Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:35])[C:24]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH2:30][CH2:29]2)=[O:25]>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:31]3[C:32]4[C:28](=[CH:27][C:26]([C:24](=[O:25])[N:23]([CH3:22])[CH3:35])=[CH:34][CH:33]=4)[CH2:29][CH2:30]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CN(C)C(=O)c1ccc2c(c1)CCN2
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Product: CN(C)C(=O)c1ccc2c(c1)CCN2c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cn1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) and N,N-dimethylindoline-5-carboxamide (intermediate-13).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[CH3:14][N:15]([CH3:17])[CH:16]=[CH:2][C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(C(=O)O)s1
Product: CN(C)C=CC(=O)c1ccc(C(=O)O)s1
Temperature: 120 °C

Procedure:
5-Acetyl-thiophene-2-carboxylic acid (1 g, 5.87 mmol) was treated with N,N-dimethylformamide dimethylacetal (10 mL) and heated at 120° C. for 16 hours. The mixture was dried in vacuo to give 5-(3-dimethylamino-acryloyl)thiophene-2-carboxylic acid which was taken to the next step. MS: m/z 226 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>C(#N)C>[C:19]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:18]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COc1ccc(CNc2ccc(Br)cc2)cc1
Solvent: CC#N
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of (4-bromophenyl)(4-methoxyphenyl)methylamine, 1-1-c, (2 g, 6.8 mmol) in acetonitrile (25 ml) was added BOC2O (1.5 equivalents) and stirred at room temperature for 24 h. The reaction mixture was evaporated to dryness and purified over silica gel (5% MeOH/DCM) to give N-Boc-(4-bromophenyl)(4-methoxyphenyl)methylamine.
Reaction SMILES: [OH:1][CH:2]([CH2:22][N:23]([CH2:34][CH2:35][CH3:36])[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:21])[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12]2)=[CH:7][CH:6]=1.[C:37]1([CH:43]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:44](Cl)=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:47]1([CH:43]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:44]([O:1][CH:2]([CH2:22][N:23]([CH2:34][CH2:35][CH3:36])[C:24]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25])[CH2:3][O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9](=[O:21])[CH:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12]3)=[CH:7][CH:6]=2)=[O:45])[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: CCCN(CC(O)COc1ccc2c(=O)cc(-c3ccccc3)oc2c1)C(=O)OCc1ccccc1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCN(CC(COc1ccc2c(=O)cc(-c3ccccc3)oc2c1)OC(=O)C(c1ccccc1)c1ccccc1)C(=O)OCc1ccccc1
Yield: 76 %

Procedure:
A mixture of 7-[2-hydroxy-3-[N-(benzyloxycarbonyl)-propylamino]propoxy]flavone in crude form (5.09 g, 11 mmol), diphenylacetyl chloride (10.20 g, 44 mmol), and triethylamine (19.0 ml, 136 mmol) in toluene (65 ml) was refluxed under nitrogen for 18 hr. Toluene was removed by evaporation and the oily residue was dissolved in chloroform, washed twice with saturated NaHCO3 and once with water, and then dried (K2CO3). The dried solution, upon evaporation, gave a brown oil which was purified by HPLC (Water Associates PrepLC/Systems 500) using 3% acetone/CH2Cl2 that contained a small amount of NH4OH. A tan syrup of the title compound was obtained; 5.57 g (76% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[C:10]([OH:24])([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:26][C:27]([O:29]CC)=[O:28].[CH3:32][C:33](C)=O>>[CH2:32]([N:21]1[CH2:20][CH:19]=[C:18]([C:10]2([OH:24])[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=3)[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:9]2)[CH2:23][CH:22]1[CH2:26][C:27]([OH:29])=[O:28])[CH3:33]
Reactant: CC(C)=O
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc2c(c1)C(O)(c1ccncc1)CC2c1ccc(F)cc1
Product: CCN1CC=C(C2(O)CC(c3ccc(F)cc3)c3ccc(C)cc32)CC1CC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
3-(4'-fluorophenyl)-1-hyroxy-6-methyl-1-pyrid-4-ylindane (12.0 g) was refluxed with ethyl bromoacetate (7.5 g) in acetone (100 ml) for 4 hrs. The reaction mixture was cooled in a refrigerator over night and the precipitate filtered off. Yield: 16.8 g (91.9%) of the pyridiniumbromide. MP: 196°-198° C. (dec.). The bromide (15.0 g) was dissolved in methanol (150 ml), and ice cooled, NaBH4 (5.0 g) was added during a period of 1 h. The reaction mixture was finally stirred for another 1/2 h at room temperature and subsequently poured into NH4Cl (25 g) in 1 L of H2O. The H2O phase was extracted with ethyl acetate (2×200 ml), the combined organic phases dried (MgSO4) and the solvent evaporated yielding 11.7 g (92.7%) of 1-(1-ethylcarboxymethyl-1,2,3,6-tetrahydropyrid-4-yl)-3-(4'-fluorphenyl)-1-hydroxy-6-methylindane. MP: 119° -20° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=1[CH2:11][C:12]1[C:13](=[O:20])[NH:14][NH:15][C:16]=1[CH:17]([CH3:19])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][C:26]([O:28][CH2:29][C@H:30]1[O:35][C@H:34](Br)[C@H:33]([O:37][C:38]([CH3:40])=[O:39])[C@@H:32]([O:41][C:42]([CH3:44])=[O:43])[C@@H:31]1[O:45][C:46]([CH3:48])=[O:47])=[O:27]>C(#N)C.C(=O)([O-])[O-].[Ag+2]>[CH:17]([C:16]1[NH:15][N:14]=[C:13]([O:20][C@@H:34]2[O:35][C@H:30]([CH2:29][O:28][C:26](=[O:27])[CH3:25])[C@@H:31]([O:45][C:46](=[O:47])[CH3:48])[C@H:32]([O:41][C:42](=[O:43])[CH3:44])[C@H:33]2[O:37][C:38](=[O:39])[CH3:40])[C:12]=1[CH2:11][C:10]1[CH:21]=[CH:22][CH:23]=[CH:24][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:19])[CH3:18]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)c1[nH][nH]c(=O)c1Cc1ccccc1OCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccccc2OCc2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
To a suspension of 4-(2-benzyloxybenzyl)-5-isopropyl-1,2-dihydropyrazol-3-one (114 mg) and acetobromo-α-D-glucose (173 mg) in acetonitrile (2 mL) was added silver carbonate (127 mg), and the mixture was stirred under shading the light at room temperature for 3 days. The reaction mixture was purified by column chromatography on aminopropyl silica gel (eluent: ethyl acetate/hexane=1/1) to give 5-isopropyl-4-(2-benzyloxybenzyl)-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole. To a solution of 5-isopropyl-4-(2-benzyloxybenzyl)-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole in tetrahydrofuran (1 mL) and methanol (0.5 mL) was added sodium methoxide (28% methanol solution, 50 μL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1-5/1) to give the title compound (22 mg).
Reaction SMILES: [C:1](OC(OC(OC(C)(C)C)=O)=O)([CH3:4])(C)[CH3:2].C([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])C.C[OH:24]>>[CH2:4]1[C:1]2([CH2:20][CH2:19][NH:18][CH2:21][C@H:22]2[OH:24])[CH2:2]1
Reactant: CO
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Product: O[C@@H]1CNCCC12CC2

Procedure:
The title compound was treated with di-tert-butyl-dicarbonate in methanol in the presence of triethylamine. The crude tert-butoxycarbonyl-protected amine product was analyzed by chiral GC (BGB-176; 30 m×0.25 mm; 80° C. to 210° C. in 43 min) and proved to be identical with intermediate 25b.
Reaction SMILES: ClC(OCC)=O.[CH2:7]([O:9][C:10]([C:12]1[S:13][C:14]([C:17]([OH:19])=O)=[CH:15][N:16]=1)=[O:11])[CH3:8].[N-:20]=[N+:21]=[N-:22].[Na+]>CC(C)=O.O>[N:20]([C:17]([C:14]1[S:13][C:12]([C:10]([O:9][CH2:7][CH3:8])=[O:11])=[N:16][CH:15]=1)=[O:19])=[N+:21]=[N-:22]
Reactant: CCOC(=O)c1ncc(C(=O)O)s1
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1ncc(C(=O)N=[N+]=[N-])s1
Reaction time: 1 h
Yield: 75.2 %

Procedure:
Ethyl chloroformate (9.8 g, 83.6 mmol) was added to a solution of 2-(ethoxycarbonyl)thiazole-5-carboxylic acid (Intermediate X, 13 g, 64.67 mmol), TEA (9.79 g, 97.01 mmol) in acetone (130 mL) at −20° C., stirred for 1 h, then a solution of NaN3 (5.4 g, 83.6 mmol) in water (15 mL) was added and stirred at RT for 30 mins. After completion, the solvent was evaporated, the crude residue was diluted with water (150 mL) and extracted with EtOAc (2×150 mL). The combined extracts were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4, filtered and evaporated to afford Ethyl 5-(azidocarbonyl)thiazole-2-carboxylate (11 g crude) as brown liquid. The crude was carried to next step without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C:5](=[NH:7])[NH2:6].C[O-].[Na+].[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([C:32](=O)[CH2:33][CH2:34][CH2:35][CH3:36])[C:27](OCC)=[O:28])=[CH:21][CH:20]=1)#[N:12]>CO.O1CCOCC1>[CH2:33]([C:32]1[N:7]=[C:5]([CH2:4][O:3][CH3:2])[NH:6][C:27](=[O:28])[C:26]=1[CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:14]2[C:13]([C:11]#[N:12])=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:24][CH:23]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: COCC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CCCCc1nc(COC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 75 %

Procedure:
To a mixture of 2-methoxyethanimidamide hydrochloride (2.1 g) and methanol (15 mL) were added sodium methoxide (28% methanol solution, 4.8 g), and then a solution of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (3.0 g) in methanol (25 mL) and 1,4-dioxane (10 mL) at 0° C., and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated, and the residue was adjusted to pH 5 with water (50 mL) and 50% aqueous acetic acid solution, and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (2.4 g, 75%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[NH:7])[CH2:4][S:3]1.[NH:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=N)[NH:10]1.C(O)CO>CO>[NH:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[C:4]2[S:3][C:2](=[O:1])[NH:6][C:5]2=[NH:7])[NH:10]1
Reactant: N=C1NC(=N)c2ccccc21
Reactant: N=C1CSC(=O)N1
Solvent: CO
Solvent: OCCO
Product: N=C1NC(=O)SC1=C1NC(=N)c2ccccc21

Procedure:
17.5 parts of 2-oxo-4-iminothiazolidine and 32 parts of the adduct of 1,3-diiminoisoindoline and ethylene glycol, in 400 parts of methanol, are refluxed for 5 hours. After the mixture has cooled, the product is filtered off, washed with methanol and dried. 33 parts of 1-imino-3-(2'-oxo-4'-iminothiazolidinylidene)-isoindoline (formula II, Z=°O) are obtained as a yellowish brown powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2([CH:21]3[CH2:26][CH2:25][CH:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23][CH2:22]3)C(=O)OC(C)(C)O[C:12]2=[O:20])=[CH:6][CH:5]=1.[Br:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1.C(OCC)(=O)C.CCCCCC>CN1CCCC1=O>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:12](=[O:20])[NH:37][C:36]2[CH:38]=[CH:39][C:33]([Br:32])=[CH:34][CH:35]=2)[CH:21]2[CH2:22][CH2:23][CH:24]([C:27]([CH3:28])([CH3:29])[CH3:30])[CH2:25][CH2:26]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CC2(C3CCC(C(C)(C)C)CC3)C(=O)OC(C)(C)OC2=O)cc1
Reactant: Nc1ccc(Br)cc1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1ccc(CC(C(=O)Nc2ccc(Br)cc2)C2CCC(C(C)(C)C)CC2)cc1
Reaction time: 0.13 h

Procedure:
To 1 eq (2.32 mmol) of 4-[5-(4-tert-Butyl-cyclohexyl)-2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylmethyl]-benzoic acid methyl ester was added 1.5 eq (3.5 mmol) of 4-bromoaniline in 2 mL of n-methyl-pyrrolidinone in a microwave vial. The reaction was run for eight minutes at 220 degrees C. The reaction mixture was worked up by partitioning with ethyl acetate/diethyl ether (1:1)/1 N HCl. Product was isolated by chromatography gradient: 10% ethyl acetate/hexane to 40% ethyl acetate hexane.
Reaction SMILES: C[O:2][C:3](=[O:34])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:23](=[O:33])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[CH:20][C:21]=1[Br:22])=[O:16])[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].O.[OH-].[Li+].Cl>C1COCC1.O>[Br:22][C:21]1[CH:20]=[C:19]([C:23](=[O:33])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)[S:18][C:17]=1[C:15]([NH:14][C@@H:4]([CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8])[C:3]([OH:34])=[O:2])=[O:16]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1Br
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC[C@H](NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1Br)C(=O)O)c1cccs1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (S)-2-{[3-Bromo-5-(3-hydroxy-benzylcarbamoyl)-thiophene-2-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid methyl ester (24.2 mg, 0.043 mmol) in THF (3 mL) was added a solution of lithium hydroxide monohydrate (120 mg, 2.87 mmol) in water (4 mL). The mixture was then stirred at room temperature 15 h. The mixture was then acidified with 1N HCl and extracted with EtOAc (×3). The extracts were combined, washed with water and brine, dried over sodium sulfate, filtered, and evaporated to pure product, 20.6 mg (87%). MS m/e 553.8 (M+H+).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][CH:8]=[CH:9][N:10]=1.CCCCCC.C([Li])CCC.[C:22](OCC)(=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][C:8]([C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:9][N:10]=1
Reactant: c1csc(C2OCCO2)n1
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1cnc(C2OCCO2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
To a solution of 2-(1,3-dioxolan-2-yl)-1,3-thiazole (14.2 g) in tetrahydrofuran (400 mL) was slowly added a 1.6M n-butyllithium hexane solution (62 mL) at −78° C. The reaction mixture was stirred for 30 min, diethyl oxalate (16.5 g) was added, and the mixture was further stirred for 2 hr. The reaction mixture was warmed to room temperature, 1M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (12.2 g, yield 52%) was obtained as a pale-yellow oil from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). MS: 258 (MH+).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([CH2:12][CH2:13][C:14](O)=[O:15])=O)=[CH:8][CH:7]=1)=[O:4].O.[NH2:20][NH2:21]>C(O)C>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]2[CH2:12][CH2:13][C:14](=[O:15])[NH:20][N:21]=2)=[CH:8][CH:7]=1)=[O:4]
Reactant: NN
Reactant: O=C(O)CCC(=O)c1ccc(NC(=O)CCl)cc1
Solvent: CCO
Solvent: O
Product: O=C1CCC(c2ccc(NC(=O)CCl)cc2)=NN1
Yield: 83.9 %

Procedure:
4.0 g (14.8 millimoles) of β-(p-chloroacetylaminobenzoyl)-propionic acid are refluxed with 0.74 g (14.8 millimoles) of hydrazine hydrate and 70 ml of ethanol for 3 hours. After filtering off the product at 10° C. and drying it under reduced pressure at 50° C., 3.3 g (84% of theory) of 6-(p-chloroacetylaminophenyl)-4,5-dihydropyridaz-3-one are obtained as pale yellow crystals (identical with the compound from Example 1, according to its melting point and infrared and NMR spectra).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([CH2:18][N:19]([CH3:32])[CH:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:21]([O-])=[O:22])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].Cl.Cl.[N:36]1([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[N:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH2:40][CH2:39][CH2:38][CH2:37]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH:17]([CH2:18][N:19]([CH:20]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[C:21](=[O:22])[N:51]2[CH2:50][CH2:49][N:48]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[CH2:41][N:36]3[CH2:37][CH2:38][CH2:39][CH2:40]3)[CH2:53][CH2:52]2)[CH3:32])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: c1ccc(N2CCNCC2)c(CN2CCCC2)c1
Reactant: CN(CC1Cc2ccccc2CN1C(=O)OC(C)(C)C)C(Cc1ccc(Cl)cc1)C(=O)[O-]
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CN(CC1Cc2ccccc2CN1C(=O)OC(C)(C)C)C(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2CN2CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
Lithium 2-[(2-tert-butoxycarbonyl-1,2,3,4-tetrahydro-isoquinolin-3-ylmethyl)-methyl-amino]-3-(4-chloro-phenyl)-propionate (0.59 gm, 1.27 mmol), the compound of Step A (0.27 gm, 0.85 mmol), EDC (0.24 gm, 1.27 mmol) and HOBt (0.17 gm, 1.27 mmol) were combined and dissolved in anhydrous DMF (5 mL). DIPEA was added (440 microliter, 2.54 mmol), and the reaction was stirred under nitrogen overnight at room temperature. The reaction was concentrated and reconstituted in CH2Cl2 and then diluted with NaHCO3. After separation of the organic phase, the aqueous layer was extracted with CH2Cl2 (2×). The combined organics were dried (Na2SO4), filtered and concentrated. Chromatography (EtOAc to 5% MeOH/EtOAc) gave about 100 mg of 3-[({1-(4-Chloro-benzyl)-2-oxo-2-[4-(2-pyrrolidin-1-ylmethyl-phenyl)-piperazin-1-yl]-ethyl}-methyl-amino)-methyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid t-butyl ester. MS (m/z, ES+): 686.4.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][C:27]1=[O:32]>CN1C(=O)CCC1.CC#N>[F:22][C:21]1[CH:20]=[C:19]2[C:15]([CH:16]=[N:17][N:18]2[CH3:23])=[CH:14][C:13]=1[C@@H:11]([C:8]1[N:6]2[N:7]=[C:2]([N:29]3[CH2:30][CH2:31][NH:26][C:27](=[O:32])[CH2:28]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[CH3:12]
Reactant: C[C@@H](c1cc2cnn(C)c2cc1F)c1cnc2ccc(Cl)nn12
Reactant: O=C1CNCCN1
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: C[C@@H](c1cc2cnn(C)c2cc1F)c1cnc2ccc(N3CCNC(=O)C3)nn12
Temperature: 180 °C
Reaction time: 3 h

Procedure:
6-Chloro-3-[(S)-1-(6-fluoro-1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine (Intermediate E, 66.0 mg, 0.2 mmol), KF (59.3 mg, 1.0 mmol) and piperazin-2-one (61.9 mg, 0.6 mmol) were suspended in NMP (0.5 mL). The RM was stirred at 180° C. for 3 h. The mixture was diluted with CH3CN and purified by reverse phase chromatography (Büchi MPLC: 5-24% CH3CN, 0.1% HCOOH). The fractions was combined, concentrated and neutralized with NaHCO3, extracted with EtOAc. The combined organics layers were tried over Na2SO4, filtered, concentrated to afford the title compound as a yellow foam (tR 3.53 min (conditions 4), (tR 8.25 (conditions 5), MH+=394.3, 1H-NMR in DMSO-d6: 8.04 (s, 1H); 7.92 (s, 1H); 7.81 (d, 1H); 7.50 (m, 1H); 7.46 (d, 1H); 7.06 (d, 1H); 4.78 (m, 1H); 3.95 (s, 3H); 3.95 (d, 1H); 3.80 (d, 1H); 3.58 (m, 2H); 3.22 (m, 2H); 1.71 (d, 3H)).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[NH:15][C:14](=[O:16])[C:13]2[C:8](=[CH:9][C:10]([Cl:18])=[C:11]([CH3:17])[CH:12]=2)[N:7]=1)(=[O:3])[CH3:2].[H-].[Na+].I[CH3:22]>CN(C=O)C.ClCCl>[C:1]([O:4][CH2:5][C:6]1[N:15]([CH3:22])[C:14](=[O:16])[C:13]2[C:8](=[CH:9][C:10]([Cl:18])=[C:11]([CH3:17])[CH:12]=2)[N:7]=1)(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)OCc1nc2cc(Cl)c(C)cc2c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)OCc1nc2cc(Cl)c(C)cc2c(=O)n1C
Reaction time: 0.02 h
Yield: 66.8 %

Procedure:
To a suspension of 2-acetoxymethyl-7-chloro-6-methyl-3,4-dihydroquinazolin-4-one 0.428 g, 1.6 mmol) in anhydrous DMF (13 ml) was added sodium hydride (60% dispersion, 0.070 g, 1.76 mmol) under argon. Stirring was continued at room temperature for 1 min and then iodomethane (0.20 ml, 3.2 mmol) was added into the reaction mixture with a syringe via a septum. Stirring was continued at room temperature for 1 hour and the reaction mixture was then partitioned between ethyl acetate (130 ml) and brine (80 ml). The organic layer was washed with dilute brine (80 ml), dried (Na2SO4) and concentrated in vacuo to leave an orange residue. This orange residue was dissolved in dichloromethane and to this solution silica gel (Art 7734, 1.7 g) was added. The solvent was removed in vacuo and the orange free running powder was placed on a silica gel column made up in 5% ethyl acetate in dichloromethane. The column was eluted with 5% ethyl acetate in dichloromethane to afford a pale yellow solid (0.300 g, 67%), mp 110-112° C.; 1H-NMR (DMSO-d6) 2.17 (s, 3H, CH3CO), 2.47 (s, 3H, 6-CH3), 3.54 (s, 3H, N3—CH3), 5.23 (s, 2H, 2-CH2O), 7.71, 8.09 (2×s, 2H, 5-H, 8-H).
Reaction SMILES: C([Li])CCC.CCCCCC.[F:12][C:13]1C=C[CH:16]=[CH:15][C:14]=1[F:19].C[S:21]SC.[O:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[F:12][C:13]1[C:14]([F:19])=[C:15]([CH3:16])[CH:25]=[CH:26][C:27]=1[C:28]([OH:24])=[S:21]
Reactant: CSSC
Reactant: C1CCOC1
Reactant: Fc1ccccc1F
Agent: [Li]CCCC
Solvent: CCCCCC
Product: Cc1ccc(C(O)=S)c(F)c1F
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
A 2.5M solution of butyllithium in hexane (4.5 mL, 11 mmol) was added dropwise with stirring to a solution of 1.00 mL (10.2 mmol) of 1,2-difluorobenzene in 10 mL of dry tetrahydrofuran cooled to -70° C. under a nitrogen atmosphere. After 10 min, 0.80 mL (11 mmol) of dimethyl disulfide was added dropwise with stirring. Another 11 mmol of 2.5M butyllithium was then added and, after 10 min, the reaction mixture was quenched by bubbling a stream of dry carbon dioxide into the solution. The resulting mixture was diluted with water and the mixture was washed with ether and then acidified with 1N aqueous hydrochloric acid. The resulting heavy white precipitate was recrystallized from a mixture of ethyl acetate and heptane to obtain 0.65 g (31 percent of theory) of the title compound as a white solid melting at 214-215° C.