Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:3]([N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=O.Cl.Cl.[NH2:24][CH:25]([C:29]1([SH:36])[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)[C:26]([OH:28])=[O:27].C([O-])(=O)C.[Na+]>C(O)C.O>[C:26]([CH:25]1[C:29]2([CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)[S:36][CH:1]([CH:3]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[NH:24]1)([OH:28])=[O:27]
Reactant: CN1CCC(S)(C(N)C(=O)O)CC1
Reactant: CC(C)(C)OC(=O)C(C=O)N1C(=O)c2ccccc2C1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN1CCC2(CC1)SC(C(C(=O)OC(C)(C)C)N1C(=O)c3ccccc3C1=O)NC2C(=O)O
Reaction time: 24 h
Yield: 81 %

Procedure:
To a solution of 166.9 g (0.57 mole) of tert-butyl 2-formyl-2-phthalimido-acetate in 1150 ml of ethanol, preheated to 60° C., there is added a solution of 160 g (0.57 mole) of alpha-amino-4-mercapto-1-methyl-4-piperidineacetic acid dihydrochloride and 235.6 g (1.73 mole) of sodium acetate (crystallized with three molecules of water) dissolved in 1150 ml of water. The reaction mixture is stirred for about ten minutes and then left to stand for 24 hours. The precipitate is filtered off, washed with water and dried. 223 g of the gamma-isomer of tert-butyl 4-carboxy-8-methyl-alpha-phthalimido-1-thia-3,8-diazaspiro-[4.5]decane-2-acetate is obtained; Yield: 81%; M.P. 276°-278° C. (decomposition).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH:3]([C:24]1[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=1)/[CH:4]=[CH:5]/[C:6]1[CH:23]=[CH:22][C:9]([O:10][N:11]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:8][CH:7]=1.O.NN>CCO>[F:34][C:2]([F:1])([F:33])[CH:3]([C:24]1[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=1)/[CH:4]=[CH:5]/[C:6]1[CH:23]=[CH:22][C:9]([O:10][NH2:11])=[CH:8][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Oc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NOc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1
Temperature: 90 °C
Yield: 50.4 %

Procedure:
To a stirred solution of (E)-2-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)phenoxy) isoindoline-1,3-dione (0.2 g, 0.4 mmol) in EtOH was added hydrazine hydrate (0.1 g, 1.9 mmol), and the resultant reaction mixture was heated at 90° C. for 1 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2Cl2. washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude title compound as a gummy liquid (0.08 g, 53%): 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 2H), 6.98 (s, 1H), 6.82 (s, 2H), 6.48 (m, 1H), 6.20 (m, 1H), 5.02 (s, 1H), 4.08 (m, 1H); ESIMS m/z 394.94 ([M−H]−).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:16])=O>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([Cl:16])=[O:13])=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCCCc1ccc(C(=O)O)nc1
Product: CCCCc1ccc(C(=O)Cl)nc1

Procedure:
A solution of 5-butylpicolinic acid (1 mL) in thionyl chloride (24 eq.) was heated at 60-70° C. for 1 hour to form 5-butylpicolinoyl chloride. Excess of thionyl chloride was removed. Methyl 2-(5-(4-aminophenyl)thiazole-2-carboxamido)-3-methylbutanoate (Intermediate 2, 200 mg) in DCM (5 mL) and pyridine (5 mL) was added to 5-butylpicolinoyl chloride and the reaction mixture was stirred for 1 hour at RT. Solvent was removed and ether was added to it. The solution was stirred, filtered, washed with water and dried obtain the title compound. 1H NMR (DMSO-d6; 300 MHz): δ 10.81 (s, 1H), 8.57 (d, 1H), 8.60 (s, 1H), 8.41 (s, 1H), 8.12 (m, 3H), 7.92 (d, 1H), 7.81 (d, 2H), 4.35 (t, 1H), 3.68 (s, 3H), 2.75 (t, 2H), 2.28 (m, 1H), 1.64 (m, 2H), 1.37 (m, 2H), 0.97 (m, 9H); MS (ESI) m/z 495.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]=[CH:12][NH:13][C:14](=[O:15])[C:5]=3[C:4]=2[CH:3]=1.C1C(=O)N([Br:23])C(=O)C1.[Al].O>CN(C=O)C>[Br:23][C:11]1[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=3[C:5]=2[C:14](=[O:15])[NH:13][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1[nH]ccc2[nH]c3ccc(F)cc3c12
Agent: [Al]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]cc(Br)c2[nH]c3ccc(F)cc3c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 8-fluoro-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (46 g, 228 mmol) in DMF (370 mL) was added NBS (44.5 g, 250 mmol) in small portions at 0° C. The reaction mixture was covered with aluminum foil and left to stir at room temperature overnight. The reaction mixture was treated with water (460 mL), left to stir for 3 h, filtered, and washed with water. The cake was dissolved in MeOH and filtered to remove residual solids. The filtrate was treated with charcoal, and warmed to 40° C. for 2 h. The mixture was cooled to room temperature, filtered through a pad of Celite, and concentrated. The residue was treated with isopropanol and heptane, filtered, and washed with MTBE to afford the title compound as the isopropanol solvate. 1H NMR (600 MHz, CD3SOCD3) 3 12.03 (s, 1H); 11.47 (s, 1H); 7.71 (dd, 1H); 7.59 (s, 1H); 7.52 (dd, 1H); 7.17 (dt, 1H). LRMS (APCI) calc'd for (C11H6BrFN2O) [M+H]+, 281.0. found 280.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH2:13][NH2:14])=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[F:26][C:27]1[CH:28]=[C:29]([NH:35][C:36](=O)[O:37]C2C=CC=CC=2)[CH:30]=[CH:31][C:32]=1[CH2:33][OH:34]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH2:13][NH:14][C:36]([NH:35][C:29]3[CH:30]=[CH:31][C:32]([CH2:33][OH:34])=[C:27]([F:26])[CH:28]=3)=[O:37])=[CH:11][C:10]([C:15]([F:16])([F:17])[F:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Reactant: O=C(Nc1ccc(CO)c(F)c1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)Nc1ccc(CO)c(F)c1
Reaction time: 16 h
Yield: 57.2 %

Procedure:
To a stirred solution of (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine (100 mg, 0.316 mmol, 1.0 eq.) in DCM (2.0 mL) was added Et3N (0.07 mL, 0.632 mmol, 3.0 eq) followed by phenyl 3-fluoro-4-(hydroxymethyl)phenylcarbamate (82.4 mg, 0.316 mmol, 1.0 eq.) at RT and stirred for 16 h. After completion of the reaction, a solid precipitate was filtered and washed with DCM (2 mL) followed by n-pentane (5 mL) and dried to get 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(hydroxymethyl)phenyl)urea (compound A59) (80 mg; 47%, white solid; TLC system: EtOAc/PE (3:2); Rf: 0.2).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)[N:17]=3)[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.C1COCC1>CO.[Pd]>[F:25][C:22]([F:23])([F:24])[C:20]1[CH:19]=[C:18]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[N:17]=[C:16]([C:12]2[CH:11]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([NH2:1])[CH:5]=3)[CH:15]=[CH:14][CH:13]=2)[N:21]=1
Reactant: O=[N+]([O-])c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
To a stirred suspension of 2-(3′-nitro-biphenyl-3-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (1.6 g, 3.27 mmol) in MeOH (40 mL) was added at room temperature Pd—C (10%, 0.16 g) and THF (40 mL). The mixture was stirred at room temperature under H2 atmosphere for 2 h, the catalyst was removed by filtration and the obtained solution evaporated. The crude product was further purified by crystallization from diethyl ether/hexane to yield the title compound as an off-white solid (1.28 g, 85%). MS (ISP) 460.2 [(M+H)+]; mp 156.5° C.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([SH:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[O-]CC.[Na+].[Na].Br[CH2:23][CH2:24][Cl:25]>C(O)C.C1(C)C=CC=CC=1>[Cl:25][CH2:24][CH2:23][S:16][CH:6]1[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH2:9][CH2:10][C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: ClCCBr
Reactant: SC1c2ccccc2CCc2ccccc21
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: Cc1ccccc1
Product: ClCCSC1c2ccccc2CCc2ccccc21
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A solution of the above crude thiol (4.53 g, 0.020 mol) in absolute ethanol (7 ml) was added dropwise to a stirred solution of sodium ethoxide, freshly prepared from absolute ethanol (25 ml) and sodium (0.46 g, 0.020 mol). Stirring was continued for 0.5 h at ambient temperature. 1-Bromo-2-chloroethane (8.60 g, 0.060 mol) was added dropwise and the reaction mixture was stirred at ambient temperature for 16 h. The mixture was diluted with toluene (20 ml) and filtered. The filtrate was evaporated in vacuo and stripped with toluene, affording 5.72 g (99%) of crude 5-(2-chloroethylsulfanyl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene as an oil.
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][C:8]([CH3:12])=[C:9]([CH3:11])[CH3:10])=[CH:3][C:4]#[N:5].[H][H]>[Pd].C(OCC)(=O)C>[CH3:1][CH:2]([CH2:6][CH2:7][CH:8]([CH3:12])[CH:9]([CH3:11])[CH3:10])[CH2:3][C:4]#[N:5]
Reactant: CC(=CC#N)CCC(C)=C(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(CC#N)CCC(C)C(C)C
Yield: 98.1 %

Procedure:
3,6,7-Trimethyl-2,6-octadienenitrile (15 g; 0.092 mol), palladium on charcoal (5% Pd/C, 1.5 g) and ethyl acetate (60 ml) were charged in a 500 ml stirred autoclave and hydrogenated (4 bar hydrogen) at 25° C. for 24 hours. Filtration over celite and removal of the solvent afforded 15.1 g of the saturated nitrile as a mixture of two isomers. Distillation using a 10 cm Vigreux column gave 13.8 g of 98.2% pure 3,6,7-trimethyloctanenitrile (mixture of isomers; 56/42) in a yield of 88%.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:10]=2[C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4].[C:19]([O:22][CH2:23][CH2:24][CH2:25]Br)(=[O:21])[CH3:20]>>[CH2:1]([O:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:25][CH2:24][CH2:23][O:22][C:19](=[O:21])[CH3:20])[C:10]=2[C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(O)c2c(O)cccc2oc1=O
Reactant: CC(=O)OCCCBr
Product: CCCCOc1c(O)c2c(OCCCOC(C)=O)cccc2oc1=O

Procedure:
In the same manner as in Reference Example 1, except that an equimolar amount of 3-butoxy-4,5-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-ethoxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and 3-bromopropyl acetate was used in place of 2-bromoethyl acetate in Reference Example 1, 3-butoxy-4-hydroxy-5-(3-acetoxypropoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[C:4]([C:22]([OH:24])=[O:23])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(C(C)=O)C>[CH2:31]([O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)=[CH:17][CH:16]=2)[C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=2[C:22]([O:24][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:23])=[CH:13][CH:12]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(O)c1ccccc1C(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(OCc1ccccc1)c1ccccc1C(c1ccc(OCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1

Procedure:
In 500 ml of methyl ethyl ketone were dissolved 50 g of phenolphthalin and 75 g of anhydrous potassium carbonate, and the solution was ice cooled. Subsequently, 58 ml of benzyl bromide was added dropwise to the solution, and the mixture was heated under reflux for 24 hours. The temperature of the mixture was brought back to room temperature, and concentrated. Thereafter, water was added to the residue, and the aqueous mixture was extracted with ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with an aqueous 10% citric acid and then dried over anhydrous magnesium sulfate. The solvent was evaporated to give 114.61 g of the desired product.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([S:19][CH3:20])[N:14]=1)[C:5]([C:7]1[S:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=O.O.NN.C([N:27](CC)CC)C>C(O)C.O>[Cl:12][C:9]1[S:8][C:7]([C:5]2[C:4]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([S:19][CH3:20])[N:14]=3)=[CH:3][NH:2][N:27]=2)=[CH:11][CH:10]=1
Reactant: CCN(CC)CC
Reactant: CSc1nccc(C(=CN(C)C)C(=O)c2ccc(Cl)s2)n1
Agent: NN
Solvent: CCO
Solvent: O
Product: CSc1nccc(-c2c[nH]nc2-c2ccc(Cl)s2)n1
Yield: 81 %

Procedure:
To a mixture of 3-(dimethylamino)-1-(5-chloro-2-thienyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]prop-2-en-1-one (1 eq, 96 mmol) in 300 mL ethanol was added dropwise hydrazine hydrate (1.5 eq, 144 mmol) and then triethylamine (1.5 eq, 144 mmol). The mixture was heated under reflux for 2 h and then overnight at room temperature. The solvent was then slowly poured in 1 L of water. The resulting precipitate was filtered and dried to afford 24 g of 4-[3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]-2-(methylsulfanyl)pyrimidine (80% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[K+].[Br-]>C(Cl)Cl.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: C1CNCCN1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: [Br-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CCNCC2)cc1
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of 4-methoxybenzenesulfonyl chloride (6.2 g, 30 mM) in CH2Cl2 (180 ml) is added to a solution of piperazine (12.9 g, 150 mM) in CH2Cl2 (570 ml) and pyridine (2.7 ml). The solution is maintained in agitation at room temperature for 15 h. The solvent is then removed under vacuum. The residue is dissolved in 3N HCl and washed with ethyl ether. The organic phase is removed and the aqueous phase is alkalized and extracted with ethyl acetate. The organic phase is dried over Na2SO4 and the solvent is removed under vacuum. A white solid is obtained (Yield=88%). P.f.: 184.3-185.6° C. FT-IR (KBr): 3082, 3058, 2975, 2944, 2907, 2840, 2810, 1597, 1580, 1495, 1465, 1442, 1413, 1346, 1318, 1298, 1286, 1254, 1179, 1159, 1110, 1095, 1066, 1027, 947, 830, 805, 734, 657, 634 cm−1. 1NMRs (300 MHz CDCl3, δ): 2.48-2.51 (m, 4H, two CH2 piperazine), 2.88-2.94 (m, 5H, two CH2 piperazine and NH), 3.86 (s, 3H, OCH3), 6.95-7.00 (m, 2H, aromatic protons), 7.64-7.68 (m, 2H, aromatic protons). 13C NMRs (75 MHz CDCl3, δ): 46.25, 50.57, 55.85, 77.82, 77.25, 77.67, 79.95, 114.40, 114.58, 127.32, 130.12, 163.27. GC-MS (70 eV) m/z (int. rel.): 258 [(34S)M+, 1], 256 [(32S)M+, 10], 171 (8), 108 (7), 92 (10), 85 (100), 77 (11), 64 (6), 63 (4), 56 (30). Anal. (C11H16N2O3S): Cal.: C, 51.54; H, 6.29; N, 10.93. Found: C, 51.59; H, 6.25; N, 10.96.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]([NH:10][C:11]([O:13][CH3:14])=[O:12])[C:7]([OH:9])=O)=[O:4].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[NH2:36][C@@H:37]([CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[C@@H:38]([OH:67])[CH2:39][C@@H:40]([NH:54][C:55]([C@@H:57]([NH:62][C:63](=[O:66])[O:64][CH3:65])[C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=2)=[CH:44][CH:43]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:68]([C@H:37]([NH:36][C:7](=[O:9])[CH:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[NH:10][C:11]([O:13][CH3:14])=[O:12])[C@@H:38]([OH:67])[CH2:39][C@@H:40]([NH:54][C:55](=[O:56])[C@H:57]([C:58]([CH3:60])([CH3:61])[CH3:59])[NH:62][C:63]([O:64][CH3:65])=[O:66])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=2)=[CH:44][CH:43]=1)[C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=1
Reactant: COC(=O)NC(NC(=O)OC)C(=O)O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)NC(NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.8 %

Procedure:
The product from Example 169A (13.2 mg, 0.06 mmol) was dissolved in N,N-dimethylformamide (0.25 mL) and N-hydroxybenzotriazole (13 mg, 0.10 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (18.4 mg, 0.10 mmol) were added followed by the product from Example 2C (34.2 mg, 0.06 mmol). Triethylamine (9 uL, 0.06 mmol) was added and the mixture was stirred at ambient temperature for 18 hours. The solution was concentrated and the crude residue was purified on a 2 mm preparative silica gel TLC plate (5% CH3OH/CHCl3) to give an amorphous solid (38.4 mg, 83%). 1H NMR (CDCl1) δ 8.65 (d, 1H), 7.86 (d, 2H), 7.78-7.60 (m, 2H), 7.27-7.11 (m, 9H), 6.94-6.70 (br s, 1H), 6.36-6.24 (br s, 1H), 6.24-6.04 (br d, 1H), 6.02-5.84 (br d, 1H), 5.41-5.25 (m, 2H), 4.23-4.10 (m, 1H), 4.10-3.95 (q, 1H), 3.75 (d, 1H), 3.67 (s, 3H), 3.66 (s, 3H), 3.63 (s, 3H), 2.98-2.8 (m, 3H), 2.8-2.65 (m, 1H), 0.91 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[CH:7]=[C:8]1[C:20]2[N:19]3[CH:21]=[CH:22][N:23]=[C:18]3[C:17](=[O:24])[NH:16][C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)([O-])=O.O.O.[Sn](Cl)(Cl)(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[CH:7]=[C:8]1[C:20]2[N:19]3[CH:21]=[CH:22][N:23]=[C:18]3[C:17](=[O:24])[NH:16][C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2
Reactant: O=c1[nH]c2c3ccccc3c(=Cc3cccc([N+](=O)[O-])c3)c2n2ccnc12
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cccc(C=c2c3ccccc3c3[nH]c(=O)c4nccn4c23)c1
Reaction time: 72 h
Yield: 61.1 %

Procedure:
To 0.5 g of 10-(3-nitrobenzylidene)-5H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one suspended in 15 ml of absolute ethanol are added 1.57 g of tin chloride dihydrate. The reaction medium is refluxed for 6 hours and then left at a temperature in the region of 20° C. for 72 hours. The reaction medium is treated with 30 ml of saturated sodium carbonate solution and the insoluble material is filtered off, washed with water, dried and then taken up in 80 ml of dimethylformamide. The new insoluble material is filtered off and discarded. The filtrate is concentrated to dryness under reduced pressure and dried (5 mmHg; 0.65 kPa) at 55° C. 0.28 g of 10-(3-aminobenzylidene)-5H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one is thus obtained in the- form of an orange-coloured powder, the melting point of which is greater than 260° C. (Analysis, C20H14 N4O.0.39 H2O.0.48 DMF; % calculated C: 73.61; H: 4.32; N: 17.17; % found C: 73.6; H: 3.9; N: 16.9).
Reaction SMILES: C=O.[C:3]([NH:7][CH2:8][CH:9]([CH3:11])[CH3:10])([CH3:6])([CH3:5])[CH3:4].[CH:12](O)=O.[OH-].[K+]>>[C:3]([N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH3:12])([CH3:6])([CH3:5])[CH3:4]
Reactant: O=CO
Reactant: CC(C)CNC(C)(C)C
Agent: C=O
Agent: [K+]
Agent: [OH-]
Product: CC(C)CN(C)C(C)(C)C
Temperature: 52.5 °C

Procedure:
A 37% solution of formaldehyde (6.89 g, 85 mmol) was added dropwise to a mixture of tert-butylisobutylamine (10.00 g, 77 mmol) and 88% formic acid (7.85 g, 0.15 mol) at room temperature. The mixture was heated at 50-55° C. for 5 h. Aqueous 8 M potassium hydroxide (12.5 ml, 0.1 mol) was added, the organic layer was separated and the aqueous layer was extracted with n-pentane (50 ml). The extract was combined with the organic layer and dried over anhydrous magnesium sulfate. The product was isolated by distillation to yield 9.25 g, (84%), bp 44-45° C./18 mm Hg; 1H NMR (CDCl3) δ0.85 (d, J=6.7 Hz, 6H, CH3), 1.01 (s, 9H, CH3), 1.64 (nonet, J=6.7 Hz, 1H, CH), 2.02 (d, J=6.7 Hz, 2H, CH2), 2.15 (s, 3H, CH3).
Reaction SMILES: [F:1][C:2]1([F:46])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([OH:33])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[CH:34]([F:45])[C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:54][CH:55]([CH3:57])[CH3:56].O>O1CCCC1>[F:46][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:19])([CH3:20])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:54][CH:55]([CH3:57])[CH3:56])=[CH:29][N:28]=4)[CH2:25][CH2:26]3)[C:9]=2[CH:34]([F:45])[C:35]2[CH:36]=[CH:37][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:39][CH:40]=2)[CH2:6][CH2:7]1
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)COc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1
Temperature: 50 °C
Reaction time: 14 h
Yield: 68.4 %

Procedure:
To a solution of 55 mg (0.085 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Example 4, in 1 ml of tetrahydrofuran, 33 mg (0.10 mmol) of cesium carbonate and 11 μl (0.094 mmol) of 1-iodo-2-methyl propane were added, and the reaction solution was stirred at room temperature for 2 hours, at 50° C. for 3 hours and further at room temperature for 14 hours. After stirring at room temperature, 50 (0.43 mmol) of 1-iodo-2-methyl propane and 50 mg (0.15 mmol) of cesium carbonate were added and the reaction solution was stirred at 70° C. for 9 hours. After stirring with heating, 50 μl (0.43 mmol) of 1-iodo-2-methyl propane and 100 mg (0.31 mmol) of cesium carbonate were further added and the reaction solution was stirred at room temperature for 14.5 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=95/5-70/30 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure. n-Hexane was added to the obtained residue and the precipitate was obtained by filtration to provide 41 mg of the title compound as a white solid (yield: 68%).