Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:16]=[C:15]([CH2:17][CH2:18][C:19]([OH:21])=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:34]([NH:36][CH2:37][CH3:38])[CH3:35]>CN(C)C=O>[CH2:34]([N:36]([CH2:37][CH3:38])[C:19](=[O:21])[CH2:18][CH2:17][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:16]=1)[CH3:35]
Reactant: CCNCC
Reactant: O=C(O)CCc1nc(-c2ccccn2)nc2ccccc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)CCc1nc(-c2ccccn2)nc2ccccc12

Procedure:
The procedure is as in Example 7, starting with 2-(2-pyridyl)-4-quinazolinepropanoic acid (1.34 g), carbonyldiimidazole (0.93 g) and diethylamine (1 cc) in dimethylformamide (25 cc). After chromatography on silica gel with a chloroform/methanol (95:5 by volume) mixture as eluant, and crystallization in ethyl acetate, N,N-diethyl-2-(2-pyridyl)-4-quinazolinepropanamide (0.58 g), m.p. 130° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[N:7]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[CH2:19][CH2:18]3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(O)(=O)C>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]([CH:20]2[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][CH2:13][N:7]3[C:6](=[O:32])[C:5]4[C:10](=[CH:11][C:2]([NH:1][C:33](=[O:35])[CH3:34])=[CH:3][CH:4]=4)[NH:9][C:8]3=[O:12])[CH2:18][CH2:19]2)=[O:31])=[CH:25][CH:26]=1
Reactant: Nc1ccc2c(=O)n(CCCCN3CCC(C(=O)c4ccc(F)cc4)CC3)c(=O)[nH]c2c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2c(=O)n(CCCCN3CCC(C(=O)c4ccc(F)cc4)CC3)c(=O)[nH]c2c1
Yield: 100 %

Procedure:
A mixture of 5.8 parts of 7-amino-3-[4-[4-(4-fluorobenzoyl)-1-piperidinyl]butyl]-2,4(1H,3H)-quinazolinedione, 100 parts of acetic acid and 2.5 parts of acetic acid anhydride was stirred at reflux temperature. The reaction mixture was evaporated. The residue was stirred in water and ammonium hydroxide. The product was filtered off, washed with water and boiled in ethanol. After cooling, the product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 6.3 parts (100%) of N-[3-[4-[4-(4-fluorobenzoyl)-1-piperidinyl]butyl]-1,2,3,4-tetrahydro-2,4-dioxo-7-quinazolinyl]-acetamide; mp. 273.1° C. (18).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]([CH2:18][CH:19]4[CH2:23][CH2:22][CH2:21][N:20]4C(OC(C)(C)C)=O)[C:15](=[O:17])[NH:16][C:11]3=[N:10][CH:9]=2)=[CH:4][CH:3]=1.BrC1N=C2N(CC3CCCN3C(OC(C)(C)C)=O)C(=O)NC2=NC=1.OC1C=CC(B(O)O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]3[N:14]([CH2:18][CH:19]4[CH2:23][CH2:22][CH2:21][NH:20]4)[C:15](=[O:17])[NH:16][C:11]3=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1Cn1c(=O)[nH]c2ncc(-c3ccc(O)cc3)nc21
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(C)(C)OC(=O)N1CCCC1Cn1c(=O)[nH]c2ncc(Br)nc21
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=c1[nH]c2ncc(-c3ccc(O)cc3)nc2n1CC1CCCN1
Yield: 41.4 %

Procedure:
tert-Butyl 2-((6-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)pyrrolidine-1-carboxylate, tert-Butyl 2-((6-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)pyrrolidine-1-carboxylate (0.5 g., 1.25 mmol), 4-hydroxyphenylboronic acid (0.17 g., 1.25 mmol), dichloro[1,1′-bis(diphenylphosphino) ferrocene]palladium(II) dichloromethane adduct (0.103 g. 0.126 mmol) and sodium carbonate (0.665 g., 6.28 mmol) were reacted for 40 min in 1,4-dioxane (4 mL) according to General Procedure B2 and purified using silica gel chromatography (60% ethyl acetate in hexanes) to afford the title compound (0.21g, 41.4% yield). MS (ESI) m/z 412.4 [M+1]+.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(CCN(C)C)C.C([Li])CCC.[CH:34](N1CCCCC1)=[O:35]>C1COCC1>[CH:34]([C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:12]=[CH:11][C:10]=1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:35]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)nc1
Reactant: O=CN1CCCCC1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnc(-c2ccccc2)cc1C=O
Temperature: -72 °C
Reaction time: 0.25 h
Yield: 43.9 %

Procedure:
A solution of 3B (3.3 g, 12.21 mmol) in dry THF (50 mL) and TMEDA (4.6 mL, 30.53 mmol) under argon was cooled to −72° C. and treated dropwise with n-butyllithium (2.5 M in hexanes, 12.2 mL, 30.53 mmol) at such a rate so that the temperature did not exceed −65° C. Upon completion of the addition, the reaction was stirred at −72° C. for an additional 15 min and then at −20° C. for 1.5 h. The reaction was cooled again to −72° C., and N-formyl piperidine (2.7 mL, 24.4 mmol) was added while the temperature was maintained below −65° C. The mixture was allowed to stir at RT for 30 min. After this time, no starting material was detected by LC-MS. The solution was cooled to 0° C. and quenched by the addition of 1 M aqueous HCl to bring the pH to 6-8. The reaction was stirred at RT for 15 min, extracted with EtOAc (3×100 mL). The combined organics were washed with saturated NaCl, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel (110 g) column chromatography, eluting with a gradient of EtOAc (0-60%) in hexane to give the title compound as a yellow solid (1.6 g, 44%). LC/MS (method A): retention time=2.79 min, (M+MeOH+H)+=331.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:25])[C@@H:10]([C:22]([OH:24])=[O:23])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]([F:46])([F:45])[C:28]([NH:30][C@H:31]([C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[CH2:32][CH2:33]O)=[O:29]>C(Cl)Cl>[CH2:1]([O:8][C@H:9]([CH3:25])[C@@H:10]([C:22]([O:24][CH2:33][CH2:32][C@@H:31]([C:35]([O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:36])[NH:30][C:28](=[O:29])[C:27]([F:46])([F:26])[F:45])=[O:23])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@H](CCO)NC(=O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC[C@H](NC(=O)C(F)(F)F)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 58.1 %

Procedure:
To a solution of O-benzyl-N-benzyloxycarbonyl-L-threonine (1.5 g), benzyl N-trifluoroacetyl-L-homoserinate (1.34 g) and 4-N,N-dimethylaminopyridine (48.8 mg) in methylene chloride (30 ml) was added N,N-diethylaminopropyl-N'-ethylcarbodiimide hydrochloride (840 mg) at 0° C. After stirring for an hour at room temperature, the reaction mixture was concentrated. The residue was dissolved in ethyl acetate and washed successively with 0.1N hydrochloric acid, water, 10% aqueous sodium hydrogen carbonate, water and brine. After drying over sodium sulfate, the ethyl acetate extract was filtered and concentrated. The residue was chromatographed on silica gel eluting successively with a 1:1 mixture of methylene chloride and hexane, methylene chloride and a 50:1 mixture of methylene chloride and acetone (50:1) to give benzyl O-(O-benzyl-N-benzyloxycarbonyl-L-threonyl)-N-trifluoroacetyl-L-homoserinate (1.6 g).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[O:17]CC2C=CC=CC=2)[C:6]1=[O:25])(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([O:4][C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[OH:17])[C:6]1=[O:25])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC(=O)N([C@@H]2CCCC[C@H]2OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)O[C@@H]1CC(=O)N([C@@H]2CCCC[C@H]2O)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of acetic acid (1R,2R)-benzyloxycyclohexyl-2,5-dioxo-pyrrolidin-3-(R)-yl ester (3a (1.1 g, 3.18 mmol) in MeOH was added 10% Pd—C (110 mg), and the reaction vessel was flushed twice with H2. The reaction mixture was agitated at ambient temperature under H2 (charged balloon). After 4 hours, the reaction mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo to give acetic acid 1R,2R-hydroxycyclohexyl-2,5-dioxopyrrolidin-3-(R)-yl ester (4a) as a white hygroscopic foam (0.82 g, 99% yield); MS (ES+) 256.1 [M+H]+, 278.0 [M+Na]+, 533.1 [2M+Na]+; 1H-NMR (400 MHz, CDCl3) δ 1.11-1.34 (m, 3H), 1.64-1.75 (m, 3H), 2.02-2.09 (m, 2H), 2.12 (s, 3H, CH3), 2.22 (br s, 1H), 2.63 (dd, 1H, J=18.0 Hz, 4.8 Hz), 3.11 (dd, 1H, J=8.8 Hz, J=18 Hz), 3.82 (ddd, 1H, J=4.16 Hz, J=10.6 Hz, J=12.8 Hz), 4.16 (ddd, 1H J=4.4 Hz, J=10.4 Hz, J=14.8 Hz), 5.34 (dd, 1H, J=8.8 Hz, J=4.8 Hz); 13C-NMR (100 MHz, CDCl3) δ 20.52, 24.16, 24.98, 27.77, 35.03, 35.40, 58.44, 67.43, 68.40, 170.11, 173.89, 174.08.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])=[CH:3][C:4](=[O:8])[CH:5]=[CH:6][CH3:7].CC(C(C)CC=C(C)C)=CC=O.B(F)(F)F.CCOCC>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]([C:4](=[O:8])/[CH:5]=[CH:6]/[CH3:7])[C:12]([CH3:13])([CH3:14])[CH2:11][CH2:10][CH:9]=1
Reactant: CC=CC(=O)C=C(C)CCC=C(C)C
Agent: CC(C)=CCC(C)C(C)=CC=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: c1ccccc1
Product: C/C=C/C(=O)C1C(C)=CCCC1(C)C
Temperature: 0 °C
Yield: 50 %

Procedure:
A mixture of 10 g. of 6,10-dimethyl-4-oxo-2,5,9-undecatriene prepared according to the method of paragraph (c) herebelow, 100 ml. of benzene and 1 g. of boron trifluoride etherate was heated to the reflux until the vapour phase chromatographic analysis of a sample showed that practically all the starting material had disappeared. The solution was cooled and stirred with ice-water. The organic layer was removed and treated as usual. Distillation of the residue of evaporation gave a 50% yield of trans-2,6,6-trimethyl-1-crotonoyl-2-cyclohexene of about 60% purity as shown by the vapour phase chromatographic analysis.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([CH2:11][CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Br[C:19]1[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1>[CH:1]1([N:5]2[CH2:6][CH2:7][CH:8]([CH2:11][CH:12]3[CH2:17][CH2:16][N:15]([C:19]4[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=4)[CH2:14][CH2:13]3)[CH2:9][CH2:10]2)[CH2:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1ncc(Br)cn1
Reactant: C1CC(N2CCC(CC3CCNCC3)CC2)C1
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: C1COCCO1
Product: FC(F)(F)c1ncc(N2CCC(CC3CCN(C4CCC4)CC3)CC2)cn1
Temperature: 120 °C
Yield: 36.8 %

Procedure:
1-Cyclobutyl-4-(4-piperidinylmethyl)piperidine (may be prepared as described in Description 6) (0.15 g), 5-bromo-2-trifluoromethylpyrimidine (may be prepared as described in F. Cottet and M. Schlosser, Eur. J. Org. Chem., 2002, 327) (0.129 g), tris(dibenzylidineacetone)dipalladium(0) (0.053 g), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.088 g) and sodium tert-butoxide (0.092 g) were added to dioxane (2 ml) and heated at 120° C. for 14 min in the microwave reactor. The crude reaction mixture was passed through an SCX column (10 g, eluting with methanol [80 ml ] then 2 N NH3 in methanol [80 ml]). Chromatography (silica gel, eluting with methanol/dichloromethane, 0-20%) afforded the title compound (E35) (0.08 g). MS electrospray (+ion) 383 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].[CH3:11][CH:12]([CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:13][CH2:14]Br.O>C(O)C>[CH3:11][CH:12]([CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:13][CH2:14][O:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1
Reactant: Oc1cccc(Br)c1
Reactant: CC(C)CCCC(C)CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)CCCC(C)CCOc1cccc(Br)c1
Temperature: 70 °C
Reaction time: 22 h
Yield: 92 %

Procedure:
Under an inert atmosphere, 90 g of 3-bromophenol was dissolved in 600 ml of ethanol. Further, 39 g potassium hydroxide was added to this and the mixture was heated up to 70° C. for dissolution thereof. From a dropping funnel, 126 g of 3,7-dimethylbromooctane was dropped over 15 minutes. After completion of dropping, the mixture was heated to 84° C. and stirred for about 22 hours under heat. After completion of heating, the mixture was left to cool to room temperature. The reaction solution was bisected, 500 ml of water was added to respective portions, then, ethanol was distilled off by an evaporator. The solutions after distilling off of ethanol were combined and trisected, 300 ml of ethyl acetate was added to respective portions to cause liquid separation, and the organic layers were washed with 200 ml of water twice. The organic layers were combined and the solvent was distilled off by an evaporator, then, the residue was dried by heating at 90° C. for 5 hours under vacuum by a rotary pump. About 150 g of 3-(3,7-dimethyloctyloxy)-bromobenzene was obtained as an oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[N+:24]([O-])=O)[C:13](=[O:27])[CH2:12]2)=[CH:4][CH:3]=1.O.NN>[Ni].C(O)C>[NH2:24][C:18]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=1[N:14]1[CH2:15][CH2:16][N:11]([CH2:10]/[CH:9]=[CH:8]/[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:12][C:13]1=[O:27]
Reactant: O=C1CN(C/C=C/c2ccc(Cl)cc2)CCN1c1cc(F)ccc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc(F)cc1N1CCN(C/C=C/c2ccc(Cl)cc2)CC1=O
Temperature: 25 °C
Yield: 45.1 %

Procedure:
Raney nickel (50% slurry in water, 200 mg) was added to a solution of the compound obtained in Step C (389 mg) in ethanol (10 ml); hydrazine hydrate (0.5 ml) was added and the reaction mixture was stirred at room temperature until gas evolution ceased (1 hour). The reaction mixture was filtered over Hyflo, the solvent removed in vacuo and the residue purified by column chromatography (2.5% methanol in ethyl acetate) to afford 1-(2-Amino-5-fluoro-phenyl)-4-[(E)-3-(4-chloro-phenyl)-allyl]-piperazin-2-one (162 mg). Retention Time LCMS 2.81 min; MS (ES+) 360/362 (M+H+).
Reaction SMILES: CS(O[C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]3[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:7]1)(=O)=O.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)C>[N:21]1([C@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[S:12][C:13]4[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:14]=4[N:15]=3)[CH2:7]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)O[C@@H]1CCN(c2nc3ccc(Br)cc3s2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Brc1ccc2nc(N3CC[C@H](N4CCCC4)C3)sc2c1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
A mixture of (R)-1-(6-bromobenzo[d]thiazol-2-yl)pyrrolidin-3-yl methanesulfonate (Reference Example 12, 0.50 g, 1.32 mmol), pyrrolidine (0.221 mL, 2.65 mmol), and potassium carbonate (0.549 g, 3.98 mmol) was placed in a 10 mL CEM microwave vial with a stirbar. N,N-Dimethylformamide (1.5 mL) was added, the vial was capped, and the reaction was heated to 100° C. under microwave irradiation for 15 minutes, then the cooling air was turned on and heating was continued at 70° C. for an additional 15 minutes. The reaction mixture was cooled to room temperature then partitioned between ethyl acetate and saturated aqueous sodium carbonate. The aqueous layer was extracted once more with ethyl acetate. The combined organic extracts were washed twice with brine, then dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give an oil that solidified on trituration with diethyl ether. The solid was collected by filtration and rinsed with diethyl ether, then purified by column chromatography on an Analogix IntelliFlash-280 (Analogix SF15-12g, 100% dichloromethane to 98:2 dichloromethane/methanol). Fractions containing product were combined and concentrated under reduced pressure to give a solid that was dried overnight in a vacuum oven at 70° C. to give (S)-2-(1,3′-bipyrrolidin-1′-yl)-6-bromobenzo[d]thiazole. 1H NMR (300 MHz, CD3OD) δ ppm 1.78-1.93 (m, 4H), 2.01-2.15 (m, 1H), 2.26-2.37 (m, 1H), 2.58-2.74 (m, 4H), 3.00-3.11 (m, 1H), 3.40-3.48 (m, 1H), 3.49-3.60 (m, 1H), 3.66-3.83 (m, 2H), 7.35 (d, J=9 Hz, 2H), 7.40 (dd, J=2, 9 Hz, 1H), 7.81 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 352 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[O:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.N1CCCC1>CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:15]1([CH2:16][CH2:17][O:12][CH2:13][CH2:14]1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: O=C1CCOCC1
Solvent: C1CCNC1
Solvent: CO
Product: O=C1CC2(CCOCC2)Oc2ccc(Br)cc21
Reaction time: 8 h
Yield: 108.1 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (10 g, 46.7 mmol), dihydro-2H-pyran-4(3H)-one (9.35 g, 93.45 mmol) and pyrrolidine (6.3 g, 88.8 mmol) in methanol (200 mL) was stirred overnight. The reaction mixture was removed in vacuo, and H2O was added. The resulting solution was extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2′,3′,5′,6′-tetrahydrospiro[chroman-2,4′-pyran]-4-one (15 g, 100%). 1HNMR (CDCl3): 1.74 (m, 2H), (m, 2H), 1.94 (t, 2H), 2.71 (s, 2H), 3.76 (m, 4H), 6.91 (d, 1H), 7.54 (d, 1H), 7.96 (s, 1H).
Reaction SMILES: FC1C=CC(C(Cl)=O)=CC=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([N:20]=[C:21]=[S:22])=[O:19])=[CH:14][CH:13]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[C:40]([CH3:45])[CH:39]=1.C1(C)C=CC=CC=1>C(O)C>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([N:20]=[C:21]=[S:22])=[O:19])=[CH:16][CH:17]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH:42][C:21]([NH:20][C:18](=[O:19])[C:15]2[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=2)=[S:22])=[C:40]([CH3:45])[CH:39]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Agent: O=C(Cl)c1ccc(F)cc1
Agent: O=C(N=C=S)c1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(F)cc4)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
4-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-Fluoro-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (35 mg, yield 44%).
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][CH:4]1[CH:6]([C:7](Cl)=[O:8])[C:5]1([CH3:11])[CH3:10].[CH3:13][O:14][CH2:15][C:16]1[C:23]([F:24])=[C:22]([F:25])[C:19]([CH2:20][OH:21])=[C:18]([F:26])[C:17]=1[F:27].N1C=CC=CC=1>O1CCCC1>[CH3:1][C:2]([CH3:12])=[CH:3][CH:4]1[CH:6]([C:7]([O:21][CH2:20][C:19]2[C:18]([F:26])=[C:17]([F:27])[C:16]([CH2:15][O:14][CH3:13])=[C:23]([F:24])[C:22]=2[F:25])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: CC(C)=CC1C(C(=O)Cl)C1(C)C
Reactant: COCc1c(F)c(F)c(CO)c(F)c1F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COCc1c(F)c(F)c(COC(=O)C2C(C=C(C)C)C2(C)C)c(F)c1F
Temperature: 25 °C

Procedure:
3-(2-methyl-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid chloride {containing the stereoisomers in a ratio of (1R)-trans form: (1R)-cis form: (1S)-trans form: (1S)-cis form=76:19:4:1} is added to a mixture of 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol, pyridine and tetrahydrofuran under ice-cooling. The resulting mixture is heated to room temperature and stirred at room temperature. The reaction mixture is poured into ice water and extracted with ethyl acetate. The combined ethyl acetate layer is washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant residue is subjected to silica gel column chromatography to obtain 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl 3-(2-methyl-1-propenyl)-2,2-dimethylcyclopropane-carboxylate (hereinafter referred to as the present compound 7).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]3[CH2:20][CH2:19]3)[N:13]=2)[CH:3]=1.[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CN1CCCC1=O>[CH:21]1([NH:27][C:2]2[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]4[CH2:20][CH2:19]4)[N:13]=3)[CH:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCCCC1
Reactant: NC(=O)c1nnc(Cl)cc1Nc1cccc(C2CC2)n1
Solvent: CN1CCCC1=O
Product: NC(=O)c1nnc(NC2CCCCC2)cc1Nc1cccc(C2CC2)n1
Temperature: 130 °C
Yield: 66.7 %

Procedure:
A suspension of 6-chloro-4-(6-cyclopropylpyridin-2-ylamino)pyridazine-3-carboxamide (100 mg, 345 μmol, prepared as described for example 12) and cyclohexylamine (342 mg, 395 μL, 3.45 mmol) in N-methyl-2-pyrrolidinone (0.5 mL) was heated at 130° C. for 14 h. The mixture was cooled and concentrated under high vacuum at 120° C. to remove all residual solvent and amine starting material. The brown solid obtained was purified by chromatography (silica, 11 g spherical, 0-20% acetone in dichloromethane, 20 min) to give 6-(cyclohexylamino)-4-(6-cyclopropylpyridin-2-ylamino)pyridazine-3-carboxamide (81 mg, 230 μmol, 67% yield) as a white solid. 1H NMR (DMSO-d6) δ: 11.72 (br. s., 1H), 8.37 (br. s., 1H), 7.83 (s, 1H), 7.62 (br. s., 1H), 7.56 (t, J=7.7 Hz, 1H), 7.10 (d, J=7.8 Hz, 1H), 6.88 (d, J=7.3 Hz, 1H), 6.66 (d, J=8.1 Hz, 1H), 3.52-3.69 (m, 1H), 2.04-2.18 (m, 1H), 1.90-2.00 (m, 2H), 1.72-1.82 (m, 2H), 1.63 (d, J=12.6 Hz, 1H), 1.24-1.45 (m, 4H), 1.09-1.23 (m, 1H), 0.95-1.03 (m, 4H); MS (EI/CI) m/z: 353.1 [M+H].