Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:20])[C:4]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8][CH:7]([CH2:10][C:11]([OH:13])=O)[CH2:6][CH2:5]1.C1(N=[C:28]=[N:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)CCCCC1.[OH-].[Na+]>CN(C)C=O.O>[CH3:20][N:3]([CH3:2])[C:4]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:5][CH2:6][CH:7]([CH2:10][C:11]([NH:3][CH2:4][CH2:5][C:6]2[C:31]3[C:30](=[CH:35][CH:34]=[CH:33][CH:32]=3)[NH:29][CH:28]=2)=[O:13])[CH2:8][CH2:9]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CN(C)C1(c2ccccc2)CCC(CC(=O)O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C1(c2ccccc2)CCC(CC(=O)NCCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(4-dimethylamino-4-phenylcyclohexyl)acetic acid hydrochloride (298 mg, 1.0 mmol) in dry dimethylformamide under argon. The clear solution was cooled in an ice-bath and dicyclohexylcarbodiimide (417 mg, 2.0 mmol) was added. The reaction mixture was stirred at RT for 3 d and worked up by separating off the urea which had precipitated out and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). The mixture was diluted with water, 5 M sodium hydroxide solution (4 ml, 20 mmol) was added and the mixture was stored at 5° C. for 16 h. The crude product thereby precipitated out as a beige-coloured substance (400 mg). After purification by chromatography on silica gel with methanol, the product was obtained as a beige-coloured solid in a yield of 35% (144 mg) and with an m.p.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([CH3:9])[OH:8])[OH:6])[OH:4].CO.[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)(=O)C>[C:12]1([NH:18][N:19]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([CH3:9])[OH:8])[OH:6])[OH:4])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NNc1ccccc1
Reactant: C[C@H](O)[C@H](O)[C@@H](O)C=O
Solvent: CO
Solvent: CC(=O)O
Product: C[C@H](O)[C@H](O)[C@@H](O)C=NNc1ccccc1
Reaction time: 1 h
Yield: 95.6 %

Procedure:
There was added 5.0 g (37.3 mmoles) of 5-deoxy-L-(+)-arabinose obtained in Example to 80 ml of methanol and the mixture was stirred to give a clear solution. With stirring there was added dropwise 4.5 g (42 mmoles) of phenylhydrazine to the obtained mixture and thereto further a drop of glacial acetic acid was added. Thus obtained yellow solution was allowed to stand for 1 hour at room temperature and then the solution was evaporated under a condition close to vacuum as far as possible to give a thick viscous residue. After the residue was washed with 30 ml of ether twice, the residue was dissolved in 150 ml of ethyl acetate. The thus obtained solution was washed with about 40 ml of water twice, the organic layer was dried with sodium sulfate and the solvent was evaporated under vacuum. There remained a pale yellow skin-like solid on the bottom of the flask. The solid was washed with 30 ml of ether twice (for half an hour per each washing) and dried to give 8.0 g of 5-deoxy-L-arabinose-phenylhydrazone (yield: 96%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=1.I[CH2:16][CH2:17][CH3:18].Cl>CN(C)C=O>[F:3][C:4]1[CH:14]=[CH:13][C:7]2[N:8]([CH2:16][CH2:17][CH3:18])[C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: O=C1COc2cc(F)ccc2N1
Reactant: CCCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1C(=O)COc2cc(F)ccc21
Temperature: 40 °C
Yield: 79.7 %

Procedure:
Under a dry argon atmosphere 2.7 grams of a 60% suspension of sodium hydride in oil (0.068 mole of sodium hydride) was waashed with petroleum ether to remove the oil. To the washed sodium hydride was added 50 ml of N,N-dimethylformamide (DMF), and the mixture was stirred. A solution of 7-fluoro-2H-1,4-benzoxazin-3 (4H)-one (10.0 grams, 0.060 mole) in 50 ml of DMF was added. This mixture was warmed to approximately 40° C. for 30 minutes, and then was cooled to room temperature. A solution of 11.2 grams (0.066 mole) of 1-iodopropane in 10 ml of DMF was added, and the mixture was stirred at room temperature for approximately 18 hours. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 10.0 grams of 7-fluoro-4-propyl-2H-1,4-benzoxazin-3(4H)-one as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[SH:9].[Br:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=1I.BrC1C=C(Br)C=CC=1N>>[Br:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=1[S:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1]
Reactant: Brc1ccc(I)c(Br)c1
Reactant: Cc1ccc(S)c(C)c1
Agent: Nc1ccc(Br)cc1Br
Product: Cc1ccc(Sc2ccc(Br)cc2Br)c(C)c1

Procedure:
Prepared from 2,4-dimethyl-benzenethiol and 2,4-dibromo-1-iodo-benzene (prepared from 2,4-dibromo-phenylamine by diazotization according to the general procedure by Tunney and Stille J. Org. Chem. 1987, 52, 748-753).
Reaction SMILES: [CH3:1][C:2]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[I:18])=[N:7][N:6]=1)([CH3:4])[CH3:3].[Cl:20][S:21](O)(=[O:23])=[O:22]>>[CH3:4][C:2]([C:5]1[S:9][C:8]([NH:10][C:11]([C:12]2[CH:17]=[C:16]([S:21]([Cl:20])(=[O:23])=[O:22])[CH:15]=[CH:14][C:13]=2[I:18])=[O:19])=[N:7][N:6]=1)([CH3:1])[CH3:3]
Reactant: O=S(=O)(O)Cl
Reactant: CC(C)(C)c1nnc(NC(=O)c2ccccc2I)s1
Product: CC(C)(C)c1nnc(NC(=O)c2cc(S(=O)(=O)Cl)ccc2I)s1
Temperature: 25 °C

Procedure:
N-[5-(1,1-dimethylethyl)-1,3,4-thiadiazol-2-yl]-2-iodobenzamide (600 mg) was added to 2 ml chlorosulfonic acid and heated at 180 C in a microwave for 1 min. The reaction was cooled to rt and added dropwise to ice water. A solid resulted, was filtered off, and was vacuum dried to give 450 mg of crude 3-({[5-(1,1-dimethylethyl)-1,3,4-thiadiazol-2-yl]amino}carbonyl)-4-iodobenzenesulfonyl chloride which was add to 5 ml of a 2M ethyl amine solution in THF. The reaction was stirred at it for 15 min and then washed with water and evaporated to give 280 mg crude product. 50 mg of this solid was purified by HPLC to give 36 mg N-[5-(1,1-dimethylethyl)-1,3,4-thiadiazol-2-yl]-5-[(ethylamino)sulfonyl]-2-iodobenzamide which was pure by LCMS.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.CC(C)([O-])C.[K+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]([NH2:25])=[O:24])[CH:18]=1>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]([NH2:25])=[O:24])[CH:18]=2)=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(O)c(F)c1
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Oc2ccc(N)cc2F)ccn1
Temperature: 110 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
A solution of 4-amino-2-fluorophenol (0.81 g, 6.4 mmol, 1.0 eq) in DMF (6.5 mL) was treated with potassium tert-butoxide (0.79 g, 7.1 mmol, 1.1 eq) at room temperature and the reaction mixture was stirred for 1 h. 4-Chloropicolinamide (1.0 g, 6.4 mmol, 1.0 eq) was added and the reaction mixture was heated to 110° C. for 8 h. The reaction was cooled to room temperature and the reaction mixture quenched with water. The resulting heterogeneous solution was filtered and the solid material was washed with water. The solid was triturated with a small amount of MeOH followed by Et2O. The solid was filtered and dried in vacuo to afford the desired product (1.3 g, 82%) as a solid. 1H NMR (DMSO-d6) δ 8.49-8.50 (m, 1H), 8.12 (br s, 1H), 7.71 (br s, 1H), 7.35-7.36 (m, 1H), 7.14-7.16 (m, 1H), 7.01-7.06 (m, 1H), 6.44-6.47 (m, 2H), 5.53 (s, 2H); MS(ESI+) m/z 248 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[C:9]1([C:2]2[CH:7]=[CH:6][C:5]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc(Br)nc1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(-c2ccc(-c3ccccc3)nc2)cc1
Yield: 72.1 %

Procedure:
2,5-dibromopyridine (10 g, 42 mmol), phenylboronic acid (13.4 g, 110 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos) (0.7 g, 1.6 mmol), and potassium phosphate (22 g, 105 mmol) were mixed in 200 mL of toluene and 20 mL of water. Nitrogen is bubbled directly into the mixture for 30 minutes. Next, Pd2(dba)3 was added (0.38 g, 0.4 mmol) and the mixture was heated to reflux under nitrogen for 2 h. The mixture was cooled and the organic layer was separated. The organic layers are washed with brine, dried over magnesium sulfate, filtered, and evaporated to a residue. The residue was purified by column chromatography eluting with 10% ethyl acetate/hexanes. 7 g of desired product was obtained after purification. (91.8% yield)
Reaction SMILES: [NH2:1][CH:2]([CH:7]([N:14]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:15]=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[C:27]([C:34]([F:37])([F:36])[F:35])[CH:26]=1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>C(Cl)Cl.C1COCC1>[CH2:17]([N:14]([CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]([NH:1][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:25]([F:24])=[CH:26][C:27]=1[C:34]([F:37])([F:35])[F:36])[C:3]([O:5][CH3:6])=[O:4])[CH:15]=[O:16])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)C(N)C(c1ccccc1)N(C=O)Cc1ccccc1
Reactant: O=C(O)c1ccc(F)cc1C(F)(F)F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)C(NC(=O)c1ccc(F)cc1C(F)(F)F)C(c1ccccc1)N(C=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.9 %

Procedure:
1.4 g (0.0052 mol) of methyl 2-amino-3-(N-benzyl-N-formylamino)-3-phenylpropionate were dissolved in methylene chloride, and 1.0 g (0.0052 mol) of 4-fluoro-2-trifluoromethylbenzoic acid and 1.0 g (0.010 mol) of triethylamine in THF were added. At 0-5° C., 1.3 g (0.0052 mol) of bis(2-oxo-3-oxazolidinyl)phosphoryl chloride were added. After 2 h at 0° C., the mixture was stirred at room temperature for 15 h. The solvents were removed and the residue was taken up in ethyl acetate, washed and dried. Chromatographic purification (silica gel column, cyclohexane/ethyl acetate) gave 0.65 g of the title compound as a colorless oil.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:8]=[C:9]([CH2:22][C:23](Cl)=[N:24][OH:25])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1.[C:27]([C:29]1[C:30]([NH2:36])=[N:31][C:32]([NH2:35])=[CH:33][CH:34]=1)#[CH:28].C(N(CC)CC)C>O>[F:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)[CH2:22][C:23]1[CH:28]=[C:27]([C:29]2[C:30]([NH2:36])=[N:31][C:32]([NH2:35])=[CH:33][CH:34]=2)[O:25][N:24]=1
Reactant: ON=C(Cl)Cc1ccc(OCc2ccc(F)cn2)c(F)c1
Reactant: C#Cc1ccc(N)nc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4ccc(F)cn4)c(F)c3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a tetrahydrofuran (5.00 mL) solution of (3-fluoro-4-(5-fluoro-pyridin-2-ylmethoxy)-phenyl)-acetohydroximoyl chloride (170 mg, 0.554 mmol) described in Manufacturing Example 94-1-3 and 3-ethynyl-pyridin-2,6-diamine (40.0 mg, 0.300 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (125 μL, 0.900 mmol) at room temperature, which was stirred for 30 minutes at room temperature. Water was added to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1→3:1) to obtain the title compound (59.0 mg, 48.0%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[C:11]([NH2:20])[N:10]([CH3:21])[N:9]=1)(=[O:3])[CH3:2].[H-].[Na+].[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>CC(N(C)C)=O.O>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[C:11]([NH:20][S:34]([C:31]2[CH:32]=[CH:33][C:28]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[N:10]([CH3:21])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)OCCOc1nn(C)c(N)c1-c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)OCCOc1nn(C)c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1-c1ccc(C)cc1
Reaction time: 0.08 h
Yield: 24.3 %

Procedure:
To 2-{[5-amino-1-methyl-4-(4-methylphenyl)-1H-pyrazol-3-yl]oxy}ethyl acetate (Preparation 5) (250 mg) in dimethyl acetamide (2 ml) at room temperature was added sodium hydride (41 mg, 60% dispersion in oil), the mixture was stirred for 5 minutes. To the mixture was added 4-tert-butylbenzenesulphonyl chloride (79 mg), the mixture was stirred for a further 1 hour. The reaction was diluted with water (20 ml) and extracted with diethyl ether (20 ml). The organic fraction was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 10 g) eluted with dichloromethane:ether (1:1) to yield the title compound as a pale orange solid (40 mg).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:13])[CH:9]=2)[NH:4][C:3]1=O.[CH2:15]([C:17]1[O:21][N:20]=[C:19]([CH2:22][N+:23]#[C-:24])[N:18]=1)[CH3:16]>>[CH2:15]([C:17]1[O:21][N:20]=[C:19]([C:22]2[N:23]=[CH:24][N:4]3[C:5]4[C:10](=[CH:9][C:8]([Cl:13])=[CH:7][CH:6]=4)[C:11](=[O:12])[N:2]([CH3:1])[C:3]=23)[N:18]=1)[CH3:16]
Reactant: [C-]#[N+]Cc1noc(CC)n1
Reactant: Cn1c(=O)[nH]c2ccc(Cl)cc2c1=O
Product: CCc1nc(-c2ncn3c4ccc(Cl)cc4c(=O)n(C)c23)no1

Procedure:
M.p. 196°-198° C. by reaction between 3-methyl-6-chloro-1,2,3,4-tetrahydro-2,4-dioxoquinazoline and 5-ethyl-3-isocyanomethyl-1,2,4-oxadiazole.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[C:6]([CH3:17])[N:5]=[CH:4][N:3]=1.[C:18]([O:22][C:23](=[O:32])[NH:24][CH2:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:21])([CH3:20])[CH3:19].CCN(C(C)C)C(C)C>C(#N)C>[C:18]([O:22][C:23](=[O:32])[NH:24][CH2:25][CH:26]1[CH2:27][CH2:28][N:29]([C:2]2[C:7]([C:8]#[C:9][C:10]3[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[C:6]([CH3:17])[N:5]=[CH:4][N:3]=2)[CH2:30][CH2:31]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: Cc1ncnc(Cl)c1C#Cc1ccc(N)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ncnc(N2CCC(CNC(=O)OC(C)(C)C)CC2)c1C#Cc1ccc(N)nc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
The title compound is synthesized according to general procedure GP7 (method 2) starting from 2.0 g (8.17 mmol) 4-chloro-6-methyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidine and 2.33 g (9.81 mmol) piperidin-4-ylmethyl-carbamic acid tert-butyl ester using 1.82 mL (10.6 mmoL) DIPEA in 50 mL ACN. The reaction mixture is stirred for 1 h at 80° C. The solvent is removed under reduced pressure. The residue is taken up in DCM/MeOH and filtered over silica. After removal of the solvent and extractive work up 3.1 g (90%) of the desired product is obtained. The product is used without further purification for the next step.
Reaction SMILES: [C:1]1([NH:7][N:8]=[CH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](OC=O)(=[O:18])C.C(O)=O.C(OC(=O)C)(=O)C>C(Cl)Cl>[CH:16]([N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[N:8]=[CH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:18]
Reactant: C(=NNc1ccccc1)c1cccnc1
Reactant: CC(=O)OC=O
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CN(N=Cc1cccnc1)c1ccccc1
Reaction time: 8 h

Procedure:
9.85 g of 3 (prepared as described in Example 3) was dissolved in 50 ml of dry methylene chloride. 15 ml of formic acetic anhydride (prepared by mixing the appropriate amounts of formic acid and acetic anhydride) was added. The mixture was allowed to stand overnight at room temperature. The solvent was evaporated under reduced pressure. The residue was dissolved in ether. The solution was washed with sodium bicarbonate solution, dried (Na2SO4) and the solvent evaporated to give 4, as a white crystalline solid, mp 129°-132° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([NH:20][C:21]([N:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)N1CCN(Cc2ccccc2)CC1

Procedure:
The title compound was prepared from 1-benzylpiperazine and phenyl isocyanate. 1H NMR (400 MHz, CDCl3): 7.35-7.22 (m, 9H), 7.02-6.97 (m, 1H), 6.55 (br s, 1H), 3.56 (s, 2H), 3.48-3.45 (m, 4H), 2.45-2.41 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)/[CH:5]=[CH:6]/[C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1>C(O)C.[C].[Pd]>[OH:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][C:7]2[S:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: Oc1cccc(/C=C/c2nc3ccccc3s2)c1
Agent: [Pd]
Solvent: CCO
Product: Oc1cccc(CCc2nc3ccccc3s2)c1
Reaction time: 3 h
Yield: 90.9 %

Procedure:
A mixture of 6.0 g of 2-(trans-3-hydroxystyryl) benzothiazole and 0.5 g of 5% palladium-carbon in 80 ml of ethanol was stirred under hydrogen gas stream under normal pressure at 50° to 60° C. for 3 hours. After completion of the reaction, the catalyst was filtered off and the filtrate was evaporated under reduced pressure to obtain 5.5 g (yield 92%) of the title compound as pale gray crystals.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[C:11]([CH3:23])([CH3:22])[C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)([CH3:14])[N:13]=1)(C)(C)C.[C:27]([C:29]1([C:32](O)=[O:33])[CH2:31][CH2:30]1)#[N:28]>>[NH2:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[C:11]([CH3:23])([CH3:22])[C@:12]([C:15]2[CH:16]=[C:17]([NH:21][C:32]([C:29]3([C:27]#[N:28])[CH2:31][CH2:30]3)=[O:33])[CH:18]=[CH:19][CH:20]=2)([CH3:14])[N:13]=1
Reactant: N#CC1(C(=O)O)CC1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cccc(N)c2)N=C1NC(=O)OC(C)(C)C
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cccc(NC(=O)C3(C#N)CC3)c2)N=C1N

Procedure:
The coupling of [(R)-4-(3-amino-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F1) and 1-cyano-cyclopropanecarboxylic acid followed by deprotection of the intermediate yielded the title compound as a white solid. MS (ESI): m/z=354.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH3:19])=[CH:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2=[O:20])=[CH:4][CH:3]=1>C(OCC)(=O)C.CCCCCC>[OH:20][CH2:9][CH:8]([C:12]1[C:13]([CH3:19])=[CH:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=1[OH:10])[C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: Cc1cc(C)c2c(c1C)OC(=O)C2c1ccc(Br)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(C)c(C(CO)c2ccc(Br)cc2)c(O)c1C
Yield: 93 %

Procedure:
Using 3-(4-bromophenyl)-4,6,7-trimethyl-1-benzofuran-2(3H)-one obtained in Reference Example 229, the title compound was synthesized in the same manner as in Reference Example 8. Yield 93%. Melting point: 114-115° C. (ethyl acetate-hexane).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[C:13]([F:23])=[C:14]4[C:18](=[CH:19][C:20]=3[F:21])[N:17]([CH3:22])[N:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[C:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])[CH3:27]>CN1C(=O)CCC1.CCOC(C)=O>[F:23][C:13]1[C:12]([CH2:11][C:8]2[N:6]3[N:7]=[C:2]([N:32]4[CH2:33][CH2:34][N:29]([C:26](=[O:28])[CH3:27])[CH2:30][CH2:31]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[C:20]([F:21])[CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][N:17]2[CH3:22]
Reactant: CC(=O)N1CCNCC1
Reactant: Cn1ncc2c(F)c(Cc3cnc4ccc(Cl)nn34)c(F)cc21
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(=O)N1CCN(c2ccc3ncc(Cc4c(F)cc5c(cnn5C)c4F)n3n2)CC1
Temperature: 180 °C
Reaction time: 3 h

Procedure:
6-chloro-3-((4,6-difluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazine (Intermediate T, 40.0 mg, 0.12 mmol), KF (34.8 mg, 0.6 mmol) and 1-acetylpiperazine (46.1 mg, 0.36 mmol) were suspended in NMP (0.3 mL). The RM was stirred at 180° C. for 3 h. The mixture was diluted with EtOAc and washed with NaHCO3 10% (2×) and water (4×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography and afforded the title compound as a light brown foam (tR 3.72 min (conditions 5), MH+=426.3, 1H-NMR in DMSO-d6: 8.16 (s, 1H); 7.80 (d, 1H); 7.46 (d, 1H); 7.27 (s, 1H); 7.10 (d, 1H); 4.27 (s, 2H); 3.98 (s, 3H); 3.50 (s, 6H); 3.44 (m, 2H); 2.03 (s, 3H)).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]=[C:6]=[O:7].[CH3:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH2:15].C(OC(=O)C)C>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([NH:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[CH3:8])=[O:7]
Reactant: Cc1ccncc1N
Reactant: O=C=NCCCCl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccncc1NC(=O)NCCCCl
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.7 %

Procedure:
1-Chloro-3-isocyanato-propane (1.6 g, 13.87 mmol) was added dropwise to a stirred solution of 4-methyl-pyridin-3-ylamine (1 g, 9.25 mmol) in toluene (15 mL) at 0° C. The reaction mixture was stirred at room temperature for 18 hours. The reaction was monitored by TLC (100% ethylacetate). The reaction mixture was filtered, washed with toluene and dried under reduced pressure to afford 2.12 g (99.5% yield) of 1-(3-chloro-propyl)-3-(4-methyl-pyridin-3-yl)-urea.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][N:10]([CH2:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=1)[C:11](=[O:33])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[B-](F)(F)(F)F.CN(C(O[N:66]1[C:71](=[O:72])[CH2:70][CH2:69][C:67]1=[O:68])=[N+](C)C)C>C1COCC1>[O:68]=[C:67]1[CH2:69][CH2:70][C:71](=[O:72])[N:66]1[O:40][C:39](=[O:41])[C:38]1[CH:37]=[CH:36][C:35]([CH2:34][N:10]([CH2:9][CH2:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:11](=[O:33])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[CH:43][CH:42]=1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)N(CCC(=O)OC(C)(C)C)Cc1ccc(C(=O)O)cc1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)N(CCC(=O)OC(C)(C)C)Cc1ccc(C(=O)ON2C(=O)CCC2=O)cc1
Temperature: 0 °C
Yield: 86.8 %

Procedure:
4-{[(2-tert-Butoxycarbonylethyl)-(15-tert-butoxycarbonyl-pentadecanoyl)amino]methyl}benzoic acid (70 mg, 0.12 mmol) was dissolved in THF (5 mL). The mixture was cooled with an ice bath. Diisopropylethylamin (0.024 mL, 0.14 mmol) and O—(N-succinimidyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (42 mg, 0.14 mmol) was added. The mixture was stirred under nitrogen at 0° C. After 30 minutes the ice cooling was removed and the mixture was stirred for an additional 3 hours. Solvent removed in vacuo flowed by reevaporation from toluene. The crude product was dissolved in ethyl acetate (25 mL), washed with water (10 mL). The organic phase dried (Na2SO4), solvent removed in vacuo to yield the title compound (73 mg, 87%) which was used in subsequent step.