Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[OH-].[K+].[NH2:20]OS(O)(=O)=O>O>[NH2:20][N:8]1[C:9]2[C:4](=[C:3]([N+:15]([O-:17])=[O:16])[C:2]([Cl:1])=[C:11]([Cl:12])[CH:10]=2)[NH:5][C:6](=[O:14])[C:7]1=[O:13]
Reactant: NOS(=O)(=O)O
Reactant: O=c1[nH]c2cc(Cl)c(Cl)c([N+](=O)[O-])c2[nH]c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nn1c(=O)c(=O)[nH]c2c([N+](=O)[O-])c(Cl)c(Cl)cc21
Reaction time: 0.17 h
Yield: 81.1 %

Procedure:
The procedure of Shin, S. C. and Lee, Y. Y., Taehan Hwahakhoe Chi 27(5):382-4 (1983) was adapted. A red solution of 6,7-dichloro-5-nitro-1,4-dihydro-2,3-quinoxalinedione (100 mg, 0.36 mMol, Cheeseman, supra) and 3N KOH (2 mL) in distilled water (5 mL) at 65° C. was dropwise added to a colorless solution of NH2OSO3H (75 mg, 0.66 mMol, Aldrich) in distilled water (0.5 mL) with stirring. A yellow precipitate came out after 10 mins. The mixture was stirred at 65° C. for 1 h and allowed to stand at room temperature overnight, then the precipitate was collected by filtration at 50° C. and was washed with distilled water (2 ml), then dried at 50° C. overnight, affording 85 mg (80% ) of crude 1-amino-5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione, as a yellow amorphous solid (80% of desired 1-amino-5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione with 20% starting material by NMR). A 85 mg sample of crude 1-amino-5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (free base Na+, 0.293 mMol) was dissolved into distilled water (10 mL) at 50° C., then was acidified with AcOH to pH=5. After removal of the insoluble material by filtration, the mixture was heated at 60°-70° C. until a clear solution was obtained, which was slowly cooled, whereupon a yellow precipitate came out. The precipitate was crystallized from hot EtOH and the yellow microcrystals were collected by filtration, washed with cold ethanol (2 mL), and dried in the air at 60° C. for 4 h, affording 31 mg (29%) of pure 1-amino-5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione. Mp was measured: the color of 1-amino-5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione changed to dark yellow at 275° C.; the decomposition of 1-amino-5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione is obvious at 280° C. and it melted to a black liquid at 290°-1° C. IR (KBr, cm-1): 3442; 3315; 3231; 1747; 1723; 1680; 1632; 1547. NMR (1H, DMSO-d6): δ5.848 (s, 2H); 7.951 (s, 1H); 12.595 (s, 1H). HRMS: calcd for C8H4N4O4Cl2 (M+) m/z: 289.9623; found 289.9616.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.[N:13]([O-])=O.[Na+].O.O.Cl[Sn]Cl.[CH:22]1([C:27](=O)[CH2:28][C:29]#[N:30])[CH2:26][CH2:25][CH2:24][CH2:23]1>Cl.O>[NH2:30][C:29]1[N:1]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]3)[N:13]=[C:27]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:28]=1
Reactant: O=N[O-]
Reactant: Nc1ccc2[nH]c(=O)ccc2c1
Reactant: N#CCC(=O)C1CCCC1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Nc1cc(C2CCCC2)nn1-c1ccc2[nH]c(=O)ccc2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
To a suspension of 6-aminoquinolin-2(1H)-one (0.72 g, 4.5 mmol, see Example A41) in conc. HCl (5 mL) was slowly added NaNO2 (0.43 g, 6.3 mmol) solution in H2O (5 mL) at 0° C. After stirring for 1 h, SnCl2.2H2O (2.0 g, 9.0 mmol), dissolved in conc. HCl (7 mL), was slowly added at such a rate that the temperature of the mixture did not rise above 5° C., After stirring for 2 h, the resultant solid was filtered, dried, and suspended in EtOH. To this were added 3-cyclopentyl-3-oxopropanenitrile (0.68 g, 4.9 mmol) and a few drops of HCl and the mixture was heated at 80° C. for 16 h. The solution was concentrated, dissolved in satd. NaHCO3 solution and the product was extracted with EtOAc (2×30 mL). The combined organic extracts were washed with brine, dried (Na2SO4), concentrated and the resultant solid triturated with toluene (10 mL) and filtered to yield 6-(5-amino-3-cyclopentyl-1H-pyrazol-1-yl)quinolin-2(1H)-one (0.75 g, 57% yield) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 7.95 (d, J=10.0 Hz, 1H), 7.81 (d, J=2.4 Hz, 1H), 7.68 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 6.54 (d, J=8.8 Hz, 1H), 5.32 (s, 1H), 5.24 (brs, 2H), 2.92-2.84 (m, 1H), 1.94-1.86 (m, 2H), 1.73-1.57 (m, 6H); MS (ESI) m/z: 295.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:17]([CH3:34])[C:18]([CH2:21][N:22]([CH2:30][CH2:31][O:32][CH3:33])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][N:20]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.[F:38][C:39]1[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=1[N:46]=[C:47]=[O:48]>C(Cl)Cl>[F:38][C:39]1[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=1[NH:46][C:47](=[O:48])[NH:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:17]([CH3:34])[C:18]([CH2:21][N:22]([CH2:30][CH2:31][O:32][CH3:33])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][N:20]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: ClCCl
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)Nc5ccc(F)cc5F)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.7 %

Procedure:
To a solution of aniline 46 (500 mg, 0.948 mmol) in DCM (10 ml) was added 2,4-difluoro-1-isocyanatobenzene (441 mg, 3 eq, 2.84 mmol) and the reaction mixture was stirred at RT for 24 hours. The mixture was concentrated and purified via column chromatography (eluent 10% MeOH in EtOAc) to afford 350 (600 mg, 93%) as a white solid. MS (m/z)=683.7 (M+H)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14])([O-])=O.O.O.[Sn](Cl)[Cl:22].Cl>C(O)C>[ClH:22].[CH:15]1[C:12]2[C:13]([NH2:14])=[N:1][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[NH:10][C:11]=2[CH:18]=[CH:17][CH:16]=1
Reactant: Cl[Sn]Cl
Reactant: N#Cc1ccccc1Nc1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCO
Product: NC1=Nc2ccccc2Nc2ccccc21
Temperature: 25 °C
Yield: 100.1 %

Procedure:
Combine 2-(2-Nitro-phenylamino)-benzonitrile (6.14 g, 25.66 mmol), tin(II) chloride dihydrate (17.37 g, 76.99 mmol), 5N HCl (105 ml), and ethanol (65.0 ml). Stir the mixture at reflux for 24 hours then cool it to ambient temperature and chill it in the refrigerator for 2 hours. Remove the ethanol under vacuum and chill in the refrigerator again. Filter off the resulting precipitate by vacuum filtration and dry it in a vacuum oven to give 6.31 g (100%) of a yellow solid: mass spectrum (ion spray): m/z=210.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:21])[N:4]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:13]([O:15][CH3:16])=[O:14])[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].CN(C)C=O.C([O-])([O-])=O.[K+].[K+].[F:33][C:34]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:35]=1[CH2:36]Cl>O>[F:33][C:34]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:35]=1[CH2:36][O:8][C:7]1[CH:6]=[C:5]([CH3:9])[N:4]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:13]([O:15][CH3:16])=[O:14])[C:3](=[O:21])[C:2]=1[Br:1]
Reactant: COC(=O)c1ccc(C)c(-n2c(C)cc(O)c(Br)c2=O)c1
Reactant: Fc1ccc(CCl)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 55 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
Methyl 3-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-4-methylbenzoate (4) (1.9 kg, 5.4 moles), N,N-dimethylformamide (4.8 L) and powdered K2CO3 (1.1 kg, 8.1 moles) were mixed together and heated to 55° C. under nitrogen. 2,4-difluorobenzyl chloride (964 g, 5.9 moles) was added at a rate such that the temperature was maintained below 65° C. After the addition, the mixture was heated at 65° C. for 3.5 hours. After 3 hours the reaction was complete and the reaction mixture was cooled to 20-25° C. with the addition of 19 L water. The solid was filtered and washed with 15 L water. The crude product was then purified by trituration in refluxing methanol (4 L). The mixture was cooled and the solid filtered to yield 2.32 kg (90%) product. 1H NMR (300 MHz, CDCl3) δ 1.90 (s, 3H), 2.11 (s, 3H), 3.87 (s, 3H), 5.25 (s, 2H), 6.11 (s, 1H), 6.88 (dt, J=4.8, 1.8 Hz, 1H), 6.96 (t, J=4.8 Hz, 1H), 7.42 (d, J=6 Hz, 1H), 7.59 (q, J=4.8 Hz, 1H), 7.74 (s, 1H), 8.02 (d, J=6 Hz, 1H). Anal. Cald. for C22H18BrF2NO4: C, 55.25; H, 3.79; N, 2.93. Found: C, 55.34; H, 3.83; N, 3.14.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:15]=[CH:16]/[C:17]2[N:18]=[C:19]3[N:23]([C:24]=2[C:25](O)=[O:26])[CH:22]=[CH:21][S:20]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:28][C:29]([F:37])([F:36])[C:30]1[N:31]=[C:32]([NH2:35])[S:33][CH:34]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH:1]1([O:6][C:7]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:15]=[CH:16]/[C:17]2[N:18]=[C:19]3[N:23]([C:24]=2[C:25]([NH:35][C:32]2[S:33][CH:34]=[C:30]([C:29]([F:37])([F:36])[F:28])[N:31]=2)=[O:26])[CH:22]=[CH:21][S:20]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OC1CCCC1
Reactant: Nc1nc(C(F)(F)F)cs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc(/C=C/c2nc3sccn3c2C(=O)Nc2nc(C(F)(F)F)cs2)c1OC1CCCC1

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 4 (200 mg, 0.520 mmol) with 4-(trifluoromethyl)-1,3-thiazol-2-amine (105 mg, 0.624 mmol) in the presence of EDCI hydrochloride (200 mg, 1.040 mmol) and DMAP (159 mg, 1.300 mmol) in a mixture of DCM and DMF (4:1, 5 mL) to give 86 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.52-1.62 (m, 4H), 1.76-1.79 (m, 4H), 3.81 (s, 3H), 4.85 (br s, 1H), 7.00 (d, J=7.8 Hz, 1H), 7.10 (t, J=8.1 Hz, 1H), 7.34 (d, J=7.8 Hz, 1H), 7.43-7.49 (m, 2H), 7.82 (d, J=16.2 Hz, 1H), 8.06-8.10 (m, 2H), 12.99 (br s, 1H); ESI-MS (m/z) 535.11 (MH)+.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:18](O)=O)=[N:9][O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[OH:35][N:36]=[C:37]([NH2:49])[C:38]1[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][C:39]=1[C:45]([F:48])([F:47])[F:46]>CN(C)C=O>[C:1]1([C:7]2[C:8]([C:18]3[O:35][N:36]=[C:37]([C:38]4[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][C:39]=4[C:45]([F:47])([F:46])[F:48])[N:49]=3)=[N:9][O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1noc(-c2ccccc2)c1-c1ccccc1
Reactant: Cc1ccc(C(N)=NO)c(C(F)(F)F)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ccc(-c2noc(-c3noc(-c4ccccc4)c3-c3ccccc3)n2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.3 %

Procedure:
A 2 dram reaction vial containing a stir bar was charged with 4,5-diphenylisoxazole-3-carboxylic acid (17-B, 48.6 mg, 0.183 mmol), EDC (43.9 mg, 0.229 mmol), HOBT (35.1 mg, 0.229 mmol), and dimethylformamide (1 mL). The vial was flushed with dry nitrogen, sealed, and the reaction was stirred at room temperature for 30 minutes. N′-Hydroxy-4-methyl-2-(trifluoromethyl)benzimidamide (40.0 mg, 0.183 mmol) was introduced. The vial was flushed with dry nitrogen, sealed, stirred at room temperature for 30 minutes, and then placed on a reactor block set to 60° C. overnight. Water was added dropwise (−0.5 mL) until the solution remained cloudy, and then the reaction was cooled to room temperature. Additional water (5 mL) was added after cooling, and the reaction was placed in a sonicator bath for 60 min. A gummy solid formed on the side of the flask and stir bar. The aqueous solution was decanted and the residue washed with water and then partially dried under a stream of air. The gummy solid was dissolved in methanol (1-2 mL), transferred, and evaporated to dryness to give a pale yellow solid The pale yellow solid was purified by flash chromatography (12 g Isco silica gel). Elution with dichloromethane afforded the major product. The product containing fractions were evaporated to afford 5-(4,5-diphenylisoxazol-3-yl)-3-(4-methyl-2-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (24 mg) MS M+1=448.1.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15]2[CH2:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:24]([Li])[CH2:25][CH2:26][CH3:27].[Cl-:29].[Cl-].[Cl-].[Cl-].[Hf+4:33]>C(OCC)C>[Cl-:29].[Cl-:29].[C:1]([C:5]1[CH:6]=[C:7]([C:15]2[CH:23]([Hf+2:33][CH:24]3[C:17]4[C:27](=[CH:22][CH:23]=[CH:15][CH:16]=4)[CH:26]=[C:25]3[C:7]3[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=3)[C:22]3[C:17]([CH:16]=2)=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: [Li]CCCC
Reactant: CC(C)(C)c1cc(C2=Cc3ccccc3C2)cc(C(C)(C)C)c1
Reactant: [Hf+4]
Agent: [Cl-]
Solvent: CCOCC
Product: CC(C)(C)c1cc(C2=Cc3ccccc3C2[Hf+2]C2C(c3cc(C(C)(C)C)cc(C(C)(C)C)c3)=Cc3ccccc32)cc(C(C)(C)C)c1
Temperature: -10 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
2-(3,5-Di-t-butylphenyl)indene (23.3 g, 0.077 mol) and anhydrous diethyl ether (250 mL) were placed in a 1 L three-necked flask under argon. n-Butyl lithium (48 mL of a 1.6 M solution in hexanes, 0.077 mol) was added over a thirty minute period at 0° C. The solution was stirred for an additional two hours. Hafnium tetrachloride (12.2 g, 0.038 mol) was added incrementally over a one-hour period. The mixture was then stirred overnight. The ethereal solution was chilled to −10° C. and the solids were collected by filtration. The solids were taken up in 300 mL of dichloromethane and the residual solids were removed by filtration through celite. The celite was washed with an additional 100 mL of dichloromethane, and the solvents were evaporated to give 23.5 g of bis(2-(3,5-di-t-butylphenyl)indenyl)hafnium dichloride(72% yield).
Reaction SMILES: [Na].CO.[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH:15]=[N:14][C:13]([OH:16])=[N:12]1.Br[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CS(C)=O>[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH:15]=[N:14][C:13]([O:16][CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:24])=[N:12]1
Reactant: Oc1ncn(-c2ccccc2Cl)n1
Reactant: CCOC(=O)C(C)Br
Agent: [Na]
Solvent: CS(C)=O
Solvent: CO
Product: CCOC(=O)C(C)Oc1ncn(-c2ccccc2Cl)n1
Yield: 92.6 %

Procedure:
The process was carried out essentially according to that of Example 2 above, starting with 1.2 g of sodium, 30 ml of methanol, 10 g of 1-(2-chlorophenyl)-3-hydroxy-1,2,4-1H-triazole and 9.3 g of ethyl 2-bromopropionate. The solvent was 100 ml of dimethylsulfoxide. The product obtained was 14 g of the desired product, an oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[N:3]1.[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][CH:29](OCC)OCC)=[CH:22][N:21]=1.[CH2:36]([NH2:38])[CH3:37].O1CCCC1>>[ClH:19].[Cl:26][C:25]1[C:20]([O:18][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[N:11]=[CH:10][N:9]=[C:8]3[NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)=[N:21][CH:22]=[C:23]([O:27][CH2:28][CH2:29][NH:38][CH2:36][CH3:37])[CH:24]=1
Reactant: CCOC(COc1cnc(Cl)c(Cl)c1)OCC
Reactant: CCN
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Solvent: C1CCOC1
Product: CCNCCOc1cnc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)c(Cl)c1
Product: Cl

Procedure:
Using 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol obtained in Example 1-1) and 2), and 2,3-dichloro-5-(2,2-diethoxyethoxy)pyridine and 2 M ethylamine/tetrahydrofuran solution, and in the same manner as in Example 1-3) and Example 10-2), or according to a method similar to it or according to a combination thereof with an ordinary method, the entitled compound (223 mg) was obtained as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:30])=[C:11]([CH:15]([C:23]2[C:28](Cl)=[N:27][CH:26]=[CH:25][N:24]=2)[NH:16][C:17]([CH:19]2[CH2:22][CH2:21][CH2:20]2)=O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(F)=C(C(N)C2C(Cl)=NC=C[N:47]=2)C=CC=1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.C1(C(Cl)=O)CCC1>C(Cl)Cl>[NH2:47][C:28]1[C:23]2[N:24]([C:17]([CH:19]3[CH2:22][CH2:21][CH2:20]3)=[N:16][C:15]=2[C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:10]=2[F:30])[CH:25]=[CH:26][N:27]=1
Reactant: NC(c1cccc(OCc2ccccc2)c1F)c1nccnc1Cl
Reactant: O=C(NC(c1cccc(OCc2ccccc2)c1F)c1nccnc1Cl)C1CCC1
Agent: O=C(Cl)C1CCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nccn2c(C3CCC3)nc(-c3cccc(OCc4ccccc4)c3F)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
N-[(3-benzyloxy-2-fluorophenyl) (3-chloropyrazin-2-yl)methyl]cyclobutylcarboxamide: To a solution of C-(3-benzyloxy-2-fluoro-phenyl)-C-(3-chloro-pyrazin-2-yl)-methylamine (1.1 g, 3.2 mmole) in methylene chloride (10 mL) was added diisopropylethylamine (1.1 mL, 6.4 mmole) under a nitrogen atmosphere. The reaction mixture was cooled in an ice bath and cyclobutanecarboxylic acid chloride (0.55 mL, 4.8 mmole) was added in one portion. The reaction mixture was stirred overnight at room temperature then quenched with water (10 mL). The organic layer separated and washed with 10% aqueous NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography using hexane:ethyl acetate (60:40) as an eluant to give the title compound (911 mg, 67%). FAB-MS: m/z 426.3 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:23]=[C:22]2[C:12]([NH:13][CH:14]=[C:15]2[CH2:16][CH:17]([C:19]([OH:21])=[O:20])[NH2:18])=[CH:11][CH:10]=1.[CH2:24]([O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1)[C:25]#[C:26][CH3:27]>O.O1CCOCC1>[CH2:24]([O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:18][CH:17]([CH2:16][C:15]2[C:22]3[C:12](=[CH:11][CH:10]=[C:9]([CH3:8])[CH:23]=3)[NH:13][CH:14]=2)[C:19]([OH:21])=[O:20])(=[O:37])=[O:36])=[CH:31][CH:30]=1)[C:25]#[C:26][CH3:27]
Reactant: Cc1ccc2[nH]cc(CC(N)C(=O)O)c2c1
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)NC(Cc2c[nH]c3ccc(C)cc23)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.6 %

Procedure:
Triethylamine (0.38 mL, 2.75 mmol) was added to a solution of 5-methyl-DL-tryptophan (0.20 g, 0.92 mmol) and 4-but-2-ynyloxy-benzenesulfonyl chloride (0.25 g, 1.01 mmol) in H2O-dioxane (1.6 mL/2.4 mL) at room temperature. The reaction mixture was stirred for 20 hours at room temperature. The mixture was then concentrated and acidified with HCl. The mixture was extracted with ethyl acetate (3×10 mL). The organic solution was washed with H2O and brine, dried over Na2SO4, and concentrated. The residue was purified by RP-HPLC to give 0.32 g (81%) of the title compound as a pale yellow solid. Mp=45-46° C.; 1H NMR (DMSO-d6): 400 MHz δ 12.54 (bs, 1H), 10.64 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.53 (m, 2H), 7.17 (d, J=8.0 Hz, 1H), 7.00 (m, 2H), 6.95 (m, 2H), 6.86 (dd J=8.0, 4.0 Hz, 1H), 4.78 (q, J=2.4 Hz, 2H), 3.81 (q, J=7.6 Hz, 1H), 3.00 (dd J=14.4, 6.8 Hz, 1H), 2.79 (dd J=14.4, 7.8 Hz, 1H), 2.33 (s, 3H), 1.82 (t, J=2.4 Hz, 3H); HRMS: calcd for C22H23N2O5S (ESI+, [M+H]1+), 427.1322; found 427.1327; LCMS m/z (ESI) [M+H]1+ 427, retention time=2.69 min.
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[C:6]([CH3:13])[CH:5]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)(Cl)[Cl:15]>>[CH:1]1([C:4]2[CH:12]=[CH:11][C:7]([C:8]([Cl:15])=[O:9])=[C:6]([CH3:13])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1cc(C2CC2)ccc1C(=O)O
Product: Cc1cc(C2CC2)ccc1C(=O)Cl
Yield: 95.8 %

Procedure:
4-Cyclopropyl-2-methylbenzoic acid (25.01 g, 142 mmol) and phosphorus pentachloride (32.84 g, 158 mmol) were charged into a 100 mL round bottom flask fitted with a stir bar, reflux condenser, and calcium chloride drying tube exhausted through a dilute aqueous solution of NaOH as a gas trap. Refluxed the mixture at a bath temperature of 120° for 2 hr. Removed the POCl3 byproduct by distillation at atmospheric pressure. Vacuum distilled the residue. Collected the fraction distilling at 116-118°/3 torr to obtain 4-cyclopropyl-2-methylbenzoyl chloride as a clear colorless liquid (26.39 g, 136 mmol). 1H NMR (300 MHz, chloroform-d) ppm 0.77-0.86 (m, 2H) 1.06-1.16 (m, 2H) 1.87-1.99 (m, 1H) 2.54 (s, 3H) 6.93-7.03 (m, 2H) 8.14 (d, J=8.29 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([N:17]=[C:18]=[O:19])=[N:14][C:13]=2[CH3:20])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH2:21][CH2:22][CH2:23][OH:24]>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:18]([NH:21][CH2:22][CH2:23][OH:24])=[O:19])=[N:14][C:13]=2[CH3:20])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cc1nc(N=C=O)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Reactant: NCCO
Solvent: C1COCCO1
Product: Cc1nc(NC(=O)NCCO)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Temperature: 80 °C

Procedure:
5-(3-fluoro-4-methanesulfonyl-phenyl)-2-isocyanato-4-methyl-thiazole (88a)(0.58 mmol, 0.183 g) is dissolved in dioxane (5 ml) and treated with 2-aminoethanol (0.64 mmol, 0.039 ml) under argon. The reaction mixture is stirred and heated to 80° C. for 1 hour. The solvent is then removed and the residue dissolved in EtOAc and washed with water (2×20 ml) followed by brine (20 ml) and dried over MgSO4. After filtration, the solvent is removed in vacuo and the residue purified by chromatography on silica eluting with ethyl acetate—methanol (9:1) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.[NH:28]1[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(Cl)Cl.CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:5][N:28]2[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]2)[CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2
Reactant: O=C(O)C1CNC1
Reactant: Cc1cc(C=O)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(CN2CC(C(=O)O)C2)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-methyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)-benzaldehyde (85.0 mg, 229 μmol), azetidine-3-carboxylic acid (116 mg, 1147 μmol), and acetic acid (106 μL, 1836 μmol) in 1:1 CH2Cl2/MeOH (7.0 mL) was stirred at 25° C. for 1 h. Sodium cyanoborohydride (26 mg, 413 μmol) was then added, and the resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was then concentrated in vacuo, dissolved in 2 mL DMSO+20 μL trifluoroacetic acid, filtered, and purified by rpHPLC (10-100% acetonitrile/water+0.1% TFA) to provide 1-((3-methyl-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)-azetidine-3-carboxylic acid as a white solid. MS (ESI) m/z: Calculated: 455.2; Observed: 456.1 (M++1). 1H NMR (400 MHz, MeOH) δ ppm 8.11 (d, J=8.6 Hz, 1 H), 7.88 (d, J=7.8 Hz, 1 H), 7.35-7.55 (m, 6 H), 7.27-7.34 (m, 1 H), 7.11 (d, J=8.6 Hz, 1 H), 4.47 (s, 2 H), 4.32-4.42 (m, 4 H), 3.63-3.81 (m, 1 H), 2.67 (s, 3 H), 1.70-1.77 (m, 2 H), 1.36-1.47 (m, 2 H)