Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]([CH:35](OC)OC)[CH2:10][CH2:11][CH2:12][C:13]2[CH:34]=[CH:33][C:16]([C:17]([NH:19][C@H:20]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:18])=[CH:15][CH:14]=2)=[C:4]([NH2:40])[N:3]=1.Cl.[NH3:42]>C(O)C.O>[NH2:42][C:2]1[N:7]=[C:6]([NH2:8])[C:5]2[C:9]([CH2:10][CH2:11][CH2:12][C:13]3[CH:34]=[CH:33][C:16]([C:17]([NH:19][C@H:20]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:18])=[CH:15][CH:14]=3)=[CH:35][NH:40][C:4]=2[N:3]=1
Reactant: N
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCCC(c2c(N)nc(N)nc2N)C(OC)OC)cc1)C(=O)OCC
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCCc2c[nH]c3nc(N)nc(N)c23)cc1)C(=O)OCC
Temperature: 25 °C

Procedure:
To a suspension of the product of Example 17 (100 mg) in ethyl alcohol (2.0 ml), ethyl alcohol containing 20% (w/w) of hydrogen chloride (2.0 ml) and water (0.02 ml) were added and the mixture was heated at room temperature for 2 hours. The reaction mixture was diluted with water (10 ml), and neutralized by adding aqueous ammonia thereto, followed by removing solvent therefrom by distillation under reduced pressure. The resulting residue was purified by column chromatography (15 g of silica gel; dichloromethane separated from conc. ammonia→dichloromethane separated from conc. ammonia-ethanol=40:1→30:1) to give the subject compound (68 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: C1CCNC1
Product: O=C(c1ccc2cc(O)ccc2c1)N1CCCC1

Procedure:
The title compound was synthesised from 6-hydroxy-2-naphtoic acid (commercially available) and pyrrolidine (commercially available) according to the procedure described for Example A. MS (m/e): 240.4 (MH−, 100%)
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][O:1][C:2]2[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[O:13][CH3:14])=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Reactant: Fc1ccc(CBr)cc1
Product: COc1cc(C(=O)O)ccc1OCc1ccc(F)cc1
Yield: 96.5 %

Procedure:
In a manner identical to Reference Example 4, ethyl 4-hydroxy-3-methoxybenzoate (4.10 g) was benzylated with 4-fluorobenzyl bromide (4.35 g) and then hydrolyzed to yield 5.57 g of 4-(4-fluorobenzyloxy)-3-methoxybenzoic acid. In a manner similar to Example 8, this material (1.38 g) were subjected to a condensation reaction with 1-isobutylpiperazine dihydrochloride (1.08 g), thereby yielding 2.24 g of 1-[4-(4-fluorobenzyloxy)-3-methoxybenzoyl]-4-isobutyl piperazine. This material was dissolved in diethyl ether (50 ml) and then 1N hydrogen chloride ether solution (10 ml) was added thereto. The mixture was stirred at room temperature for 10 minutes and then the resulting crystals were collected by filtration and recrystallized (from n-hexane/ethanol), thereby yielding 1.60 g of the aimed compound.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C@@H:6]([NH:9]C(=O)C2C=CC=CC=2)[C@@H:5]([F:18])[CH2:4]1)[CH3:2].[ClH:19]>>[ClH:19].[ClH:19].[CH2:1]([N:3]1[CH2:8][CH2:7][C@@H:6]([NH2:9])[C@@H:5]([F:18])[CH2:4]1)[CH3:2]
Reactant: CCN1CC[C@@H](NC(=O)c2ccccc2)[C@@H](F)C1
Agent: Cl
Product: CCN1CC[C@@H](N)[C@@H](F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A solution of N-((3S,4R)-1-ethyl-3-fluoropiperidin-4-yl)benzamide (6.58 kg, 24.16 mol) in aqueous hydrochloric acid (35 L, 209 mol) was heated to 130° C. external temperature for 10 hours then was allowed to stand overnight at room temperature. The precipitated solid was filtered off and washed with water (2 L). The filtrate was concentrated, and ethanol (20 L) was added at 60° C. The solution was slowly cooled to room temperature overnight, crystallization occurred, and the yellow suspension was cooled to 0° C. for 1 h, filtered over a glass frit, washed with chilled ethanol (10 L, 0° C.), and diethyl ether (5 L). The tan solid was removed from the filter and dried in vacuum oven to yield 4.70 kg of (3S,4R)-1-ethyl-3-fluoropiperidin-4-amine dihydrochloride (85%). 1H NMR (400 MHz, MeOD) δ 5.35 (d, J=47.2 Hz, 1H), 4.32-3.43 (m, 4H), 3.32 (s, 3H), 2.32 (s, 2H), 1.40 (s, 3H), 1.16 (d, J=6.1 Hz, 2H).
Reaction SMILES: [H-].[Na+].O1CCOCC1.[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].[F:17][C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([F:29])[C:27]=1F)[N:24]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[CH:23]=[C:22]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:21]2=[O:42]>O>[C:9]([CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:27]1[C:26]([F:29])=[C:25]2[C:20]([C:21](=[O:42])[C:22]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:23][N:24]2[C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)=[CH:19][C:18]=1[F:17])#[N:10]
Reactant: CCOC(=O)CC#N
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2c(F)c(C(C#N)C(=O)OCC)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.12 g of sodium hydride are initially introduced into 15 ml of dioxane. 0.51 g of ethyl cyanoacetate is added and the mixture is first stirred for one hour at room temperature. 1.1 g of ethyl 6,7,8-trifluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinoline-carboxylate are then added in portions. The mixture is boiled for 3 hours, diluted using water and acidified. It is extracted using methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[C:4]([CH3:10])[CH:3]=1.[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH2:17]([O:16][C:11](=[O:15])[C:12](=[N:9][NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[CH3:10])[CH3:14])[CH3:18]
Reactant: Cc1cc(Cl)ccc1NN
Reactant: CCOC(=O)C(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C(C)=NNc1ccc(Cl)cc1C
Temperature: 35 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To a stirred solution of 0.55 g (2.85 mmol) of (4-chloro-2-methyl-phenyl)-hydrazine, in acetic acid (5 ml), was added 0.34 g (2.91 mmol) of ethyl pyruvate. The mixture was stirred 2 hours at 35° C., poured onto an aqueous solution of sat. NaHCO3 and then extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo, to afford 0.702 g (97%) of 2-[(4-chloro-2-methyl-phenyl)-hydrazono]-propionic acid ethyl ester as a light orange solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([N:19]=[O:20])[C:5]([NH:7][CH2:8][CH2:9][O:10]C(C1C=NC=CC=1)=O)=[O:6].[I-:21].[O:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[I-:21].[Cl:1][CH2:2][CH2:3][N:4]([N:19]=[O:20])[C:5]([NH:7][CH2:8][CH2:9][O:10][C:26]([CH:25]1[CH2+:24]=[CH:23][CH:2]=[CH:3][N:4]1[CH3:5])=[O:22])=[O:6]
Reactant: O=NN(CCCl)C(=O)NCCOC(=O)c1cccnc1
Reactant: C1CCOC1
Agent: [I-]
Product: CN1C=CC=[CH2+]C1C(=O)OCCNC(=O)N(CCCl)N=O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A solution of the product of Example 122 (1.5 g, 5 mmol) in 40 mL of tetrahydrofuran was treated with excess iodide. The mixture was stirred at 50° C. for 4 hours. The finely crystalline, yellow solid thus obtained (1.8 g, 82%) melted at 120°-121° C. and had the structure ##STR153## as confirmed by elemental analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@H:12]([OH:21])[CH:11]=[CH:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([O:21][C@@H:12]1[CH:11]=[CH:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C:18]1[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:6][CH2:7]3)(=[O:24])[CH3:23]
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@H](O)C=C[C@@H]12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@H](OC(C)=O)C=C[C@@H]12

Procedure:
200 mg. of 3-methoxy-1,3,5(10),15-estratetraen-17α-ol is agitated for 3 hours in 2.5 ml. of pyridine with 0.5 ml. of acetic anhydride. After the product has been worked up as described in Example 4 and purified by preparative layer chromatography (eluent: hexane/ethyl acetate = 7 : 3), 170 mg. of 17α-acetoxy-3-methoxy-1,3,5(10),15-estratetraene is isolated as an oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([OH:25])[CH2:23][CH3:24])[C:17]=3[N:13]2[CH2:12][CH2:11][CH2:10]1.[H-].[Na+].[CH3:28][O:29][CH2:30][CH2:31]Br>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([O:25][CH2:31][CH2:30][O:29][CH3:28])[CH2:23][CH3:24])[C:17]=3[N:13]2[CH2:12][CH2:11][CH2:10]1
Reactant: COCCBr
Reactant: CCC(O)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(OCCOC)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-[1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (300 mg, 0.797 mmol) in N,N-dimethylformamide (3.0 mL) was added sodium hydride (60% in oil, 35.0 mg, 0.877 mmol), and the mixture was stirred at room temperature for 10 min. To the mixture was added 2-bromoethyl methyl ether (166 mg, 1.19 mmol), and the mixture was stirred at room temperature for 3 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a colorless amorphous (218 mg, 0.502 mmol, 63%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[NH:3]1.Br[C:20]1[S:21][CH:22]=[C:23]([Br:25])[N:24]=1>>[C:11]([O:10][C:8](=[O:9])[CH2:7][N:6]1[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]([C:20]2[S:21][CH:22]=[C:23]([Br:25])[N:24]=2)[C:2]1=[O:1])([CH3:14])([CH3:13])[CH3:12]
Reactant: Brc1csc(Br)n1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc21
Product: CC(C)(C)OC(=O)Cn1c(=O)n(-c2nc(Br)cs2)c2ccccc21

Procedure:
Essentially following the procedures described for Intermediate 7, but using 2,4-dibromothiazole in place of 2-bromopyridine, the title compound was prepared. MS: m/z=412 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:24][CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][NH:29][C:28]2=[O:32])=[O:21])=[CH:17][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NCCN1CCNC1=O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCCN2CCNC2=O)cn1
Yield: 64 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using (1-(2-aminoethyl)imidazolidin-2-one instead of 2-aminoethyl isopropylether, to the title compound (175 mg, 64%) which was obtained as a white solid. MS: m/e=422.1 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH:19]([C:22]1[N:26]=[C:25]([C:27](O)=[O:28])[O:24][N:23]=1)([CH3:21])[CH3:20].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:27]([C:25]3[O:24][N:23]=[C:22]([CH:19]([CH3:21])[CH3:20])[N:26]=3)=[O:28])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: CC(C)c1noc(C(=O)O)n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1noc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)n1

Procedure:
The title compound was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.33 g, 1.28 mmol), 3-isopropyl-1,2,4-oxadiazole-5-carboxylic acid (0.2 g, 1.28 mmol), HOBt (0.26 g, 1.92 mmol), DIPEA (0.7 mL, 3.84 mmol) and EDCI (0.37 g, 1.92 mmol) using DMF (10 mL) as solvent. Yield 0.197 g. 1H NMR (400 MHz; MeOD): δ 1.24 (d, 3H), 1.33 (d, 6H), 3.15 (m, 1H), 4.38 (m, 2H), 4.57 (m, 1H), 6.78 (d, 1H), 7.71 (d, 1H), 7.77 (m, 1H), 7.87 (dd, 1H), 8.02 (dd, 1H).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:31]2[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[F:21])[CH2:33][CH2:32]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: Cc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(c4ccccc4F)CC3)nn2C(C)(C)C)cc1

Procedure:
79 mg (76%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (60 mg, 0.222 mmol), 1-(2-fluorophenyl)piperazine (40 mg, 0.222 mmol), DIPEA (0.06 mL, 0.333 mmol) and NaBH(OAc)3 (141 mg, 0.666 mmol).
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([N:29]3[CH2:35][CH2:34][CH2:33][N:32]([CH3:36])[CH2:31][CH2:30]3)=[O:28])[CH2:10]2)=CC=1.FC(F)(F)C(O)=O.[F:46][C:47]([F:53])([F:52])[S:48]([OH:51])(=[O:50])=[O:49]>C1(OC)C=CC=CC=1>[F:46][C:47]([F:53])([F:52])[S:48]([OH:51])(=[O:50])=[O:49].[F:46][C:47]([F:53])([F:52])[S:48]([OH:51])(=[O:50])=[O:49].[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([C:27]([N:29]2[CH2:35][CH2:34][CH2:33][N:32]([CH3:36])[CH2:31][CH2:30]2)=[O:28])[CH2:10]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCCN(C)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
620 mg of (2S, 4S)-4-(4-methoxybenzylthio)-2-(4-methyl-1-homopiperazinylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 5) were suspended in 1.23 ml of anisole, and the suspension was placed on an ice bath. Whilst the suspension was still on the ice bath, 6.2 ml of trifluoroacetic acid and 200 μl of trifluoromethanesulfonic acid were added to it, and the resulting mixture was stirred for 1 hour at room temperature. At the end of this time, the mixture was treated in a similar manner to that described in Example 1(1), to give 640 mg of the title compound.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH:11](B1OB(C=C)OB(C=C)O1)=[CH2:12].N1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:11]([C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)=[CH2:12]
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: CC(=O)c1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: c1ccncc1
Product: C=Cc1ccc(C(C)=O)cn1
Temperature: 115 °C

Procedure:
The reaction mixture of 1-(6-bromopyridin-3-yl)ethanone (0.68 g, 3.41 mmol), 2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane:pyridine (1:1) (0.57 g, 2.39 mmol), potassium carbonate (0.85 g, 6.14 mmol), and Pd(Ph3P)4 (0.16 g, 0.14 mmol) in acetonitrile (10 mL) was degassed with argon for 5 minutes. Then it was heated in the microwave for 30 min at 115° C. The organic phase was removed using a pipette, dried (MgSO4), filtered and concentrated and purified by flash chromatography (SiO2; heptane/EtOAc, gradient 20-80%). Yield: 0.36 g (72%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][C:15]2[C:16]3[N:17]([CH:31]=[CH:32][N:33]=3)[N:18]=[C:19]([C:21]3[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=3)[C:24]([O:26]C)=[O:25])[CH:20]=2)[CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>O1CCOCC1.O>[OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][C:15]2[C:16]3[N:17]([CH:31]=[CH:32][N:33]=3)[N:18]=[C:19]([C:21]3[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=3)[C:24]([OH:26])=[O:25])[CH:20]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1cccc(-c2cc(Nc3cccc(N4CCCC4CO)n3)c3nccn3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccc(-c2cc(Nc3cccc(N4CCCC4CO)n3)c3nccn3n2)c1
Temperature: 40 °C
Reaction time: 4 h
Yield: 53.6 %

Procedure:
To a solution of methyl 3-(8-(6-(2-(hydroxymethyl)pyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (185 mg, 0.416 mmol) in dioxane (5 mL) and water (4.5 mL) was added NaOH (167 mg, 4.16 mmol), then the mixture was heated to 40° C. with stirring for 4 h. The solution was concentrated in vacuo then water (10 mL) was added and the solution was washed with dichloromethane (10 mL×3). The aqueous layer was adjusted to pH=4 by addition of concentrated HCl. The solid formed was filtered to give 3-(8-(6-(2-(hydroxymethyl)pyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (0.096 g, 54%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.84 (s, 1H), 9.19 (s, 1H), 8.60 (s, 1H), 8.51 (s, 1H), 8.31 (s, 1H), 8.23 (d, 1H, J=7.5 Hz), 8.13 (d, 1H, J=7.5 Hz), 7.71 (t, 1H, J=7.8 Hz), 7.53 (t, 1H, J=7.8 Hz), 6.72 (d, 1H, J=7.5 Hz), 6.27 (d, 1H, J=8.1 Hz), 3.96 (brs, 2H), 3.61 (brs, 1H), 3.46-3.37 (m, 2H), 2.07-1.95 (m, 4 h). LC-MS: [M+H]+, 431, tR=1.459 min, HPLC: 99.27% at 214 nm, 99.49% at 254 nm, tR=5.08 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:10]2=[N:11][C:12]([Sn](C)(C)C)=[CH:13][N:14]=[C:9]2[NH:8][CH2:7][C:6]1=[O:19].Br[C:21]1[C:22]([CH3:38])=[N:23][C:24]([C:27]2[N:31]=[CH:30][N:29](C3CCCCO3)[N:28]=2)=[CH:25][CH:26]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:10]2=[N:11][C:12]([C:21]3[C:22]([CH3:38])=[N:23][C:24]([C:27]4[NH:31][CH:30]=[N:29][N:28]=4)=[CH:25][CH:26]=3)=[CH:13][N:14]=[C:9]2[NH:8][CH2:7][C:6]1=[O:19]
Reactant: COCCN1C(=O)CNc2ncc([Sn](C)(C)C)nc21
Reactant: Cc1nc(-c2ncn(C3CCCCO3)n2)ccc1Br
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCN1C(=O)CNc2ncc(-c3ccc(-c4nnc[nH]4)nc3C)nc21
Temperature: 130 °C
Reaction time: 3 h
Yield: 10.1 %

Procedure:
1-(2-Methoxyethyl)-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.5 g, 1.348 mmol), 3-bromo-2-methyl-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)pyridine (0.436 g, 1.348 mmol), tris(dibenzylidineacetone)dipalladium(0) (0.123 g, 0.135 mmol), tri-o-tolylphosphine (0.082 g, 0.270 mmol), triethylamine (0.584 mL, 4.04 mmol) and N,N-dimethylformamide (10 mL) were combined in a 75 mL sealable flask, the atmosphere in the flask was removed and replaced with nitrogen. The mixture was stirred at 130° C. for 3 h. The resulting mixture was cooled to room temperature and filtered. The organic layer was concentrated under reduced pressure. The resulting residue was diluted with methanol and dimethylsulfoxide, filtered and purified using reverse-phase preparatory HPLC (10-30% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min). Fractions containing clean product were passed through a Phenomenex Strata-X—C solid phase extraction column. The column was washed successively with water, acetonitrile, methanol and 5% ammonium hydroxide in methanol. The product eluted with the 5% ammonium hydroxide in methanol eluent and was concentrated under reduced pressure. The residue was triturated with ethyl ether in hexane to make a fine powder and dried under vacuum at 50° C. to give the desired product (0.05 g, 0.136 mmol, 10% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.10 (br. s., 1H), 7.98 (br. s., 1H), 7.94 (s, 1H), 7.73 (br. s., 1H), 4.13-4.28 (m, 4H), 3.55 (t, J=6.25 Hz, 2H), 3.24 (s, 3H), 2.70 (br. s., 3H); MS (ESI) m/z 367.2[M+1]+.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([O:23][CH3:24])[CH:14]=1)OC1C=CC=CC=1)#[N:2].[CH:25]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26]1.C(N(CC)CC)C>C(#N)C>[C:1]([NH:3][C:4]([NH:30][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)=[N:12][C:13]1[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[C:15]([O:23][CH3:24])[CH:14]=1)#[N:2]
Reactant: COc1cc(N=C(NC#N)Oc2ccccc2)cc(C(F)(F)F)c1
Reactant: NC1CCCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(N=C(NC#N)NC2CCCC2)cc(C(F)(F)F)c1
Temperature: 75 °C
Reaction time: 19 h
Yield: 64.8 %

Procedure:
To a solution of N-Cyano-N'-(3-methoxy-5-trifluoromethyl-phenyl)-O-phenylisourea (0.52 mmol, 175 mg) in dry acetonitrile (1 ml), cyclopentylamine (1.04 mmol, 0.113 ml) and triethylamine (0.080 ml) were added. The mixture was stirred for 19 h at 75° C. under nitrogen. After concentration the residue was dissolved in dichloromethane, washed with 1 N aqueous HCl (2×), water, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (ethyl acetate/heptane 1:2) to give a syrup. Crystallisation from ethyl acetate/heptane 1:4 gave grey crystals (110 mg, 65%). Mp 101-102° C.; 1H-NMR (CDCl3): δ 1.40 (m, 2H), 1.65 (m, 4H), 2.02 (m, 2H), 4.13 (sextet, 1H), 5.05 (br, 1H), 6.96 (s, 1H), 7.00 (s, 1H), 7.03 (s, 1H), 8.15 ppm (br, 1H); EI SP/MS: 326 (M+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[CH3:35][C:36]1([NH2:40])[CH2:39][O:38][CH2:37]1>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:40][C:36]5([CH3:35])[CH2:39][O:38][CH2:37]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Reactant: CC1(N)COC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C)COC4)c3n2)c2ccc(F)cc21
Reaction time: 16 h
Yield: 38.7 %

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (105 mg, 0.34 mmol) in 6 mL of DMF were added EDCI (128 mmol, 0.67 mmol), DMAP (82 mg, 0.67 mmol) and 3-methyloxetan-3-amine (44 mg, 0.50 mmol) in one portion at room temperature. Then the mixture was stirred for 16 hours. The solvent was evaporated at 70° C. under reduced pressure and the residue was triturated with water (10 mL), dichloromethane (10 mL), methanol (15 mL) then decanted and dried to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-(3-methyloxetan-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (50 mg, 38.9%) as a yellow solid. MS: (M+H)+=381; 1H NMR (300 MHz, DMSO): δ 12.90 (brs, 1H), 9.13 (s, 1H), 8.53-8.47 (m, 3H), 7.72 (d, 1H, J=7.8 Hz), 7.26-7.21 (m, 1H), 4.91 (d, 2H, J=6.0 Hz), 4.55 (d, 2H, J=6.3 Hz), 4.18 (s, 3H), 1.77 (s, 3H).