound was synthesized from 2-amino-4,5-dimethylthiazole (5.0 g, 30.365 mmol) and ethyl chloroacetoacetate (6.519 g, 42.511 mmol) in polyphosphoric acid (40.0 g) according to the procedure described in Step 1, Intermediate 2 to afford 10.0 g of the desired compound as a black solid; 1H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 2.60 (s, 3H), 4.52 (s, 1H), 6.25 (s, 1H); ESI-MS (m/z) 229.60 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:23]3[C:22](=[O:24])[NH:21][C:20]([CH3:25])=[N:19][C:18]=3[N:17]=[C:16]([S:26][CH2:27][C:28]3[N:29]=[C:30]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)[S:31][CH:32]=3)[C:15]=2[C:40]#[N:41])=[CH:10][CH:9]=1)(=O)C.O1CCOCC1.[OH-].[Li+]>O>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C:30]2[S:31][CH:32]=[C:28]([CH2:27][S:26][C:16]3[C:15]([C:40]#[N:41])=[C:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][OH:4])=[CH:9][CH:10]=4)[C:23]4[C:22](=[O:24])[NH:21][C:20]([CH3:25])=[N:19][C:18]=4[N:17]=3)[N:29]=2)=[CH:34][CH:35]=1
Reactant: CC(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc3nc(C)[nH]c(=O)c23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2nc(SCc3csc(-c4ccc(Cl)cc4)n3)c(C#N)c(-c3ccc(OCCO)cc3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
24 mg (0.04 mmol) of the compound from Example 8A were initially charged in 2.3 ml of a 2:1 mixture of dioxane and water, and 1.9 mg (0.08 mmol) of lithium hydroxide were added. The reaction mixture was stirred at RT for 4 h. A further 1.9 mg (0.08 mmol) of lithium hydroxide were added, and the mixture was stirred for another 4 h. 2 ml of water were added to the reaction. The mixture was extracted three times in total with in each case 4 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate and the solvent was removed on a rotary evaporator. The residue was purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[N:19][C:20]([OH:24])=[C:21]([OH:23])[CH:22]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:16][C:17]1[CH:22]=[C:21]([O:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)[C:20]([OH:24])=[N:19][CH:18]=1
Reactant: Oc1cc(Cl)cnc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc(Cl)cnc3O)c2cc1OC
Temperature: 160 °C
Reaction time: 3 h
Yield: 24.7 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (226 mg), 3-chloro-5,6-dihydroxypyridine (290 mg), and 4-dimethylaminopyridine (360 mg) were suspended in o-dichlorobenzene (13 ml), and the suspension was stirred at 160° C. for 3 hr. The reaction solution was cooled to room temperature, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give 4-(5-chloro-2-hydroxy-pyridin-3-yloxy)-6,7-dimethoxyquinoline (83 mg, yield 25%).