Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[C:8]([Cl:30])[CH:7]=1)C.[OH-].[Na+]>C1COCC1.C(O)C>[Br:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([C:23]2[CH:24]=[CH:25][C:26]([Br:29])=[CH:27][CH:28]=2)=[CH:14][CH2:13][O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:31])=[O:3])=[CH:7][C:8]=2[Cl:30])=[CH:21][CH:20]=1
Reactant: CCOC(=O)Cc1ccc(OCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(OCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of {4-[3,3-bis-(4-bromo-phenyl)-allyloxy]-3-chloro-phenyl}-acetic acid ethyl ester (example 9) (1.0 g, 1.8 mmol) in THF (8 ml) and ethanol (5 ml) was added 1N NaOH (4.0 ml) and the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated in vacuo. The residue was suspended in water and 817 mg (82%) of the title compound was isolated by filtration as the sodium salt.
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:14]([O-])=[CH:15][C:16](=O)[C:17]([O:19]CC)=[O:18])[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.Cl.[Cl:48][C:49]1[N:54]=[CH:53][C:52]([NH:55][NH2:56])=[CH:51][CH:50]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:14]2[N:55]([C:52]3[CH:53]=[N:54][C:49]([Cl:48])=[CH:50][CH:51]=3)[N:56]=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:11])([F:12])[F:13])[CH:8]=1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Br)cc(OC(F)(F)F)c1
Reactant: NNc1ccc(Cl)nc1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccc(Cl)nc2)n1

Procedure:
280 mg (0.72 mmol) of the compound of Example 5A is reacted analogously to the synthesis of the compound of Example 20A with 171 mg (0.79 mmol) of 6-chloropyridin-3-yl-hydrazine dihydrochloride. After hydrolysis, 202 mg (61% of theory) of the title compound is obtained.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O=[C:11]1[CH2:20][CH2:19][CH2:18][C:17]2[N:16]([CH2:21][CH:22]=[CH2:23])[C:15](=[O:24])[CH:14]=[CH:13][C:12]1=2.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:3]1([CH2:2][CH2:1][NH:9][CH:11]2[CH2:20][CH2:19][CH2:18][C:17]3[N:16]([CH2:21][CH:22]=[CH2:23])[C:15](=[O:24])[CH:14]=[CH:13][C:12]2=3)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=CCn1c2c(ccc1=O)C(=O)CCC2
Reactant: NCCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=CCn1c2c(ccc1=O)C(NCCc1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.6 %

Procedure:
A mixture of phenethylamine (6.1 g), 5,6,7,8-tetrahydro-5-oxo-1-(2-propenyl)-2(1H)-quinolinone (10.0 g), and a catalytic amount of para-toluenesulfonic acid was heated in refluxing toluene (150 ml), with azeotropic removal of water, for 18 hrs. The solution was cooled and washed with water. The aqueous phase was extracted with dichloromethane, and the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. Sodium borohydride (1.8 g) was added to the residue in ethyl alcohol (150 ml) and the resulting mixture was stirred at room temperature for 0.5 hr. The mixture was concentrated in vacuo, and the residue was quenched with water. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by high performance liquid chromatography (silica gel, eluted with methanol/ethyl acetate) to afford 13.6 g (89%) of product. Recrystallization from diethyl ether/petroleum ether provided the analytical sample, mp 60°-62° C.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([Cl:29])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:19]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:15]2[CH:28]=[C:27]([Cl:29])[S:26][C:16]=2[N:17]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: Clc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: Clc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-methylenedioxyphenethylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]1([N:7]2[CH:16](O)[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.Cl>O>[CH:1]1([N:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1c2ccccc2CC(O)N1C1CCCCC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=c1c2ccccc2ccn1C1CCCCC1
Yield: 88.3 %

Procedure:
The compound (22 mg) obtained in step (b) just above was stirred in a mixed solution of ethanol:concentrated hydrochloric acid=10:1 at room temperature for 30 min. Water was added to the reaction solution. The mixture was extracted with ethyl acetate, and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation. The residue was purified by chromatography on silica gel (hexane ethyl acetate=1:1) to give 2-cyclohexyl-2H-isoquinolin-1-one (18 mg).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:29][C:28]([CH3:30])=[N:27][C:26]=2[C:31](O)=[O:32])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[S:29][C:28]([CH3:30])=[N:27][C:26]=2[C:31]([N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]2[CH2:11][C:3]2[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]=2[CH3:1])=[O:32])=[CH:23][CH:24]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: Cc1c(CC2CCCCN2)oc2ccccc12
Product: Cc1nc(C(=O)N2CCCCC2Cc2oc3ccccc3c2C)c(-c2ccc(F)cc2)s1

Procedure:
The title compound (18 mg) was prepared from (RS)-2-(3-methyl-benzofuran-2-ylmethyl)-piperidine, D74 (92 mg) and 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (190 mg) according to a procedure similar to that described for Example 4.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][OH:12].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.O>C1C=CC=CC=1>[CH2:11]1[O:12][CH:6]([C:5]2[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=2)[O:7][CH2:10]1
Reactant: O=Cc1ccc(Br)cc1
Reactant: OCCO
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: O
Solvent: c1ccccc1
Product: Brc1ccc(C2OCCO2)cc1
Yield: 100 %

Procedure:
To a solution of 4-bromobenzaldehyde (102 g, 0.55 mol) and ethylene glycol (100 g, 1.65 mol) in benzene (1l) were added a small amount of 10-camphorsulfonic acid, and the mixture was refluxed for 3 hours, while water was removed with Dean-Stark. After allowing to cool, saturated sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled to give the title compound (126 g, 0.55 mol, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1/[CH:12]=[C:13]1\[CH2:14][N:15]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:17][CH:18]\1O)=[O:5])[CH3:2].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[C:55]([OH:58])(=[S:57])[CH3:56]>C1(C)C=CC=CC=1>[C:55]([S:57][CH:12]([C:8]1[N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=[CH:10][N:9]=1)[C:13]1[CH2:14][N:15]([C:20]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:16][CH2:17][CH:18]=1)(=[O:58])[CH3:56]
Reactant: CCOC(=O)Cn1ccnc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Reactant: CC(O)=S
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)Cn1ccnc1C(SC(C)=O)C1=CCCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of (E)-3-{[1-(ethoxycarbonylmethyl)-1H-imidazol-2-yl]methylidene}-1-(triphenylmethyl)piperidin-4-ol (4.52 g) in toluene (80 ml) were added N,N-dimethylformamide dineopentyl acetal (5.0 ml) and thioacetic acid (1.3 ml) at 0° C. After the mixture was stirred at room temperature, the reaction was quenched by addition of water. The product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure followed by purification of the residue by silica gel chromatography using ethyl acetate and hexane (25:75 to 70:30) gave 5-{(acetylsulfanyl)[1-(ethoxycarbonylmethyl)-1H-imidazol-2-yl]methyl}-1-(triphenylmethyl)-1,2,3,6-tetrahydropyridine (3.92 g, yield: 78%) as a pale yellow amorphous solid.
Reaction SMILES: B.[Br:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([NH:12][CH3:13])=O)[CH:6]=[CH:7][CH:8]=1.[ClH:14]>O1CCCC1>[ClH:14].[Br:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:12][CH3:13])[CH:6]=[CH:7][CH:8]=1
Reactant: CNC(=O)Cc1cccc(Br)c1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CNCCc1cccc(Br)c1
Temperature: 90 °C

Procedure:
Borane in tetrahydrofuran (1.0M, 26.3 ml) was added dropwise to a tetrahydrofuran solution of 2-(3-bromophenyl)-N-methyl-acetamide (1.5 g, Example 12a)) at 0° C. Once addition was complete the solution was refluxed at 90° C. for 20 hours. The solution was cooled to room temperature, acidified with 6M hydrochloric acid (10 ml) and refluxed for a further hour. The solution was cooled to room temperature and extracted with diethyl ether. The aqueous layer was basified with 10% sodium hydroxide and extracted with ethyl acetate. The extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was converted to the hydrochloride salt by treatment with a 4M solution of hydrochloric acid in dioxan to give the sub-title compound as a solid (0.727 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[CH3:23][C:24]([OH:29])([C:27]#[CH:28])[CH2:25][OH:26].CN(C)C=O>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C>[NH2:1][C:2]1[N:3]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6]([C:28]#[C:27][C:24]([OH:29])([CH3:23])[CH2:25][OH:26])[N:5]=2
Reactant: CNC(=O)c1c(N)n(C2CCCC2)c2nc(Cl)ccc2c1=O
Reactant: C#CC(C)(O)CO
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(N)n(C2CCCC2)c2nc(C#CC(C)(O)CO)ccc2c1=O
Temperature: 100 °C
Yield: 97.4 %

Procedure:
15 g of 2-amino-7-chloro-1-cyclopentyl-N-methyl-4-oxo-1,4-dihydro[1,8]-naphthyridine-3-carboxamide (53.44 mmol) and 11.11 g of (±)-2-methylbut-3-yne-1,2-diol (83.39 mmol) are introduced successively into a mixture of 267 ml of dimethylformamide and 104 ml of triethylamine in a 500 ml three-necked flask. The reaction mixture is sparged with argon for 15 minutes and then 1.02 g of CuI (5.34 mmol) and 1.87 g of bis(triphenylphosphine) palladium(II)dichloride (2.67 mmol) are successively added. The reaction mixture is heated for 30 minutes at 100° C. and then concentrated under reduced vacuum. The residue is taken up in a chloroform/water mixture and the insoluble material is filtered off. 20 g of a solid are obtained, which is purified by silica chromatography (solid deposit after solubilization in a tetrahydrofuran/methanol mixture and then elution with a dichloromethane/methanol gradient, 99:1 to 80:20) so as to give 7.5 g of expected product in the form of a beige solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:17]2[CH:22]=[CH:21][NH:20][C:19](=[O:23])[CH:18]=2)[C:4]([CH3:16])=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=1.[CH3:24]I>>[CH3:1][C:2]1[N:3]([C:17]2[CH:22]=[CH:21][N:20]([CH3:24])[C:19](=[O:23])[CH:18]=2)[C:4]([CH3:16])=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=1
Reactant: Cc1cccc(C#Cc2nc(C)n(-c3cc[nH]c(=O)c3)c2C)c1
Reactant: CI
Product: Cc1cccc(C#Cc2nc(C)n(-c3ccn(C)c(=O)c3)c2C)c1

Procedure:
The title compound, brown solid, MS: m/e=318.2 (M+H+), was prepared in accordance with the general method of example 3 from 4-[2,5-dimethyl-4-m-tolylethynyl-imidazol-1-yl]-1H-pyridin-2-one and methyl iodide.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][CH2:8]2)=[O:4].O[Li].O>C1COCC1.O>[C:14]([N:10]1[C:11]2[C:7](=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:13][CH:12]=2)[CH2:8][CH2:9]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc2c(c1)CCN2C(=O)c1ccccc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2c(c1)CCN2C(=O)c1ccccc1
Yield: 99 %

Procedure:
A solution of compound 55g (87 mg, 0.31 mmol), and LiOH.H2O (52 mg, 1.24 mmol) in THF/H2O (2/2 mL) was stirred at room temperature overnight. The resulting mixture was concentrated and diluted with water. The water layer was acidified with 1N aqueous HCl to pH ˜6 and extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated to give 55h (82 mg), which was used in the next reaction without further purification. MS m/z (M+H+) 268.0.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](=[NH:18])[NH2:17])=[CH:10][CH:9]=2)=[CH:5][C:4]=1[C:21]([F:24])([F:23])[F:22].[OH:25][CH:26]=[C:27]([CH2:32][C:33]1[CH:34]=[N:35][C:36]([O:39][CH3:40])=[N:37][CH:38]=1)[C:28](OC)=O.C([O-])(=O)C.[K+]>C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3[NH:17][CH:28]=[C:27]([CH2:32][C:33]4[CH:34]=[N:35][C:36]([O:39][CH3:40])=[N:37][CH:38]=4)[C:26](=[O:25])[N:18]=3)=[CH:10][CH:9]=2)=[CH:5][C:4]=1[C:21]([F:22])([F:23])[F:24]
Reactant: COC(=O)C(=CO)Cc1cnc(OC)nc1
Reactant: N=C(N)CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ncc(Cc2c[nH]c(CCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Yield: 42.3 %

Procedure:
The suspension of 3-(4-(4-chloro-3-(trifluoromethyl)phenoxy)phenyl)propanimidamide hydrochloride (5.9 g, 15.56 mmol), methyl 3-hydroxy-2-((2-methoxypyrimidin-5-yl)methyl)acrylate (3.49 g, 15.56 mmol) and potassium acetate (4.58 g, 46.7 mmol) in toluene (100 mL) was heated under reflux overnight. Dean-Stark apparatus was used to remove water formed in the reaction. The residue was recrystallized in ethyl acetate and washed with ether to provide the title compound (3.4 g, 42%). LCMS: rt=1.71 min, [M+H+]=517
Reaction SMILES: [I-].[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:14]([N:16]1[CH:21]=[CH:20]C(=[N+](C)C)[CH:18]=[CH:17]1)=[O:15])[CH2:3][CH2:4][CH3:5].N1CC[O:28]CC1>O1CCOCC1>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:14]([N:16]1[CH2:21][CH2:20][O:28][CH2:18][CH2:17]1)=[O:15])[CH2:3][CH2:4][CH3:5]
Reactant: C1COCCN1
Reactant: CCCCN1C(C)=C(C)S/C1=C\C(=O)n1ccc(=[N+](C)C)cc1
Agent: [I-]
Solvent: C1COCCO1
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)N1CCOCC1
Temperature: 80 °C

Procedure:
A mixture of product from Example 4 (46 mg, 0.1 mmol) and morpholine (175 mg, 2 mmol) in dioxane (10 mL) was heated to 80° C. for 2 hours then concentrated in vacuo. Column chromatography over silica gel (CH2Cl2-MeOH 4:1) provided the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.96 (t, J=7 Hz, 3H), 1.32 (sextet, J=7 Hz, 2H), 1.53 (quintet, J=7 Hz, 2H), 2.00 (s, 3H), 2.05 (s, 3H), 3.29 (t, J=6 Hz, 4H), 3.55 9t, J=6 Hz, 4H), 3.72 (t, J=7 Hz, 2H), 5.30 (s, 1H); MS (ESI) m/z 297 (M+H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]N[CH2:3][CH2:2]1.[NH:20]1[C:24]2=[CH:25][N:26]=[CH:27][CH:28]=[C:23]2[C:22]([CH:29]=O)=[CH:21]1>>[NH:20]1[C:24]2=[CH:25][N:26]=[CH:27][CH:28]=[C:23]2[C:22]([CH:29]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:21]1
Reactant: O=Cc1c[nH]c2cnccc12
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCC(c4c[nH]c5cnccc45)CC3)nn12
Yield: 68 %

Procedure:
Obtained in 68% yield by General Synthetic Method 5, starting from 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine and 1H-pyrrolo[2,3-c]pyridine-3-carboxaldehyde (obtained as described in J. Chem. Soc. (C) 1970, 498).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:8]([CH3:17])=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([O:12][CH3:13])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[CH:1]1([N:6]([CH3:18])[C:7]2[C:8]([CH3:17])=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([O:12][CH3:13])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cccc(NC2CCCC2)c1C
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cccc(N(C)C2CCCC2)c1C
Temperature: 80 °C
Yield: 85.7 %

Procedure:
To a stirred solution of methyl 3-(cyclopentylamino)-2-methylbenzoate (2.2 g, 9.44 mmol) in acetonitrile (20 mL) was added cesium carbonate (6.13 g, 18.8 mmol) and methyl iodide (6.7 g, 47.2 mmol). The resulting mixture was heated at 80° C. for 12 h. On completion, the mixture was cooled to room temperature and filtered, washing with ethyl acetate. The filtrate was concentrated and then purified by column chromatography to afford methyl 3-(cyclopentyl(methyl)amino)-2-methylbenzoate (2 g, 85%).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19]([Sn](CCCC)(CCCC)CCCC)[N:18]=1>O1CCOCC1>[Cl:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:19]1[CH:20]=[N:21][CH:22]=[C:17]([O:16][CH3:15])[N:18]=1)[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(OC)n1
Reactant: O=Cc1cc2cccc(Cl)c2nc1Cl
Solvent: C1COCCO1
Product: COc1cncc(-c2nc3c(Cl)cccc3cc2C=O)n1
Temperature: 110 °C
Yield: 63.4 %

Procedure:
A mixture of 2,8-dichloroquinoline-3-carbaldehyde (0.5 g, 2.21 mmol), 2-methoxy-6-(tributylstannanyl)pyrazine (1.0 g, 2.51 mmol) and tetrakis(triphenyl-phosphine)palladium(0) (0.2 g, 0.173 mmol) in 1,4-dioxane (10 mL) was degassed and heated at 110° C. overnight. The mixture was allowed to cool to room temperature and diluted with EtOAc. The resulting solid was collected by filtration, washed with EtOAc, then ether, and dried to give the title compound (0.42 g, 63%) as a yellow solid. δH(DMSO-d6) 10.58 (s, 1H), 9.24 (s, 1H), 8.93 (s, 1H), 8.53 (s, 1H), 8.27 (dd, J 8.3, 1.2 Hz, 1H), 8.17 (dd, J 7.5, 1.2 Hz, 1H), 7.75 (m, 1H), 3.96 (s, 3H). LCMS (ES+) 300 (M+H)+, RT 1.51 minutes.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][NH:3]1.Cl.O1CCOC[CH2:17]1>CO>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:17])=[O:13])[CH:10]=2)[N:5]=[CH:4][NH:3]1
Reactant: C1COCCO1
Reactant: O=C(O)c1ccc2nc[nH]c(=O)c2c1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc2nc[nH]c(=O)c2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a sealed tube was added 4-oxo-3,4-dihydroquinazoline-6-carboxylic acid (0.88 g, 4.6 mmol), methanol (70 mL) and 4.0 M hydrochloric acid in 1,4-dioxane (4.63 mL, 18.5 mmol). The reaction mixture was heated to 90° C. and stirred overnight. The mixture was then cooled to rt, and concentrated to yield methyl 4-oxo-3,4-dihydroquinazoline-6-carboxylate (0.94 g, quant). LC-MS: (FA) ES+ 205; 1H NMR (400 MHz, DMSO) δ 8.65 (d, J=2.1 Hz, 1H), 8.30 (dd, J=8.5, 2.1 Hz, 1H), 8.22 (s, 1H), 7.77 (d, J=8.5 Hz, 1H), 3.88 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:3](C(=O)N)[N:4]=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:9][CH:8]=1.[OH-].[Na+]>CO>[NH2:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)=[CH:11][CH:12]=2)=[CH:5][NH:4][N:3]=1
Reactant: COc1cccc(Cc2ccc(-c3cnn(C(N)=O)c3N)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(Cc2ccc(-c3c[nH]nc3N)cc2)c1
Yield: 50.7 %

Procedure:
To a solution of 3-amino-2-carbamoyl-4-[4-(3methoxyphenylmethyl)phenyl]pyrazole (4.1 g) in methanol (50 ml) was added 5N sodium hydroxide solution (20 ml), and the mixture was refluxed for 30 minutes. Methanol was distilled away under reduced pressure. To the residue was added water (150 ml), and the mixture was neutralized (pH 7 to 8) with conc. hydrochloric acid, and extracted with chloroform. The extract was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The residue was separated and purified by using a silica-gel column chromatography (ethyl acetate:n-hexane=1:1, followed by ethyl acetat) to give the title compound (1.8 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:18])[CH2:11][CH:12]1[S:17][CH2:16][CH2:15][CH2:14][S:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21](Br)[CH:22]=[CH2:23]>C1COCC1>[CH2:23]([O:18][C@@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:11][CH:12]1[S:17][CH2:16][CH2:15][CH2:14][S:13]1)[CH:22]=[CH2:21]
Reactant: O[C@@H](COCc1ccccc1)CC1SCCCS1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCO[C@@H](COCc1ccccc1)CC1SCCCS1
Reaction time: 0.2 h

Procedure:
A solution of (R)-1-benzyloxy-3-[1,3]dithian-2-yl-propan-2-ol (22.1 g) in THF (300 mL) was cooled to 0° C. 60% sodium hydride (4.35 g) was added, followed by stirring. After 12 minutes, allyl bromide (10 mL) was added and then the ice bath was removed. The mixture was further stirred at room temperature. After stirring overnight, the reaction solution was added to a mixture of ice and t-butyl methyl ether, and the organic layer was separated. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was subjected to silica gel chromatography to obtain the title compound (24.7 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.Cl.[NH2:23][CH2:24][CH2:25][C:26]([CH3:29])([OH:28])[CH3:27].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[CH3:27][C:26]([OH:28])([CH2:25][CH2:24][NH:23][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1)[CH3:29]
Reactant: FC(F)(F)Oc1cccc(-c2cnc3ccc(Cl)nn23)c1
Reactant: CC(C)(O)CCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)(O)CCNc1ccc2ncc(-c3cccc(OC(F)(F)F)c3)n2n1
Temperature: 180 °C
Reaction time: 0.75 h
Yield: 47.9 %

Procedure:
To a solution of 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (300 mg, 0.96 mmol) and 4-amino-2-methylbutan-2-ol hydrogenchloride (493 mg, 4.78 mmol) in NMP (2.0 mL) was added NaHCO3 (516 mg, 4.78 mmol), the mixture was stirred at 180° C. for 45 mins under microwave irridation. The mixture was purified by flash chromatograph to give 2-methyl-4-((3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)butan-2-ol (175 mg, 48%) as a pale yellow solid.