Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=3[O:20][CH3:21])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>>[CH3:21][O:20][C:11]1[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:10]=1[C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:36][C:33]3[CH:32]=[CH:31][C:30]([N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)=[CH:35][CH:34]=3)[N:22]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Cl)nc12
Product: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc(N4CCN(C)CC4)cc3)nc12

Procedure:
[8-(2-methoxy-5-trifloromethylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 2-chloro-8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.150 g, 0.5 mmol), and 4-(4-methylpiperazin-1-yl)phenylamine (0.096 g, 0.5 mmol) in a manner analogous to Example 2d. Product was isolated as a foam (0.1 g, 40%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.43 (d, J=7.6 Hz, 1H), 7.94 (s, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.53 (d, J=7.1 Hz, 1H), 7.48 (d, J=7.1 Hz, 2H), 7.12 (d. J=8.2 Hz, 1H), 6.99-6.90 (m, 3H), 6.67 (s, 1H), 3.88 (s, 3H), 3.21-3.11 (m, 4H), 3.06 (s, 3H), 2.65-2.55 (m, 4H). MS=483 (MH)+.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:15])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[NH2:5].[C:16]1(=[O:23])[O:22][C:20](=[O:21])[CH:19]=[C:17]1[CH3:18]>C(Cl)(Cl)Cl>[C:16]([C:17]([CH3:18])=[CH:19][C:20]([NH:5][C@H:4]([C:3]([NH:2][CH3:1])=[O:15])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)=[O:21])([OH:23])=[O:22]
Reactant: CC1=CC(=O)OC1=O
Reactant: CNC(=O)[C@@H](N)Cc1ccc(OC)cc1
Solvent: ClC(Cl)Cl
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=C(C)C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 26 %

Procedure:
A mixed solution consisting of 50 g of N,O-dimethyltyrosine amide, 400 ml of dry chloroform and 27 g of citraconic anhydride was stirred at room temperature for 6 hours, concentrated under a reduced pressure, subjected to a silica gel column chromatography and eluted with chloroform-methanol-acetic acid to obtain 20 g of Nα -(3-carboxy-2-butenoyl)-N,O-dimethyltyrosine amide.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][CH2:17][O:18][C:19]([CH3:21])=[O:20]>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]=[CH:21][C:19]([O:18][CH2:17][CH3:16])=[O:20])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Reactant: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C=CC1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 15.5 mL of 1 M sodium bis(triemthylislyl)amide in 20 ml of THF was added 2.8 g triethyl phosphonoacetate at 0° C., and stirred at 0° C. for 15 min. After the addition of 1-benzyl-piperidine-4-carbaldehyde (from Example 162, step A) in 10 mL of 1BF, the reaction was stirred at 0° C. for 15 min. The reaction was warmed up to rt and stirred for 14 hr. The mixture was diluted with 35 ml of EtOAc and washed with H2O. Aqueous phase was extracted with 2×30 mL EtOAc. The combined organic phases were washed with brine and dried over MgSO4. Concentration gave a 2.43 g of title compound as a viscous oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[NH:22]1[CH:27]=[CH:26][C:25](=O)[N:24]=[CH:23]1>COCCOC>[N:22]1[CH:27]=[CH:26][C:25]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[N:24][CH:23]=1
Reactant: O=c1cc[nH]cn1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Solvent: COCCOC
Product: N#Cc1ccc(N(CCOc2ccncn2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 27B from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (Example 15B) and 4(1H)-pyrimidinone, using dry DME as the reaction solvent: MS (ESI) m/z 391 (M+1).
Reaction SMILES: C([O:5][C:6](=[O:37])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])=[O:20])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.C(O)=O>O>[F:29][C:23]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]=1[NH:21][C:19](=[O:20])[N:18]([CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:37])=[O:5])[S:12][CH:13]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)C(=O)Nc1ccc(F)cc1F
Solvent: O=CO
Solvent: O
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)C(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To 2-[(4-{2-[3-(2,4-difluorophenyl)-1-heptylureido]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (0.67 g) obtained in Example 319-1 was added formic acid (10 mL), and the mixture was stirred at room temperature overnight, stirred at 50° C. for 3 hr and further stirred at 70° C. for 4 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel chromatography (elution solvent hexane-ethyl acetate=1:1) to give the title compound (0.55 g) as a pale-brown oil.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([CH:22]=O)=[C:15]3[N:14]=2)=[CH:8][CH:7]=1.[NH:25]1[CH2:31][C:29](=[O:30])[NH:28][C:26]1=[O:27].N1CCCCC1>CCO>[CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([CH:22]=[C:31]4[NH:25][C:26](=[O:27])[NH:28][C:29]4=[O:30])=[C:15]3[N:14]=2)=[CH:8][CH:7]=1
Reactant: CN(C)CCOc1ccc(Nc2ccn3ncc(C=O)c3n2)cc1
Reactant: O=C1CNC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CN(C)CCOc1ccc(Nc2ccn3ncc(C=C4NC(=O)NC4=O)c3n2)cc1
Temperature: 70 °C

Procedure:
To 5-(4-(2-(dimethylamino)ethoxy)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (90 mg, 0.276 mmol) in EtOH was added hydantoin (28 mg, 0.276 mmol) and piperidine (28 μL, 0.276 mmol). The mixture was heated at 70° C. overnight three times. Solvent was removed under reduced pressure and MeOH was added. Insolubilities were filtered off, and the filtrate was purified by HPLC to yield 5-((5-(4-(2-(dimethylamino)ethoxy)phenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=408)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][C:14]2[O:18][CH:17]=[C:16]([C:19]([OH:21])=O)[CH:15]=2)[CH3:12])(=[O:10])=[O:9])=[C:4]([CH2:22][CH3:23])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N:36]1([CH2:41][CH2:42][CH2:43][N:44]2[CH2:50][CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:40][CH2:39][CH2:38][CH2:37]1>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:12])[CH2:13][C:14]2[O:18][CH:17]=[C:16]([C:19]([N:47]3[CH2:48][CH2:49][CH2:50][N:44]([CH2:43][CH2:42][CH2:41][N:36]4[CH2:37][CH2:38][CH2:39][CH2:40]4)[CH2:45][CH2:46]3)=[O:21])[CH:15]=2)(=[O:9])=[O:10])=[C:4]([CH2:22][CH3:23])[CH:3]=1
Reactant: C1CCN(CCCN2CCCNCC2)C1
Reactant: CCc1cc(Br)ccc1S(=O)(=O)N(C)Cc1cc(C(=O)O)co1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: CCc1cc(Br)ccc1S(=O)(=O)N(C)Cc1cc(C(=O)N2CCCN(CCCN3CCCC3)CC2)co1

Procedure:
The title compound was prepared according to general procedure AA using 5-({[(4-bromo-2-ethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (50 mg, 0.12 mmol), CDI (41 mg, 0.25 mmol) and 1-[3-(pyrrolidin-1-yl)propyl]-1,4-diazepane (53 mg, 0.25 mmol) in DCE (2 mL). The crude product was purified using prep method A.
Reaction SMILES: [C:1]1([C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=3[N:13]([C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:12][CH:11]([NH:27]C(OC(C)(C)C)=O)[C:10]2=[O:35])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1>Cl.O1CCOCC1>[C:1]1([C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=3[N:13]([C:21](=[O:26])[C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:12][CH:11]([NH2:27])[C:10]2=[O:35])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc2c(c1)N(CC(=O)c1cccs1)C(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)N(CC(=O)c1cccs1)C(=O)C(N)CN2C(=O)C(C)(C)C
Temperature: 55 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
1-(2-Thenoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.00 g) was dissolved in 4N HCl-dioxane (10 ml), the solution was stirred for one hour at 55° C. The reaction mixture was concentrated under reduced pressure. The residue was neutralized with saturated aqueous sodium bicarbonate, extracted with methylene chloride. The organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, to thereby obtain 0.74 g of the titled compound as brown crystals (Yield: 92%).
Reaction SMILES: [N+:1]([N:4]=[C:5]([NH2:15])[NH:6][C:7]1[CH:8]=[C:9]([CH2:13][NH2:14])[CH:10]=[CH:11][CH:12]=1)([O-:3])=[O:2].C[N:17](N=O)[C:18]([NH:20][N+:21]([O-:23])=[O:22])=N>>[N+:21]([N:20]=[C:18]([NH2:17])[NH:14][CH2:13][C:9]1[CH:8]=[C:7]([NH:6][C:5]([NH:4][N+:1]([O-:3])=[O:2])=[NH:15])[CH:12]=[CH:11][CH:10]=1)([O-:23])=[O:22]
Reactant: NCc1cccc(NC(N)=N[N+](=O)[O-])c1
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Product: N=C(Nc1cccc(CNC(N)=N[N+](=O)[O-])c1)N[N+](=O)[O-]
Yield: 25 %

Procedure:
Using the compound obtained in Example 34 as a starting material and also using N-methyl-N′-nitro-N-nitrosoguanidine as a reagent, reaction was performed as in Example 83 to give the titled compound (yield, 25%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[N:15]1[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:21]([C:18]2[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=2)=[O:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2ccncc2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A cooled (0° C.) stirred solution of (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 5.36 mmol) and TEA (1.5 ml, 11.0 mmol) in THF (10 ml) is treated dropwise over 1 minute with pyridine-4 carbonyl chloride hydrochloride (0.935 g, 5.25 mmol). After 5 minutes, the reaction mixture is allowed to warm to room temperature and stirred overnight. The resulting mixture is diluted with EtOAc and washed twice with saturated sodium bicarbonate solution followed by brine. The organic portion is dried (MgSO4) and concentrated in vacuo. The crude product is purified by recrystallisation from EtOAc/iso-hexane to afford the title product. [MH+ 292].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:10][C:11](=O)[CH2:12][C:13](=O)[CH:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15]1)C>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][CH2:23][CH:14]1[C:13]1[NH:1][C:2]2[C:7]([C:11](=[O:10])[CH:12]=1)=[CH:6][CH:5]=[CH:4][CH:3]=2
Reactant: Nc1ccccc1
Reactant: CCOC(=O)CC(=O)C1CCc2ccccc2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=c1cc(C2CCc3ccccc3C2)[nH]c2ccccc12
Temperature: 25 °C
Yield: 31.6 %

Procedure:
A mixture containing aniline (0.7 ml, 7.7 mmol), p-toluene sulfonic acid (0.037 g,0.19 mmol) and (RS)-3-oxo-3-(1,2,3,4-tetrahydro-naphthalen-2-yl)-propionic acid ethyl ester (1.9 g, 7.7 mmol) in toluene (10 ml) was refluxed for 2.5 hours, and water was removed azeotropically. Reaction mixture was concentrated, diluted with diphenylether (8 ml), refluxed for 45 min., cooled to room temperature and diluted with Et2O (150 ml). The resulting solid was filtered, washed with Et,O and CH2Cl2 to provide (RS)-2-(1,2,3,4-Tetrahydro-naphthalen-2-yl)-1H-quinolin-4-one (0.67 g, 32%) as a light yellow solid, mp.>300° C., MS: m/e=275 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][C:26]3=[O:35])[CH2:21][CH2:20]2)=[O:18])[C:13]([OH:15])=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.CCN=C=NCCCN(C)C.[N:47]12[CH2:54][CH2:53][CH:50]([CH2:51][CH2:52]1)[CH:49](O)[CH2:48]2>CN(C)C1C=CN=CC=1.CN(C)C=O>[N:47]12[CH2:54][CH2:53][CH:50]([CH2:51][CH2:52]1)[CH:49]([O:14][C:13](=[O:15])[CH:12]([NH:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([N:25]3[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][C:26]3=[O:35])[CH2:23][CH2:24]1)=[O:18])[CH2:11][C:4]1[CH:5]=[C:6]3[C:10](=[C:2]([CH3:1])[CH:3]=1)[NH:9][N:8]=[CH:7]3)[CH2:48]2
Reactant: OC1CN2CCC1CC2
Reactant: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc2cn[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)OC2CN3CCC2CC3)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid (50 mg, 0.105 mmol), EDCI (100 mg), and 4-dimethylaminopyridine (0.2 equiv.) in dimethylformamide was added aza-bicyclo[2.2.2]oct-3-yl alcohol (0.525 mmol, 5 equiv.). The mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate, washed with brine, dried over magnesium sulfate, and purified by preparative HPLC to yield the desired compound. LC/MS: tR=1.62 min, 586.41 (MH)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][CH2:13][CH2:14]Cl)[C:4]=2[O:3]1.[OH:17][C:18]1([C:24]2[CH:25]=[N:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH3:1][C:2]1([CH3:16])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][CH2:13][CH2:14][N:21]3[CH2:22][CH2:23][C:18]([OH:17])([C:24]4[CH:25]=[N:26][C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH2:19][CH2:20]3)[C:4]=2[O:3]1
Reactant: OC1(c2cnc3ccccc3c2)CCNCC1
Reactant: CC1(C)Cc2cccc(OCCCCl)c2O1
Product: CC1(C)Cc2cccc(OCCCN3CCC(O)(c4cnc5ccccc5c4)CC3)c2O1
Yield: 46.6 %

Procedure:
Beginning with 0.316 gm (1.3 mMol) 3-chloropropyl 2,2-dimethyl-2,3-dihydrobenzofur-7-yl ether and 0.300 gm (1.3 mMol) 4-hydroxy-4-(quinolin-3-yl)piperidine, 0.262 gm (46%) of the title compound were recovered as a white solid.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:3]=1[C:14]([N:40]1[CH2:39][CH2:38][N:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([O:30][CH3:29])[CH:32]=2)[CH2:42][CH2:41]1)=[O:16]
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: Nc1onc(-c2ccccc2F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1cccc(N2CCN(C(=O)c3c(-c4ccccc4F)noc3N)CC2)c1
Yield: 76.6 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(2-fluorophenyl)isoxazol-4-carboxylic acid (409 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (558 mg, 1.41 mmol, 77%) was obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)(Cl)Cl>[O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([S:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[O:27])[CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: O=C1Cc2cccc(Sc3ccccc3Cl)c2N1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=C1Cc2cccc(S(=O)c3ccccc3Cl)c2N1

Procedure:
A solution of 2-oxo-7-(2-chlorophenylthio)indoline (1.0 g.) in chloroform (20 ml.) and m-chloroperbenzoic acid (purity: 85%, 0.73 g.) was treated in a similar manner to that of the Preparation 28-(2) to give crystals of the captioned compound (0.7 g.). mp 243° to 245° C.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br.[OH:13][C:14]1[CH:18]=[C:17]([N:19]2[C:23]3[CH:24]=[N:25][CH:26]=[CH:27][C:22]=3[N:21]=[CH:20]2)[S:16][C:15]=1[C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][O:13][C:14]1[CH:18]=[C:17]([N:19]2[C:23]3[CH:24]=[N:25][CH:26]=[CH:27][C:22]=3[N:21]=[CH:20]2)[S:16][C:15]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: FC(F)Oc1ccccc1CBr
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1ccccc1OC(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
207.7 mg of 2-(difluoromethoxy)benzyl bromide is added to a mixture of 200 mg of methyl 3-hydroxy-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate and 110.9 mg of potassium carbonate in 6 ml anhydrous DMF. The mixture is stirred for 14 h at room temperature. Additional 207.7 mg of 2-(Difluoromethoxy)benzyl bromide and 110.9 mg of potassium carbonate are added and the mixture is stirred at 75° C. for 3 h. Ice water is added to the mixture at room temperature and the organic phase is extracted with dichloromethane. The organic phase is poured on a phase separator and the solvent is removed under vacuum. The residue is dissolved in ethyl acetate and purified by flash column chromatography (eluent: hexane/ethyl acetate 1/1 (v/v) to 0/100 (v/v)) to yield the title compound.
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]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH:19]=1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([Cl:45])[C:31]=1[OH:46]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH:19]=2)=[CH:3][C:2]([C:34]2[CH:35]=[C:30]([Cl:29])[C:31]([OH:46])=[C:32]([Cl:45])[CH:33]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CN(C)CCc1cccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)c1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CN(C)CCc1cccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)c1
Yield: 71.3 %

Procedure:
Following general procedure F, {6-Bromo-4-[3-(2-(dimethylamino)ethyl)phenylamino]quinolin-3-yl}(cyclopropyl)methanone (58 mg, 0.132 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (57 mg, 0.198 mmol) to afford the desired product (49 mg, 71%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.46 (s, 1H), 8.22 (dd, J=8.7, 2.0 Hz, 1H), 8.02 (d, J=8.7 Hz, 1H), 7.89 (s, 1H), 7.67-7.59 (m, 1H), 7.56 (d, J=7.7 Hz, 1H), 7.8 (s, 1H), 7.39 (d, J=7.7 Hz, 1H), 7.20 (s, 2H), 3.40-3.34 (m, 2H), 3.19-3.12 (m, 2H), 2.98-2.85 (s, 8H), 1.27-1.16 (m, 4H); ESI MS m/z 520 [C29H27Cl2N3O2+H]+; HPLC 95.9% (AUC), tR=11.40 min.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:12]([OH:14])=O)=[CH:7][C:6]=1[CH3:22])(=[O:4])=[O:3].C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[OH:38][C:36]([CH3:39])([CH3:37])[CH2:35][N:32]1[CH:33]=[CH:34][C:30]([NH:29][C:12](=[O:14])[C@@H:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[C:6]([CH3:22])[CH:7]=2)[CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:31]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: Cc1cc([C@@H](CC2CCOCC2)C(=O)O)ccc1S(C)(=O)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: Cc1cc([C@@H](CC2CCOCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
2(R)-(4-methanesulfonyl-3-methyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionic acid (75 mg, 0.23 mmol) was dissolved in methylene chloride (2 mL) and N,N-dimethylfomamide (two drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 120 μL, 0.24 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes. After this time, the reaction was concentrated in vacuo and the residue was then taken up in methylene chloride (2 mL). This solution was then added dropwise to a flask containing a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in Example 80, 36 mg, 0.23 mmol), 2,6-lutidine (54 μL, 0.46 mmol), and methylene chloride (2 mL) which was cooled to 0° C. The reaction was allowed to warm to 25° C. and stirred for a period of 2 h. After this time, the reaction quenched with a small amount of methanol and then concentrated in vacuo. It was then dissolved in ethyl acetate (25 mL) and washed with a 1N hydrochloric acid solution (1×10 mL) and a saturated aqueous sodium chloride solution (1×10 mL). The organic layer was then dried over sodium sulfate and concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 10% methanol/ethyl acetate) to afford N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionamide (70 mg, 66%) as a white foam: [α]30589=−6.9° (c=0.16, methanol); ES-HRMS m/e calcd for C23H33N3O5S (M+H)+ 464.2214, observed 464.2208; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03, 1.04 (2×s, 6 H, 2×CH3), 1.07-1.43 (m, 3H, 3×CH of 2×CH2), 1.49-1.70 (m, 3H, 3×CH of 2×CH2), 1.98-2.12 (m, 1H, CH), 2.62 (s, 3H, ArCH3), 3.14-3.25 (m, 2H, OCH2), 3.17 (s, 3H, SO2CH3), 3.73-3.83 (m, 2H, OCH2), 3.84 (s, 2H, NCH2), 3.90-3.99 (m, 1H, ArCH), 4.64 (s, 1H, OH), 6.43 (d, J=2.3 Hz, 1H, Ar), 7.41-7.46 (m, 2H, Ar), 7.48 (d, J=2.3 Hz, 1H, Ar),), 7.83 (d, J=8.5 Hz, 1H, Ar), 10.72 (s, 1H, NH)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][S:11]([O-:14])(=O)=[O:12])=[N:2]1.[Na+].P(Cl)(Cl)(Cl)=O.[NH3:21]>ClCCCl.C(N(CC)CC)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][S:11]([NH2:21])(=[O:14])=[O:12])=[N:2]1
Reactant: N
Reactant: O=S(=O)([O-])Cc1noc2ccccc12
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: NS(=O)(=O)Cc1noc2ccccc12
Reaction time: 1.5 h

Procedure:
Water is removed by distillation from the above mixture of 1,2-benzisoxazole-3-acetic acid and 1,2-dichloroethane, and thereto is added dropwise chlorosulfonic acid (15.5 g) while the internal temperature is kept at 63° C.–79° C. After the addition, the mixture is stirred for 90 minutes while the reaction temperature is kept at 63° C.–79° C. After cooling, a 25% aqueous sodium hydroxide solution is added to the reaction mixture so as to adjust the pH value thereof to pH 11 or above. Water is removed by distillation from the reaction mixture to give a mixture of sodium 1,2-benzisoxazole-3-methanesulfonate and 1,2-dichloroethane. Triethylamine (2.4 g) and phosphoryl chloride (17.5 g) are added to this mixture, and the mixture is stirred at a temperature of 77° C.–83° C. for 6 hours. After cooling, to the reaction mixture is added 1,2-dichloroethane (80 ml), and ammonia gas is blown into the mixture until saturated while the reaction temperature is kept at 30° C.–60° C. The reaction mixture is concentrated, and water is added thereto. The mixture is stirred, and the precipitated crystals are collected by filtration, and washed with water to give crude crystals of 1,2-benzisoxazole-3-methanesulfonamide. The purity of the crude crystals is 96%.