Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:17][C:16]([C:18]([OH:20])=O)=[C:15]([CH3:21])[CH:14]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1.C(N1C(=O)N(C2SC(C(O)=O)=C(C)C=2)C=N1)C1C=CC=CC=1.[NH2:46][CH2:47][C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1>>[CH2:6]([N:7]1[C:11](=[O:12])[N:10]([C:13]2[S:17][C:16]([C:18]([NH:46][CH2:47][C:48]3[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=3)=[O:20])=[C:15]([CH3:21])[CH:14]=2)[CH:9]=[N:8]1)[C:5]1[CH:4]=[CH:3][CH:2]=[CH:23][CH:22]=1
Reactant: NCc1cccnc1
Reactant: Cc1cc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Agent: Cc1cc(-n2cnn(Cc3ccccc3)c2=O)sc1C(=O)O
Product: Cc1cc(-n2cnn(Cc3ccccc3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 89 %

Procedure:
Following the procedure as described in Example 31, making variations as required to replace 5-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-3-methylthiophene-2-carboxylic acid with 5-(1-benzyl-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-3-methylthiophene-2-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 89% yield: mp 180-181° C.; 1H NMR (300 MHz, CDCl3) δ 8.61 (s, 1H), 8.54 (s, 1H), 7.73 (s, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.43-7.25 (m, 6H), 6.88 (s, 1H), 6.48 (t, J=5.6 Hz, 1H), 5.00 (s, 2H), 4.61 (d, J=5.6 Hz, 2H), 2.52 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.6, 150.4, 149.2, 149.0, 140.8, 135.6, 135.3, 134.5, 132.2, 128.8, 128.4, 128.2, 125.1, 120.0, 49.8, 41.4, 16.0; MS (ES+) m/z 406.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18](=[O:23])N(OC)C)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][Mg]Br.[Cl-].[NH4+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18](=[O:23])[CH3:24])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)c1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
To 2.30 g (7.18 mmol) 6-(methoxy-methyl-carbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 29a) in 50 mL THF is added under an argon atmosphere at 0° C. 7.18 mL (21.5 mmol; 3 M solution in diethylether) methylmagnesium bromide. The reaction mixture is stirred 1.5 h at −5° C. and is then transferred into a saturated aqueous ammonium chloride solution. The aqueous phase is extracted three times with tert-butylmethylether, dried over MgSO4, filtered and the solvent is evaporated. The residue is purified by silica gel column chromatography with PE/EtOAc (8:2) as eluent.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.[CH3:8][NH:9][C:10]([NH:12][NH2:13])=[S:11].C(O)(=O)C>CO>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:9]([CH3:8])[C:10](=[S:11])[NH:12][N:13]=1
Reactant: O=C1CCCCO1
Reactant: CNC(=S)NN
Solvent: CO
Solvent: CC(=O)O
Product: Cn1c(CCCCO)n[nH]c1=S
Temperature: 120 °C

Procedure:
Tetrahydro-2H-pyran-2-one (2 ml), N-methylhydrazinecarbothioamide (3.4 g) and acetic acid (0.3 ml) were suspended in methanol (10 ml). The reaction was heated in microwave oven at 120° C. for 20′ followed by further 10′ at 110° C. Acetic acid was added (0.3 ml) and reaction was heated in a microwave oven at 140° C. for 20′, further acetic acid (0.3 ml) was added and the reaction was in a microwave oven at 140° C. for 20′. The solvent was removed under reduced pressure, DCM was added to the crude and solid filtered-off. Solvent was removed under reduced pressure to give a crude product that was purified by flash chromatography on silica gel (DCM/MeOH from 0 to 10%) to give the title compound as a white solid (1 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=O.[NH2:9][C:10]1[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=1[CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[N:9][C:10]1[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=1[CH2:12][N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: CN1CCN(C)C1=O
Reactant: Nc1ccccc1CN1CCOCC1
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(C)C1=Nc1ccccc1CN1CCOCC1

Procedure:
A mixture of 1,3-dimethyl-2-imidazolidinone (4.6 g) in benzene (40 ml), 4-(2-aminobenzyl)morpholine (3.8 g) in benzene (20 ml) and phosphorus oxychloride (3.6 ml) was heated at 65°-70° C. for 20 hours to yield 4-[2-(1,3-dimethyl-2-imidazolidinylideneamino)benzyl]morpholine (m.p. 56°-58° C.) which was recrystallised from hexane.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl.[NH2:19][OH:20]>CO>[CH3:1][N:2]([CH3:10])[N:3]1[CH2:8][CH2:7][C:6](=[N:19][OH:20])[CH2:5][CH2:4]1
Reactant: NO
Reactant: CN(C)N1CCC(=O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(C)N1CCC(=NO)CC1
Temperature: 37 °C
Yield: 68.3 %

Procedure:
19.2 g 1-Dimethylamino-piperidin-4-one (prepared as described in Journal of Medicinal & Pharmaceutical Chemistry, 4, 423-36; 1961) and 30 g triethylamine are dissolved in 80 ml methanol. 18.8 g hydroxylamin hydrochloride is added in portions at ambient temperature. The internal temperature raises during the addition to 37° C. Then the mixture is heated to reflux for 3 hours, allowed to cool to room temperature, and then the solvent evaporated. The residue is partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic layer is dried over sodium sulfate, and the solvent evaporated. Thus, 14.5 g 1-Dimethylamino-piperidin-4-one oxime is obtained. 1H-NMR (CDCl3): 8.10 ppm (s, broad, 1H), 2.75 ppm (m, 6H), 2.40 ppm (m, 2H), 2.40 ppm (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=O)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>C(O)C>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[N:14][OH:15])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccc2c(C=O)c[nH]c2c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2c(C=NO)c[nH]c2c1
Reaction time: 3 h
Yield: 91.4 %

Procedure:
To a solution of 6-methyl-1H-indole-3-carbaldehyde (0.96 g, Lit. 20) in ethanol (30 ml) was added at 22° C. hydroxylamine hydrochloride (0.46 g) and sodium acetate (0.54 g) and the mixture was stirred for 3 h. The mixture was evaporated and the residue triturated with water and dichloromethane/n-heptane (1:1) and dried to give the title compound (0.96 g) as a pink solid. MS: 175.3 ([M+H]+).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[NH:9]1[CH:13]=[N:12][CH:11]=[N:10]1.Br[CH:15](Br)[C:16](=[O:22])[C:17]([O:20][CH3:21])([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:15]([N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)[C:16](=[O:22])[C:17]([O:20][CH3:21])([CH3:19])[CH3:18])=[CH:4][CH:3]=1
Reactant: COC(C)(C)C(=O)C(Br)Br
Reactant: Oc1ccc(I)cc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(C)(C)C(=O)C(Oc1ccc(I)cc1)n1cncn1
Reaction time: 4 h
Yield: 44.3 %

Procedure:
A mixture of 9.9 g (0.045 mole) of 4-iodophenol, 3.45 g (0.05 mole) of 1H-1,2,4-triazole, 12.33 g (0.045 mole) of 1,1-dibromo-3-methoxy-3-methyl-2-butanone, and 14 g (0.101 mole) of potassium carbonate in 200 ml of acetone was heated at boiling temperature (reflux) with stirring for 4 hours. After evaporating the solvent, 400 ml of 5% NaOH solution was added and the mixture extracted with diethyl ether. The ether phase was dried using MgSO4 and the solvent evaporated. The residual yellow oil was purified by high pressure liquid chromatography (silica gel, 8:2 hexane/acetone). Recrystallization from hexane-ether gave 8.0 g (44% yield) of 1-(4-iodophenoxy)-1-(1H-1,2,4-triazol-1-yl)-3-methoxy-3-methyl-2-butanone, m.p. 81.5°-82.5° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[CH2:10])=[N:7][CH:8]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[CH3:21])[NH2:17].O.[OH-].[Cs+]>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:13][C:14]1[CH:15]=[C:16]([NH:17][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:11])[F:12])=[CH:8][N:7]=2)[CH:18]=[CH:19][C:20]=1[CH3:21]
Reactant: C=Cc1ccc(C(F)(F)F)cn1
Reactant: Cc1ccc(N)cc1C
Agent: [Cs+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(NCCc2ccc(C(F)(F)F)cn2)cc1C
Temperature: 120 °C
Yield: 62.8 %

Procedure:
A mixture of 200 mg (0.92 mmol) 5-trifluoromethyl-2-vinyl-pyridine (CAS: 204569-89-1), 570 mg (4.62 mmol) 3,4-dimethylaniline and 33 mg (0.18 mmol) cesium hydroxide monohydrate in 2 mL NMP was heated in a 120° C. oil-bath for 22 hours. The mixture was cooled to room temperature and diluted with ethyl acetate. The solution was washed 3 times with water, dried over Na2SO4, filtered and concentrated in vacuo. The crude oil was purified with flash column chromatography on silica eluting with a gradient formed from heptane and ethylacetate to provide 0.17 g (63%) of the title compound as a light yellow oil. MS (m/e): 295.2 [M+H]+.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22](O)=[O:23])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:23])[N:20]=2)=[CH:12]3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1COCCN1
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1
Product: O=C(C[C@@H]1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1)N1CCOCC1
Yield: 16 %

Procedure:
The compound (97 mg, 0.28 mmol) prepared in Example 42 and morpholine instead of ethylamine were reacted according to the same procedure as Example 89 to give the title compound (19 mg, Yield 16%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[S:9][C:10]([NH2:12])=[N:11][C:6]2=[CH:5][CH:4]=1.[C:13]([N:16]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH2:30][CH3:31])[CH:27]=3)[N:22]([C:32](=[O:37])C(F)(F)F)[CH2:21]2)[CH2:17]1)(=[O:15])[CH3:14]>>[C:13]([N:16]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH2:30][CH3:31])[CH:27]=3)[N:22]([C:32]([NH:12][C:10]3[S:9][C:7]4[C:6]([N:11]=3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=4)=[O:37])[CH2:21]2)[CH2:17]1)(=[O:15])[CH3:14]
Reactant: COc1ccc2nc(N)sc2n1
Reactant: CCOc1ccc2c(c1)C1(CCN(C(C)=O)C1)CN2C(=O)C(F)(F)F
Product: CCOc1ccc2c(c1)C1(CCN(C(C)=O)C1)CN2C(=O)Nc1nc2ccc(OC)nc2s1

Procedure:
The captioned compound was obtained in the form of a reddish brown solid by performing the same reactions and/or treatments as those in Step 4 of Example 198, with the exceptions that 5-methoxythiazolo[5,4-b]pyridin-2-amine was used instead of the 2-amino-5-chlorothiazole hydrochloride in Example 1, which was cited in Example 57, and that 1-(1′-acetyl-5-ethoxyspiro[indoline-3,3′-pyrrolidin]-1-yl)-2,2,2-trifluoroethanone was used instead of 1-(1′-acetyl-5-(4-fluorophenoxy)phenoxyspiro[indoline-3,3′-pyrrolidin]-1-yl)-2,2,2-trifluoroethanone.
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:17])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([CH3:14])[C:7]=1[O:15][CH3:16])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]C(C)(C)C.[CH2:31]1[O:34][CH:32]1[CH3:33]>C1COCC1.CCCCCC.O>[OH:34][CH:32]([CH3:33])[CH2:31][C:11]1[C:6]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:17])=[C:7]([O:15][CH3:16])[C:8]([CH3:14])=[C:9]([O:12][CH3:13])[CH:10]=1
Reactant: CC1CO1
Reactant: COc1ccc(C(=O)NC(C)C)c(OC)c1C
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COc1cc(CC(C)O)c(C(=O)NC(C)C)c(OC)c1C
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
4.74 g (20 mmol, 1 eq.) of amide (IX) and 6.1 mL (40 mmol, 2 eq.) of TMEDA are dissolved in 200 mL of THF in a dried round-bottomed flask under argon. The medium is then placed at −78° C. 33.9 mL (44 mmol, 2.2 eq.) of t-BuLi (1.3M as a solution in hexane) are then added and the solution is immediately warmed to −15° C. Once the red/orange coloration has appeared, the medium is cooled to −78° C. 1.43 mL (20 mmol, 1 eq.) of propylene oxide are then added dropwise. Once the addition is complete, the medium is warmed rapidly to −10° C. The solution is then slowly warmed to room temperature over 1 hour 30 minutes. A second addition of propylene oxide (1 eq.) is made if necessary (monitoring of the conversion by TLC). After 30 minutes, the reaction is hydrolyzed by addition of 100 mL of water.
Reaction SMILES: [OH:1][C:2]1[CH:6]([CH:7]([CH3:9])[CH3:8])[NH:5][C:4](=[O:10])[CH:3]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][CH2:29][NH:30][C:31](=[O:46])[C:32]2[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=2)=[CH:20]1>>[OH:1][C:2]1[CH:6]([CH:7]([CH3:9])[CH3:8])[NH:5][C:4](=[O:10])[C:3]=1[CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:20]1[NH:19][C:27]2[C:22]([C:21]=1[CH2:28][CH2:29][NH:30][C:31](=[O:46])[C:32]1[CH:33]=[C:34]([C:42]([F:43])([F:44])[F:45])[CH:35]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:37]=1)=[CH:23][CH:24]=[CH:25][CH:26]=2
Reactant: CC(C)C1NC(=O)C=C1O
Reactant: O=C(NCCc1c[nH]c2ccccc12)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=Cc1ccccc1
Product: CC(C)C1NC(=O)C(C(c2ccccc2)c2[nH]c3ccccc3c2CCNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)=C1O

Procedure:
Using general procedure C, 4-hydroxy-5-isopropyl-1,5-dihydro-pyrrol-2-one (Lit. 11) was reacted with benzaldehyde and N-[2-(1H-Indol-3-yl)-ethyl]-3,5-bis-trifluoromethyl-benzamide to give N-(2-{2-[(4-hydroxy-5-isopropyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-phenyl-methyl]-1H-indol-3-yl}-ethyl)-3,5-bis-trifluoromethyl-benzamide as a red solid. MS: 630.2 ([M+H]+).
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=[CH:15][C:16]([OH:18])=O)[CH:9]=1.C(Cl)(=O)C([Cl:22])=O>ClCCl>[ClH:22].[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=[CH:15][C:16]([Cl:22])=[O:18])[CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C=Cc1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cl
Product: O=C(Cl)C=Cc1cccnc1
Reaction time: 0.5 h

Procedure:
Triethylamine (0.5 ml) was added dropwise to a suspension of 3-pyridin-3-ylacrylic acid (5.0 g) in anhydrous dichloromethane (30 ml), and 6 ml of oxalyl chloride was added dropwise slowly in an ice-bath with the temperature no more than 5° C. After addition, the reaction was carried out for 30 min in an ice-bath, and then at room temperature overnight. The completion of reaction was indicated by TLC. The reaction mixture was concentrated under reduced pressure to give a white solid, which was left to stand at room temperature for 1 h, and used directly for the next step.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[N:19]=[CH:20][N:21]4[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[C:22]=34)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])[CH3:5].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[N:19]=[CH:20][N:21]4[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[C:22]=34)[N:16]=2)[NH:11][CH:10]=1)=[O:8])[CH3:5]
Reactant: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3ncn4cc(F)cc(F)c34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: COC[C@H](C)NC(=O)c1c[nH]c2ncc(-c3ncn4cc(F)cc(F)c34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
In a round-bottomed flask, 2-(6,8-difluoro-imidazo[1,5-a]pyridin-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide (134 mg, 0.25 mmol) was dissolved in dichloromethane (1.2 ml) and trifluoroacetic acid (0.75 ml, 9.8 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (1.2 ml) and ethylenediamine (1.0 ml, 14.8 mmol) was added. The yellow solution was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 74 mg (78%) of 2-(6,8-difluoro-imidazo[1,5-a]pyridin-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as a yellow powder. MS: (M+H)+=387; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.14 (br. s., 1H), 9.03 (s, 1H), 8.70 (d, J=1.9 Hz, 1H), 8.63 (dd, J=4.2, 1.9 Hz, 1H), 8.37 (s, 1H), 8.29 (d, J=8.3 Hz, 1H), 7.24-7.36 (m, 1H), 4.32 (dt, J=13.2, 6.6 Hz, 1H), 3.42-3.51 (m, 1H), 3.35-3.41 (m, 1H), 3.25 (s, 3H), 1.24 (d, J=6.8 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[N:11]([CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:13][CH:14]=1.[CH3:19][N:20]1[C:24]([CH3:25])=[C:23]([C:26](O)=[O:27])[C:22](=[O:29])[N:21]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:26]([C:23]2[C:22](=[O:29])[N:21]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:20]([CH3:19])[C:24]=2[CH3:25])=[O:27])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[N:11]([CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:13][CH:14]=1
Reactant: Nc1ccc(Oc2ccnn3cccc23)c(F)c1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnn4cccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 50 °C
Yield: 29.2 %

Procedure:
To a solution of 3-fluoro-4-(pyrrolo[1,2-b]pyridazin-4-yloxy)-phenylamine (50 mg, 0.206 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (32 mg, 0.137 mmol) dissolved in dimethylformamide (3 mL), HATU (78 mg, 0.206 mmol) and triethylamine (0.05 mL, 0.343 mmol) were sequentially added and heated at 50° C. for 7 hours. The resulting mixture was concentrated and the resulting residue was extracted with dichloromethane and water. After phase separation, the organic layer was washed with sodium chloride aqueous solution, dried with magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:hexane=1:3) to give the target compound as a white solid (16 mg, 0.04 mmol, 25% yield).
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5](=[O:27])[CH:6]([NH:15][C:16]([CH3:26])=[CH:17][C:18](=[O:25])[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Br:28][CH2:29][CH2:30]Br>C(O)C>[CH3:3][O:4][C:5](=[O:27])[CH:6]([NH:15][C:16]([CH3:26])=[CH:17][C:18](=[O:25])[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:30][CH2:29][Br:28])=[CH:10][CH:9]=1
Reactant: BrCCBr
Reactant: COC(=O)C(Cc1ccc(O)cc1)NC(C)=CC(=O)c1cccnc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C(Cc1ccc(OCCBr)cc1)NC(C)=CC(=O)c1cccnc1
Yield: 15.2 %

Procedure:
To a solution of potassium hydroxide (0.17 g, 2.95 mmol) in ethanol (20 ml) is added 2-[1-methyl-3-oxo-3-(3-pyridyl)-propenylamino]-3-(4-hydroxyphenyl)-propionic acid methyl ester (1.00 g, 2.95 mmol) and 1,2-dibromoethane (5.54 g, 29.50 mmol). Then the mixture is heated to reflux for 8 hours. After cooled, the reaction mixture is filtered to remove the solid formed, and then the filtrate is evaporated under a vacuum. The crude product is purified by silica gel chromatography using hexane/EtOAc (4:1) as eluent to give the title compound (0.20 g, 15%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10](Cl)=O.[S-:13][C:14]#[N:15].[NH4+].CC(C)=[O:19]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9](=[O:19])[CH2:10][N:15]=[C:14]=[S:13]
Reactant: O=C(Cl)Cc1c(Cl)cccc1Cl
Reactant: N#C[S-]
Reactant: CC(C)=O
Agent: [NH4+]
Product: O=C(CN=C=S)c1c(Cl)cccc1Cl

Procedure:
40.26 g (0.18 mol) of (2,6-dichlorophenyl)acetyl chloride and 15 g (0.198 mol) of ammonium thiocyanate are heated for about 10 minutes in 500 ml of acetone. The cooled mixture is filtered, the solid is washed with acetone and the filtrate is evaporated to dryness. Dry ether is added to the oily residue. A yellow crystalline solid is formed and is filtered off. The filtrate is evaporated to dryness. 2,6-Dichlorophenacyl isothiocyanate is obtained in the form of an orange-red oil.
Reaction SMILES: [CH3:1][C@H:2]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH2:4][C@H:3]1[OH:16].[Li]CCCC.[I-].C[CH:24]=[N+:25]=[CH:26]C.[C:28]([O-])(O)=O.[Na+]>C1COCC1.C(Cl)Cl.CO>[CH3:24][N:25]([CH2:26][C@H:4]1[CH:5]=[C:6]([S:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:8][C@H:2]([CH3:1])[C@@H:3]1[OH:16])[CH3:28]
Reactant: O=C([O-])O
Reactant: C[C@H]1C=CC(Sc2ccccc2)=CC[C@H]1O
Reactant: CC=[N+]=CC
Agent: [I-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: C[C@H]1C=CC(Sc2ccccc2)=C[C@H](CN(C)C)[C@H]1O
Temperature: -7 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A solution of alcohol 29 (80 mg, 0.34 mmol) in THF (4 mL) was cooled to −78° C., and 0.30 mL of n-BuLi (2.5M in hexanes, 0.75 mmol) was added dropwise via syringe. This mixture was brought to −7° C. over 1 h, and stirred at −7° C. for 10 min, then cooled to −78° C., and transferred to a flask containing N,N-dimethylmethyleneammonium iodide (Eschenmoser's salt, 160 mg, 0.86 mmol) in THF (4 mL) via cannula. The resulting suspension was warmed to room temperature over 2 h, then saturated aqueous NaHCO3 (5 mL) was added, the organic layer was separated, and the aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine, and dried (Na2SO4). Flash column chromatography (CH2Cl2/MeOH; 10:1) afforded 58 mg (58% yield) of 34 as a light yellow oil. 1H NMR (CDCl3, 300 MHz) δ 7.20-7.38 (m, 5H), 6.11 (dd, J=10.5 Hz, 6.3 Hz, 1H), 5.89-5.96 (m, 2H), 4.20 (dd, J=8.4 Hz, 4.2 Hz, 1H), 2.79 (t, J=12.6 Hz, 1H), 2.45-2.55 (m, 3H), 2.31 (s, 6H), 2.24-2.28 (m, 1H), 1.19 (d, J=7.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 142.0, 135.6, 134.5, 133.7, 130.3, 129.5, 129.1, 126.9, 89.3, 64.9, 45.9, 43.5, 39.4, 23.9, 14.6.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([F:17])=[CH:12][CH:11]=3)[C:5]([OH:18])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[O:28](S(C(F)(F)F)(=O)=O)[S:29]([C:32]([F:35])([F:34])[F:33])(=O)=[O:30]>C(Cl)Cl.O>[F:33][C:32]([F:35])([F:34])[S:29]([O:18][C:5]1[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([F:17])=[CH:12][CH:11]=3)=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:30])=[O:28]
Reactant: Oc1ccc(Cl)nc1-c1cc2cc(F)ccc2[nH]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(Oc1ccc(Cl)nc1-c1cc2cc(F)ccc2[nH]1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
To a degassed solution of 6-chloro-2-(5-fluoro-1H-indol-2-yl)pyridin-3-ol (600 mg, 2.28 mmol) and DIPEA (1.0 g, 7.74 mmol) in DCM (10 mL), Tf2O (1.3 g, 4.61 mmol) were added dropwise under N2 at 0° C. The mixture was stirred at RT for 2 hours. The mixture was diluted with water and extracted with DCM. The organic layers were washed with brine, dried over Na2SO4, and concentrated. The mixture was purified by column chromatography (PE:EA=10:1) to give 6-chloro-2-(5-fluoro-1H-indol-2-yl)pyridin-3-yl trifluoromethanesulfonate (700 mg, yield: 77.6%). 1H-NMR (DMSO-d6, 400 MHz) δ 11.91 (br s, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.51˜7.58 (m, 1H), 7.42˜7.50 (m, 1H), 7.18 (d, J=1.6 Hz, 1H), 7.06˜7.14 (m, 1H). MS (M+H)+: 395/397.