Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(Cl)Cl.[NH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[F:29])[C:23](Cl)=[O:24].C([O-])(O)=O.[Na+]>CCN(CC)CC>[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[F:29])[C:23]([NH:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]1)=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc(F)c(Cl)c2)CC1
Reaction time: 1.5 h
Yield: 99.4 %

Procedure:
To a CHCl3 (350 mL) solution of tert-butyl 4-aminopiperidine-1-carboxylate (35.0 g), Et3N (122 mL) and 3-chloro-4-fluorobenzoyl chloride (37.1 g) were added under ice cooling and the mixture was stirred at the same temperature for 1.5 hours. To the reaction mixture, a saturated aqueous NaHCO3 solution was added and the solution was extracted three times with CHCl3. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to obtain tert-butyl 4-[(3-chloro-4-fluorobenzoyl)amino]piperidine-1-carboxylate (62.0 g). To an EtOAc (300 mL) suspension of the compound obtained, a 4 M HCl/EtOAc solution (300 mL) was added and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and 1 M aqueous NaOH solution (300 mL) was added to the residue and the solution was extracted three times with CHCl3. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was suspended in EtOAc/hexane (200 mL, 1/1; v/v) and the mixture was stirred for one hour. The precipitate was filtrated to obtain 3-chloro-4-fluoro-N-piperidin-4-ylbenzamide (37.7 g, a colorless solid).
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]3[N:17]=[CH:18][NH:19][CH:20]=3)=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.[Pd]>[C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]([C:16]3[N:17]=[CH:18][NH:19][CH:20]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1=C(c2c[nH]cn2)c2ccccc2C1c1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: c1ccc(C2CC(c3c[nH]cn3)c3ccccc32)cc1

Procedure:
The mixture of the isomers of 4-(3-phenyl-3H-inden-1-yl)-1H-imidazole was hydrogenated in acetic acid at 50° C. using 10% palladium on charcoal as a catalyst. The mixture was filtered through Celite, and the solvent was evaporated. Water was added and the solution was made basic. The water solution was extracted with ethyl acetate. The organic phase was washed with water, dried and the solvent was evaporated. The hydrochloride salt of the product was made in ethyl acetate. The product 4-(2,3-dihydro-3-phenylinden-1-yl)-1H-imidazole was the mixture of the cis and trans diastereomers (the ratio 95:5).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl.Cl.[C:43]1([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:48]=[CH:47][C:46]([NH:49][C:50](=[O:60])[CH2:51][C:52](=[O:59])[N:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)=[CH:45][CH:44]=1>CN(C=O)C.O>[C:43]1([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:44]=[CH:45][C:46]([NH:49][C:50](=[O:60])[CH2:51][C:52]([N:53]2[CH2:54][CH2:55][N:56]([C:25](=[O:27])[C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:29][CH:28]=3)[CH2:57][CH2:58]2)=[O:59])=[CH:47][CH:48]=1
Reactant: O=C(CC(=O)N1CCNCC1)Nc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(CC(=O)N1CCN(C(=O)c2ccc(F)cc2)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 101 %

Procedure:
HOBt (34 mg, 0.25 mmol) and DIPEA (67.9 mg, 0.51 mmol) were added to a stirred solution of 4-fluorobenzoic acid (29 mg, 0.21 mmol) in DMF (1.5 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (48 mg, 0.25 mmol) followed by N-biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide.hydrochloride (75 mg, 0.2 mmol) were added. The reaction mixture was stirred at room temperature overnight, then diluted with water. The resulting precipitate was filtered to afford 90 mg (97%) of N-biphenyl-4-yl-3-[4-(4-fluoro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 446.18 (M+1)+, 97.9%. 1H NMR: (CDCl3): δ 9.8 (s, 1H), 7.6 (m, 6H), 7.44 (m, 3H), 7.34 (t, 1H), 7.14 (t, 2H), 3.7 (m, 10H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:8][CH2:9][N:10]1[CH2:14][CH2:13][NH:12][C:11]1=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.CO>[N:10]1([CH2:9][CH2:8][N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH2:14][CH2:13][NH:12][C:11]1=[O:15]
Reactant: C1CNCCN1
Reactant: O=C1NCCN1CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: O=C1NCCN1CCN1CCNCC1
Reaction time: 1.5 h
Yield: 60.5 %

Procedure:
A mixture of piperazine (86 g, 1.0 mol), 1-(2-chloroethyl)-imidazolidin-2-one (74 g, 0.5 mol) and sodium carbonate (159 g, 1.5 mol) in ethanol (500 ml) was refluxed with stirring for 1.5 hours. A solution of 1-(2-chloroethyl)-imidazolidin-2-one (74 g, 0.5 mol) in methanol (75 ml) was then added in the course of 1.5 hours, at reflux temperature, whereupon the reaction mixture was refluxed for 18 hours. After cooling, the reaction mixture was filtered and evaporated in vacuo. The residue was dissolved in hot ethanol (100 ml), whereupon ethyl acetate (200 ml) was added. The crystals were filtered and dried to give 1-(2-(2-imidazolidinon-1-yl)ethyl)piperazine (60 g) mp. 136°-140° C. Additional 22 g could be obtained from the mother liquor.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[CH:16]=[C:15]4[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:14]4=[CH:13][C:12]=3[O:11][CH2:10][C:9]=2[CH:23]=1)=[O:4].[C:24]([O:28][C:29]([N:31]1[C@@H:35]([CH3:36])[CH2:34][CH2:33][C@H:32]1[C:37]([OH:39])=[O:38])=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>CC#N.CCOC(C)=O>[CH3:36][C@@H:35]1[N:31]([C:29]([O:28][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:30])[C@H:32]([C:37]([O:39][CH2:2][C:3](=[O:4])[C:5]2[CH:6]=[CH:7][C:8]3[C:17]4[CH:16]=[C:15]5[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:14]5=[CH:13][C:12]=4[O:11][CH2:10][C:9]=3[CH:23]=2)=[O:38])[CH2:33][CH2:34]1
Reactant: O=C(CBr)c1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O
Reactant: C[C@H]1CC[C@@H](C(=O)O)N1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@H]1CC[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCCC4=O)N1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 15 h
Yield: 65 %

Procedure:
To a solution of 3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one in MeCN (30 mL) was added (2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (1.2 g, 3.23 mmol) and triethyl amine (0.48 mL, 3.55 mmol) and the solution was heated to 50° C. After stirring for 15 h, the solution was cooled to rt, and diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (20% to 50% EtOAc/hexanes) to afford (2S,5S)-1-tert-butyl 2-(2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl) 5-methylpyrrolidine-1,2-dicarboxylate (1.09 g, 65%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].F[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([C:17]3[S:21][C:20]([C:22](=[O:24])[CH3:23])=[CH:19][CH:18]=3)=[CH:15][N:16]=2)[N:13]=1.[CH2:25]([CH2:27][NH2:28])[OH:26]>CN(C)C=O>[OH:26][CH2:25][CH2:27][NH:28][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([C:17]3[S:21][C:20]([C:22](=[O:24])[CH3:23])=[CH:19][CH:18]=3)=[CH:15][N:16]=2)[N:13]=1
Reactant: NCCO
Reactant: CC(=O)c1ccc(-c2cnc3ccc(F)nn23)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-c2cnc3ccc(NCCO)nn23)s1
Temperature: 40 °C
Reaction time: 1 h
Yield: 36.4 %

Procedure:
Cesium carbonate [534-17-8] (150 mg, 0.5 mmol) was added to a solution of 1-[5-(6-fluoro-imidazo[1,2-b]pyridazin-3-yl)-thiophen-2-yl]-ethanone (60 mg, 0.2 mmol) and ethanolamine [141-43-5] (29 mg, 0.5 mmol) in N,N-dimethylformamide (3 mL). The mixture was stirred at 40° C. for 1 h then partitioned between ethyl acetate and water. Analysis of the organic extract revealed preparation ratio of the desired arylamine product to the ether to be approximately 2:1. Preparative RP-HPLC isolated 22 mg of 1-{5-[6-(2-hydroxy-ethylamino)-imidazo[1,2-b]pyridazin-3-yl]-thiophen-2-yl}-ethanone as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.83 (s, 3H) 2.57 (s, 2H) 3.04 (t, J=5.68 Hz, 1H) 4.43 (t, J=5.68 Hz, 1H) 7.04 (d, J=9.60 Hz, 1H) 7.91 (d, J=4.04 Hz, 1H) 8.03 (d, J=4.04 Hz, 1H) 8.16 (d, J=9.60 Hz, 1H) 8.36 (s, 1H). LRMS (ESI) m/z 303.1 [(M+H)]+, calc'd for C14H14N4O2S: 302.36.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1>C(O)C.[Pd]>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C=C1CCOCC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1CCOCC1
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To a solution of ethyl 2-(4-oxanylidene)acetate (22.0 g, 139 mmol) in ethanol (50 mL) was added 10% Pd/C (2.2 g) and the mixture subjected to hydrogenation overnight on a Parr apparatus (50 psi). The catalyst was removed by filtration through Celite, which was washed with ethanol (25 mL). Removal of solvent from the combined filtrates by rotary evaporation gave the desired product as a colorless oil (22.0 g, 98.5%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][N:13]=[CH:12][CH:11]=2)=[CH:6][C:5]=1[C:15]([F:18])([F:17])[F:16])([O-:3])=[O:2].O[CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][N:13]([CH2:20][CH2:21][NH2:22])[N:14]=2)=[CH:6][C:5]=1[C:15]([F:18])([F:17])[F:16])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(-c2ccn[nH]2)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCCO
Product: NCCn1ccc(-c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)n1
Yield: 62.9 %

Procedure:
The title compound was prepared from 5-(4-nitro-3-(trifluoromethyl)phenyl)-1H-pyrazole (1.69 g, 6.57 mmol) and tert-butyl 2-hydroxyethylcarbamate (1.059 g, 6.57 mmol) using the method of Example 34(c) to afford 1.24 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 3.33 (m, 2H), 4.53 (t, 2H), 7.13 (d, 1H), 8.00 (d, 1H), 8.38 (m, 1H), 13.45 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([CH:10]=[O:11])[CH:9]=1)=[O:4].[O-:12][Mn](=O)(=O)=O.[K+].OS([O-])=O.[Na+]>CC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:10]([OH:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(C=O)c[nH]1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cc(C(=O)O)c[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-formyl-1H-pyrrole-2-carboxylic acid methyl ester (589 mg) in acetone/water (50 mL, 1:1) was added a solution of KMnO4 in acetone/water (70 mL, 1:1) dropwise within one hour. The mixture was stirred for 3 h at RT whereupon it was poured into a solution of NaHSO3 (10% in 1 N HCl, 100 mL). The resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with water and extracted with 2N aqueous K2CO3 solution. The basic aqueous phase was acidified with 2N HCl and extracted with ethyl acetate The combined organic phases were dried (MgSO4) and concentrated in vacuo to provide 1H-pyrrole-2,4-dicarboxylic acid 2-methyl ester (530 mg) which was used directly in the next step.
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]([Cl:26])([Cl:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C.[OH-].[K+].Cl>C(O)C.C(O)C.O>[Cl:26][C:5]([Cl:25])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][S:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:4]([OH:27])=[O:3]
Reactant: CCOC(=O)C(Cl)(Cl)CCCCCCCCCCCCSc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(Cl)(Cl)CCCCCCCCCCCCSc1ccccc1
Reaction time: 6 h
Yield: 83.2 %

Procedure:
1.5 g (3.5 mmol) 76 was dissolved in 3.8 ml ethanol and admixed with 3.8 ml 1 N KOH. The precipitate that formed after a short time was dissolved in 20 ml ethanol/water 1:1. 1 ml 1 N KOH was added after 5 h and it was stirred for a further 6 h. After acidifying with 2 N HCl it was extracted with ether, dried over magnesium sulfate and the solvent was removed. 1.18 g (92%) 24 was obtained as colourless crystals of melting point 74° C.
Reaction SMILES: [C:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][O:11][C:12]2[N:17]=[CH:16][C:15]([S:18]([NH:21][C:22](=[O:61])[C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:34][CH2:33][N:32]([CH2:35][C:36]5[CH2:41][CH2:40][C:39]([CH3:43])([CH3:42])[CH2:38][C:37]=5[C:44]5[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=5)[CH2:31][CH2:30]4)=[CH:25][C:24]=3[O:51][C:52]3[CH:60]=[CH:59][CH:58]=[C:57]4[C:53]=3[CH:54]=[N:55][NH:56]4)(=[O:20])=[O:19])=[CH:14][C:13]=2[Cl:62])[CH2:6][CH2:5]1)(=O)[NH2:2]>O1CCOCC1.N1C=CC=CC=1>[Cl:62][C:13]1[CH:14]=[C:15]([S:18]([NH:21][C:22](=[O:61])[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:30][CH2:31][N:32]([CH2:35][C:36]4[CH2:41][CH2:40][C:39]([CH3:43])([CH3:42])[CH2:38][C:37]=4[C:44]4[CH:45]=[CH:46][C:47]([Cl:50])=[CH:48][CH:49]=4)[CH2:33][CH2:34]3)=[CH:25][C:24]=2[O:51][C:52]2[CH:60]=[CH:59][CH:58]=[C:57]3[C:53]=2[CH:54]=[N:55][NH:56]3)(=[O:20])=[O:19])[CH:16]=[N:17][C:12]=1[O:11][CH2:10][C@H:7]1[CH2:8][CH2:9][C@H:4]([C:1]#[N:2])[CH2:5][CH2:6]1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4cnc(OC[C@H]5CC[C@H](C(N)=O)CC5)c(Cl)c4)c(Oc4cccc5[nH]ncc45)c3)CC2)=C(c2ccc(Cl)cc2)C1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4cnc(OC[C@H]5CC[C@H](C#N)CC5)c(Cl)c4)c(Oc4cccc5[nH]ncc45)c3)CC2)=C(c2ccc(Cl)cc2)C1
Reaction time: 1 h

Procedure:
A solution of EXAMPLE 483D (50 mg) in dioxane (12 mL) and pyridine (1.2 mL) was cooled in an ice-water bath. The mixture was slightly warmed by removing the ice bath and then trifluoroacetic acid (0.3 mL) was added. The reaction was stirred for 1 hour and quenched with methanol and aqueous NaOH. The resulting mixture was stirred for 1 hour and concentrated. The residue was purified by reverse phase HPLC, and eluted with 40%-70% acetonitrile in 0.1% trifluoroacetic acid water over 40 minutes. The desired fractions were concentrated to remove acetonitrile, neutralized with NaHCO3 and extracted with dichloromethane. The dichloromethane layer was dried over Na2SO4, filtered, concentrated and dried to provide the title compound. 1H NMR (400 MHz, dimethylsulfoxide-d6) δ 13.10 (s, 1H), 8.27 (d, 1H), 7.85 (d, 1H), 7.80 (s, 1H), 7.58 (d, 1H), 7.37 (d, 2H), 7.02-7.11 (m, 4H), 6.80 (dd, 1H), 6.54 (d, 1H), 6.14 (d, 1H), 4.19 (d, 2H), 3.22 (s, 4H), 2.97 (s, 2H), 2.59-2.71 (m, 1H), 2.41 (s, 2H), 2.18 (s, 2H), 2.05 (dd, 2H), 1.98 (s, 2H), 1.79-1.90 (m, 3H), 1.47-1.62 (m, 2H), 1.42 (t, 2H), 1.04-1.19 (m, 2H), 0.94 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1.Cl.[CH:16]1([C:19]2[C:20]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=2)[CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:29]2[CH2:30][CH2:31][N:26]([C:20]3[C:19]([CH:16]4[CH2:18][CH2:17]4)=[CH:24][C:23]([CH3:25])=[CH:22][N:21]=3)[CH2:27][CH2:28]2)=[O:8])=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1
Reactant: Cc1cnc(N2CCNCC2)c(C2CC2)c1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C2CC2)c1
Yield: 94.1 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 27 and using 4-bromo-2-methanesulfonylbenzoic acid (558 mg) and 1-(3-cyclopropyl-5-methylpyridin-2-yl)piperazine hydrochloride (508 mg) described in Preparation Example 48, the title compound (0.9 g) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][CH3:11])=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1.[NH2:17][C:18]1[N:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][N:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([C:21]2[CH:20]=[N:19][C:18]([NH2:17])=[N:23][CH:22]=2)=[CH:3][C:4]=1[N+:14]([O-:16])=[O:15])([CH3:13])[CH2:10][CH3:11]
Reactant: CCC(C)(C)Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 82.4 %

Procedure:
A reaction mixture of crude (4-bromo-2-nitro-phenyl)-(1,1-dimethyl-propyl)-amine (600 mg, 2.09 mmol), 2-aminopyrimidine-5-boronic acid pinacol ester (330 mg, 1.49 mmol), Pd(PPh3)4 (160 mg), K2CO3 (600 mg, 4.34 mmol) in DMF (7.0 mL) and H2O (2.0 mL) is heated under microwave conditions at 100° C. for 1 hour. The reaction mixture is allowed to cool to room temperature, diluted with EtOAc (100 mL), washed with H2O (75 mL×2), dried with Na2SO4 and filtered. The filtrate is concentrated under reduced pressure and the residue is purified by silica gel flash column chromatography with 50% EtOAc in heptane as the eluent to afford 5-[4-(1,1-dimethyl-propylamino)-3-nitro-phenyl]-pyrimidin-2-ylamine (370 mg, 82%).
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[O-]CC.[Na+:16].[CH2:17](Br)[CH2:18][CH:19]([CH3:21])[CH3:20]>C(O)C>[O-:5][CH2:4][CH3:3].[Na+:16].[CH2:17]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)CCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCC(C)C)C(=O)OCC
Reaction time: 0.83 h

Procedure:
Sodium ethoxide was prepared from sodium metal (9.1 g) and freshly distilled absolute ethanol (250 ml). Diethyl malonate (63.5 g) was added to sodium ethoxide in ethanol, and the mixture was stirred at 60°-70° C. for 50 min. Isoamyl bromide (60 g) was added, and the reaction mixture was heated under reflux overnight. After the usual work-up, the resulting crude product was distilled under reduced pressure to give diethyl isoamylmalonate. Yield: 71.7 g (78%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH:5]=[N:6][NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]2[N:20]=[C:21]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:22]=[C:10]2[N:9]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([N:26]1[CH2:25][CH2:24][CH:23]([C:21]2[CH:22]=[C:10]3[N:9]=[C:8]([NH:7][N:6]=[CH:5][C:4]4[CH:29]=[CH:30][CH:31]=[C:2]([CH3:1])[CH:3]=4)[CH:13]=[C:12]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[N:11]3[N:20]=2)[CH2:28][CH2:27]1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(C=NNc2cc(N3CCOCC3)n3nc(C4CCNCC4)cc3n2)c1
Solvent: ClCCl
Product: CC(=O)N1CCC(c2cc3nc(NN=Cc4cccc(C)c4)cc(N4CCOCC4)n3n2)CC1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
There was suspended, in methylene chloride (2 mL), N-(3-methyl-benzylidene)-N′-(7-morpholin-4-yl-2-piperidin-4-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (31.0 mg, 0.0739 mM) and then acetic acid anhydride (1 mL) was added to the suspension. After this reaction liquid was heated to 90° C. and stirred for 15 minutes, the solvent was distilled off, the resulting residue was diluted with a saturated aqueous solution of sodium bicarbonate and then the mixture was extracted with ethyl acetate. The resulting extracts were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting solid was washed with diethyl ether to thus give the title compound (25.0 mg, yield: 73%).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[CH2:17]([OH:23])[C:18]1[O:22][CH:21]=[CH:20][CH:19]=1>>[CH2:1]([N:5]1[C:9]2=[C:10]([O:23][CH2:17][C:18]3[O:22][CH:21]=[CH:20][CH:19]=3)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Reactant: OCc1ccco1
Product: CC=CCn1c(C)c(C)c2cnnc(OCc3ccco3)c21
Yield: 12.2 %

Procedure:
The title compound (cis/trans=15/85) was prepared as a flesh-colored powder in 12.2% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=20/80) and furfuryl alcohol.
Reaction SMILES: ClCCl.[CH2:4]([CH:7]1[O:12][CH:11](O)[CH:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:31][CH2:30][CH:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[O:28][CH2:27]4)=[C:22]([F:37])[C:21]=3[F:38])=[C:16]([F:39])[C:15]=2[F:40])[CH2:9][CH2:8]1)[CH2:5][CH3:6]>O>[CH2:32]([CH:29]1[CH2:30][CH2:31][CH:26]([C:23]2[CH:24]=[CH:25][C:20]([C:17]3[CH:18]=[CH:19][C:14]([CH:10]4[CH2:9][CH2:8][CH:7]([CH2:4][CH2:5][CH3:6])[O:12][CH2:11]4)=[C:15]([F:40])[C:16]=3[F:39])=[C:21]([F:38])[C:22]=2[F:37])[CH2:27][O:28]1)[CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCC1CCC(c2ccc(-c3ccc(C4CCC(CCC)OC4O)c(F)c3F)c(F)c2F)CO1
Solvent: O
Solvent: ClCCl
Product: CCCCCC1CCC(c2ccc(-c3ccc(C4CCC(CCC)OC4)c(F)c3F)c(F)c2F)CO1
Reaction time: 3 h
Yield: 25.8 %

Procedure:
Dichloromethane (10 ml) was added to 6-propyl-3-(2,2′,3,3′-tetrafluoro-4′-(6-pentyltetrahydro-2H-pyran-3-yl)biphenyl-4-yl)tetrahydro-2H-pyran-2-ol (21) (1.2 g) prepared in the second step. Tiethylsilane (0.27 g) and a boron trifluoride-diethyl ether complex (0.49 g) were added dropwise to the solution at −30° C. After 3 hours of stirring, water (10 ml) was added to give two layers. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (silica gel: 20 g, eluent: heptane/ethyl acetate=50/50 by volume), and then by recrystallization (heptane/ethyl acetate=90/10 by volume) to give 2-pentyl-5-(2,2′,3,3′-tetrafluoro-4′-(6-propyltetrahydro-2H-pyran-3-yl)biphenyl-4-yl)tetrahydro-2H-pyran (22) (0.3 g) in 25.8% yield.