Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#N)=[CH:6][N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.C(O)=[O:18]>[Ni].O>[NH2:1][C:2]1[C:7]([CH:8]=[O:18])=[CH:6][N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: O=CO
Reactant: N#Cc1cnc(Nc2ccccc2)nc1N
Agent: [Ni]
Solvent: O
Product: Nc1nc(Nc2ccccc2)ncc1C=O
Reaction time: 0.33 h

Procedure:
4-Amino-2-phenylamino-pyrimidine-5-carbonitrile (2.00 g) obtained from Example 71 was combined with wet Raney nickel (2.00 g), 98% formic acid (60 mL) and water (40 mL) in a Parr shaker The reaction was placed under hydrogen (42 psi) and shaken for 20 minutes. The reaction was filtered, and the filtrate was concentrated in vacuo. The residue was suspended in water, made basic with saturated sodium bicarbonate, and extracted with ethyl acetate three times. The aqueous layer was filtered through a fiberglass filter to disperse the emulsion that was present. The aqueous filtrate was washed with ethyl acetate. The ethyl acetate washes were combined, filtered, washed with saturated sodium chloride, dried with magnesium sulfate and concentrated in vacuo. Chromatography down silica gel, eluting with ethyl acetate:hexane (2:1) gave 0.73 g of the title compound, CIMS (1% NH3 in CH4): 243=M+ +C2H5, 215=M+ +H (Base), 214=M+.
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[S:7][N:6]=1)(=O)=O.[CH2:16]([OH:20])[C:17]#[C:18][CH3:19].[H-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[CH:10]1([C:8]2[S:7][N:6]=[C:5]([O:20][CH2:16][C:17]#[C:18][CH3:19])[N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC#CCO
Reactant: CS(=O)(=O)c1nsc(C2CCCCC2)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1nsc(C2CCCCC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
200 mg of 3-methylsulfonyl-5-cyclohexyl-1,2,4-thiadiazole and 63 mg of 2-butyn-1-ol were dissolved in 2 g of N,N-dimethylformamide, 39 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 30 minutes under ice-cooling and for 1 hour at room temperature. Then, the reaction mixture was added to saturated brine, and extracted with t-butyl methyl ether. The organic layer was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography to give 79 mg of 5-cyclohexyl-3-(2-butynyloxy)-1,2,4-thiadiazole (hereinafter referred to as the present invention compound (1)).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([C:21]#[CH:22])[CH:20]=1)[C:5]([NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[O:6].[C:23]([O:27][C:28](=[O:48])[NH:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([O:40][C:41]2[CH:46]=[CH:45][N:44]=[C:43](Cl)[N:42]=2)=[CH:32][CH:31]=1)([CH3:26])([CH3:25])[CH3:24].CC1C=CC(S(O)(=O)=O)=CC=1.O.ClC1N=CC=CN=1>C1COCC1>[C:23]([O:27][C:28](=[O:48])[NH:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([O:40][C:41]2[CH:46]=[CH:45][N:44]=[C:43]([NH:1][C:2]3[CH:3]=[C:4]([C:5](=[O:6])[NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[CH:18]=[C:19]([C:21]#[CH:22])[CH:20]=3)[N:42]=2)=[CH:32][CH:31]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: C#Cc1cc(N)cc(C(=O)NCCOCCOCCOC)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(Cl)n2)c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Clc1ncccn1
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cc(Nc2nccc(Oc3ccc(NC(=O)OC(C)(C)C)c4ccccc34)n2)cc(C(=O)NCCOCCOCCOC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under N2 was charged the product from step (iv) above (301.2 g, 250.0 g active, 0.816 mol), tert-butyl(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see, for example, Ito, K. et al., WO 2010/067130, 17 Jun. 2010; 252.8 g, 0.680 mol), pTSA.H2O (24.7 g, 0.130 mol) and THF (7600 mL). The dark red solution was heated to reflux for 6 h then cooled to room temperature, after which HPLC analysis indicated 0.25% the product of step (iv), 22.24% the product of step (vi), 8.98% chloropyrimidine starting material and 64.08% the product of step (v). Further product from step (iv) above (27.1 g, 22.5 g active, 73.4 mmol) was charged and the reaction was heated back to reflux and stirred overnight, with HPLC analysis subsequently revealing 0.20% the product of step (iv), 30.23% the product of step (vi), 4.50% starting chloropyrimidine and 58.61% the product of step (v).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([CH:11]1[O:16][CH2:15][CH2:14][N:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12]1)#N.[O:24]1CCCC1>C(OCC)C>[C:9]([CH:11]1[O:16][CH2:15][CH2:14][N:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12]1)(=[O:24])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C1CCOC1
Reactant: N#CC1CN(Cc2ccccc2)CCO1
Reactant: Brc1ccccc1
Agent: [Mg]
Solvent: CCOCC
Product: O=C(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
Grignard's reagent was prepared by reaction of magnesium (932 mg, 5.93 mmol) with bromobenzene (144 mg, 5.93 mmol) in diethyl ether (20 ml) at room temperature for 10 min. After cooling to 0° C., a solution of 2-cyano-4-benzyl-morpholine (1.00 g, 4.94 mmol) in diethyl ether (2.0 ml) was added and then tetrahydrofuran (6.0 ml) was added. The mixture was stirred at room temperature for 30 min. After decomposition with saturated aqueous sodium hydrogen carbonate, the mixture was filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (n-hexane-ethyl acetate 3:1 to 2:1) to give the 2-benzoyl-4-benzylmorpholine (608 mg, 44%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9]Cl)=[C:4]([F:12])[CH:3]=1.[BH4-].[Na+].C[O-].[Na+].O>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][O:11]2)=[C:4]([F:12])[CH:3]=1
Reactant: O=C(CCl)c1ccc(Br)cc1F
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Fc1cc(Br)ccc1C1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.1 %

Procedure:
To a stirred solution of 1-(4-bromo-2-fluorophenyl)-2-chloroethanone (5.57 g) in ethanol (100 ml) at 5° C. was added portionwise over 5 min NaBH4 (838 mg). The reaction mixture was then stirred at room temperature for 1 hour to afford a light yellow solution. TLC analysis showed the reaction was complete. Sodium methoxide (2.06 ml, 30% solution in methanol) was then added and the reaction mixture was stirred at room temperature overnight. TLC analysis showed the reaction was complete. The reaction mixture was then poured into water and extracted twice with EtOAc. The combined organic layers were washed with saturated brine, then dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel; gradient: 5% to 40% EtOAc in heptane) to afford (RS)-2-(4-bromo-2-fluorophenyl)oxirane (1.35 g, 28%) as a light yellow oil which was used in the next step without further purification. MS (EI): 218 ([{81Br}M]+, 216 ([{79Br}M]+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]=[C:13]=[S:14])=[C:4]([F:15])[CH:3]=1.[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][NH:22]1)=[O:20])[CH3:17].O>C(N(CC)CC)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[CH:6][C:5]([NH:12][C:13](=[S:14])[N:22]2[CH2:23][CH2:24][CH2:25][CH2:26][N:21]2[C:19]([O:18][CH2:16][CH3:17])=[O:20])=[C:4]([F:15])[CH:3]=1
Reactant: CC(C)Oc1cc(N=C=S)c(F)cc1Cl
Reactant: CCOC(=O)N1CCCCN1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCCCN1C(=S)Nc1cc(OC(C)C)c(Cl)cc1F
Yield: 43.5 %

Procedure:
4-Chloro-2-fluoro-5-(1-methylethoxy)phenyl isothiocyanate (2.8 g) was added to a solution of 2-ethoxycarbonyl-3,4,5,6-tetrahydro-(1H,2H)-pyridazine (1.8 g) and several drops of triethylamine in toluene (5 ml), and the resultant mixture was stirred at 25° C. overnight. Water was added to the mixture, which was then extracted with toluene. The toluene layer was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography to give 2 g of ethyl 2-(4-chloro-2-fluoro-5-(1-methylethoxy)phenylaminothioxomethyl)-3,4,5,6-tetrahydro-1(2H)pyridazine carboxylate. nD27.5 1.5534. NMR δ (ppm): 1.3 (3H, t), 1.4 (6H, d), 1.8 (4H, m), 4.35 (2H, q), 7.1 (1H, d), 8.0 (1H, d), ##STR13##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[O:13][C:12](=[O:14])[NH:11][C@H:10]2[CH3:15])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][C:27]=2[CH3:36])=[CH:22][C:21]=1[C:37]1[C:38]([CH2:45]OS(C)(=O)=O)=[N:39][C:40]([S:43][CH3:44])=[N:41][CH:42]=1>C1COCC1>[Cl:8][C:6]1[CH:5]=[C:4]([C@H:9]2[O:13][C:12](=[O:14])[N:11]([CH2:45][C:38]3[C:37]([C:21]4[CH:22]=[C:23]([C:26]5[CH:31]=[CH:30][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][C:27]=5[CH3:36])[CH:24]=[CH:25][C:20]=4[O:19][CH3:18])=[CH:42][N:41]=[C:40]([S:43][CH3:44])[N:39]=3)[C@H:10]2[CH3:15])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3cnc(SC)nc3COS(C)(=O)=O)c2)c(C)c1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(Cl)cc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3cnc(SC)nc3CN3C(=O)O[C@H](c4cc(Cl)cc(Cl)c4)[C@@H]3C)c2)c(C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To (4S,5R)-5-(3,5-dichlorophenyl)-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE XX—see table 18, 202 mg, 0.821 mmol) in THF (6 mL) at 0° C. was added sodium hydride (60 wt %, 37.3 mg, 0.933 mmol). The reaction was stirred at 0° C. for 1 hour and a solution of methyl 4′-methoxy-2-methyl-3′-[2-(methylsulfanyl)-4-{[(methylsulfonyl)oxy]methyl}pyrimidin-5-yl]biphenyl-4-carboxylate (364 mg, 0.746 mmol) in THF (500 μL) was added. The reaction was allowed to warm to room temperature overnight. The reaction was cooled to 0° C. and was quenched with HCl (1 N, 373 μL) and the reaction was poured into saturated aqueous NaHCO3 and ethyl acetate. The organic was washed with brine, was dried (Na2SO4), filtered, and concentrated. The resultant residue was purified by column chromatography to yield methyl 3′-[4-{[(4S,5R)-5-(3,5-dichlorophenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-2-(methylsulfanyl)pyrimidin-5-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylate (295 mg, 0.462 mmol). LCMS calc.=638.1. found=638.2.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:9]([OH:11])=O)=[C:6]([CH3:8])[N:7]=1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[F:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[N:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:43]=[CH:44][C:45]([F:46])=[C:24]([NH:23][C:9]([C:5]5[O:4][C:3]([CH2:1][CH3:2])=[N:7][C:6]=5[CH3:8])=[O:11])[CH:25]=4)=[N:33][N:32]3[CH:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: CCc1nc(C)c(C(=O)O)o1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCc1nc(C)c(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)o1
Yield: 71.8 %

Procedure:
In the same manner as in Example 259 and using 2-ethyl-4-methyl-1,3-oxazole-5-carboxylic acid (230 mg, 1.5 mmol), tetrahydrofuran (6 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (520 μL, 6.0 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (400 mg, 1.2 mmol) and N,N-dimethylacetamide (10 mL) as starting materials, the title compound (400 mg, 70%) was obtained as a white solid. melting point 228° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH:5]([N:14]1[CH:21]=[C:20]([F:22])[C:18](=[O:19])[NH:17][C:15]1=[O:16])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([O:1][CH2:2][CH2:3][O:4][CH:5]([N:14]1[CH:21]=[C:20]([F:22])[C:18](=[O:19])[NH:17][C:15]1=[O:16])[CH:6]=[CH:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:25])[CH3:24]
Reactant: O=c1[nH]c(=O)n(C(C=Cc2ccccc2)OCCO)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCOC(C=Cc1ccccc1)n1cc(F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of 1-[1-(2-hydroxyethoxy)-3-phenyl-2-propenyl]-5-fluorouracil (3 g) obtained in Example 19 in pyridine (10 ml), acetic anhydride (10 ml) was added followed by stirring at room temperature for 3 hours. The reaction mixture was poured into ice-water and extracted with chloroform. The chloroform layer was washed with water, dried and evaporated to remove chloroform. The residue was treated with a small amount of ethanol to give 2.8 g of crystalline 1-[1-(2-acetoxyethoxy)-3-phenyl-2-propenyl]-5-fluorouracil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9](O)[C:10]([C:12]2[C:16]([CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=[N:15][O:14][N:13]=2)=[NH:11])[CH:5]=[CH:6][C:7]=1[F:8].C1N=CN([C:35](N2C=NC=C2)=[O:36])C=1.[O:42]1CCCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:35](=[O:36])[O:42][N:11]=[C:10]2[C:12]2[C:16]([CH2:17][O:18][Si:19]([CH:23]([CH3:24])[CH3:25])([CH:26]([CH3:28])[CH3:27])[CH:20]([CH3:21])[CH3:22])=[N:15][O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)[Si](OCc1nonc1C(=N)N(O)c1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Reactant: C1CCOC1
Product: CC(C)[Si](OCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Temperature: 70 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
N-(3-chloro-4-fluorophenyl)-N-hydroxy-4-[(triisopropylsilyl)oxy]methyl-1,2,5-oxadiazole-3-carboximidamide (2.2 g, 5.0 mmol) was dissolved in anhydrous tetrahydrofuran (THF) (31 mL) followed by addition of N,N-carbonyldiimidazole (980 mg, 6 mmol). The reaction was heated to 70° C. and monitored by LCMS. Another 0.5 eq of N,N-carbonyldiimidazole was added and the reaction was stirred overnight at 70° C. The reaction was cooled and concentrated in vacuo. The crude oil was dissolved in chloroform and loaded onto a 120 g ISCO cartridge, eluted with 25% EtOAc/Hexane. The combined fractions were stripped to dryness to give the desired product as a white solid (1.74 g, 73%). 1H NMR (400 MHz, DMSO-d6) δ: 7.95 (m, 1H), 7.65 (m, 1H), 7.64 (m, 1H), 5.12 (s, 2H), 1.14 (m, 3H), 1.04 (d, J=7.0 Hz, 18H); MF=C20H26ClFN4O4Si; LCMS calculated for C20H27ClFN4O4Si(M+H)+: m/z=469.147.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11]CC(C=O)C[CH2:7]1.[NH:24]=[C:25]1[CH2:29][N:28]([CH3:30])[C:27](=[O:31])[N:26]1C(C1C=CC=CC=1)=O.[CH3:40][C:41]([CH3:44])([O-])[CH3:42].[K+].[Cl-].[NH4+]>C(O)C>[NH2:24][C:25]1=[N:26][C:27](=[O:31])[N:28]([CH3:30])/[C:29]/1=[CH:40]\[CH:41]1[CH2:44][CH2:11][N:6]([CH2:5][C:4]2[CH:14]=[CH:15][C:16]([C:18]([F:20])([F:19])[F:21])=[CH:17][C:3]=2[C:2]([F:23])([F:22])[F:1])[CH2:7][CH2:42]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CN1CC(=N)N(C(=O)c2ccccc2)C1=O
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCO
Product: CN1C(=O)N=C(N)/C1=C/C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 0.8 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (26.0 g) in ethanol (100 mL) were added 4-imino-1-methyl-3-(phenylcarbonyl)imidazolidin-2-one (16.7 g) and potassium tert-butoxide (8.60 g) under ice-cooling. The reaction mixture was stirred at 80° C. for 2 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution at room temperature, and the solvent was evaporated under reduced pressure. Water and ethyl acetate were added to the residue, and the insoluble material was removed by filtration. The filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate under reduced pressure, and the solvent was evaporated. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) and recrystallized from ethanol/water to give the title compound (270 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([NH2:21])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24](=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN1C(=O)CCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:17](=[CH:18][CH:19]=2)[N:20]=[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:23]=[N:21]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(N)c2)CC1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cnc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.8 %

Procedure:
A mixture of tert-butyl-4-(3,4-diaminophenyl)piperazine-1-carboxylate (8 g, 27.6 mmol), Ethyl bromopyruvate (8 g, 41.4 mmol), and NMP (40 ml) was stirred at r.t. overnight. The solution was extracted by EA and purified by gel chromatography (PE:EA=3:1) to afford ethyl 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)quinoxaline-2-carboxylate (2 g, yield: 20%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36]([CH:38]4[CH2:40][CH2:39]4)=[O:37])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: O=C(Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)c1)C1CC1

Procedure:
Example 113 was prepared from bis(4-chlorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.84–7.80 (br, 1H), 7.80–7.69 (br, 1H), 7.64–7.46 (br, 1H), 7.40–6.90 (m, 9H), 6.85–6.66 (m, 1H), 4.94–4.74 (br, 1H), 4.69 (s, 1H), 3.41–3.25 (m, 2H), 3.25–3.07 (m, 2H), 2.77–2.61 (m, 2H), 2.61–2.45 (m, 1H), 2.45–2.17 (m, 2H), 1.99–1.63 (m, 6H), 1.61–1.39 (m, 1H), 1.14–0.94 (m, 2H), 0.92–0.70 (m, 2H); ESMS m/e: 564.2 (M+H)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([Li])[CH2:7][CH2:8][CH3:9].[B:11]([O:16]C)(OC)[O:12]C.Cl>CCCCCC>[CH:6]1[C:3]2[C:4]3[CH:2]=[CH:3][CH:4]=[CH:5][C:5]=3[O:1][C:2]=2[CH:9]=[CH:8][C:7]=1[B:11]([OH:16])[OH:12]
Reactant: [Li]CCCC
Reactant: COB(OC)OC
Reactant: C1CCOC1
Agent: Cl
Solvent: CCCCCC
Product: OB(O)c1ccc2oc3ccccc3c2c1
Temperature: -80 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
Into a 500-mL three-neck flask was put 5.0 g (17 mmol) of 2-iodedibenzofuran, and the air in the flask was replaced with nitrogen. Into this flask was added 150 mL of tetrahydrofuran (THF), and this solution was cooled to −80° C. Then, 13 mL (20 mmol) of n-butyllithium (a 1.6 mol/L hexane solution) was dripped into this solution with a syringe. After the dripping, this solution was stirred at the same temperature for 1 hour. After the solution was stirred, to this solution was added 2.8 mL (25 mmol) of trimethyl borate, and the mixture was stirred for about 15 hours while the temperature of the mixture was being brought back to room temperature. After the stirring, about 50 mL of dilute hydrochloric acid (1.0 mol/L) was added to this solution, followed by stirring for 1 hour. After the stirring, the aqueous layer of this mixture was extracted with ethyl acetate, and the solution of the extract was combined with the organic layer, and washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated brine. The organic layer was dried with magnesium sulfate. After the drying, the mixture was filtered. The obtained filtrate was concentrated, so that a pale brown solid was obtained. This solid was recrystallized with toluene/hexane to give 2.0 g of a white powder, which was the objective substance, in 55% yield. The synthesis scheme of Step 2 is shown in (a-2).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([CH2:11]O)[CH:8]=[CH:7][C:6]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)([CH3:4])[CH3:3].S(Cl)([Cl:23])=O>C(Cl)Cl>[Cl:23][CH2:11][C:9]1[CH:8]=[CH:7][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[CH:10]=1
Reactant: COc1cccc(-c2ccc(CO)cc2C(C)(C)C)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cccc(-c2ccc(CCl)cc2C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
A dry, round bottom flask containing 12.2 (0.82 g, 3.04 mmol) and DCM (8.5 mL) was cooled to 0° C. After 15 minutes, thionyl chloride (1.50 mL, 20.56 mmol) was carefully added dropwise at 0° C. Upon complete addition of thionyl chloride, the mixture was allowed to warm to room temperature and stirred overnight. After 25 hours, the reaction was concentrated under reduced pressure. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0%-15% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated to provide 12.3 as a colorless oil (0.82, 93%). 1H NMR (500 MHz, CDCl3) δ ppm 7.53 (1H, d, J=1.7 Hz), 7.28 (3H, m), 7.03 (1H, d, J=7.8 Hz), 6.90 (3H, m), 4.65 (2H, s), 3.82 (3H, s), 1.23 (9H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:14]1([C@@H:20]([NH:23][C:24]([C:26]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])[CH2:21][CH3:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCCCCCC.[C:45](OCC)(=[O:47])C>C1COCC1>[C:14]1([C@@H:20]([NH:23][C:24]([C:26]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:31][CH2:30][N:29]([C:45]([N:11]3[CH2:12][CH2:13][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)=[O:47])[CH2:28][CH2:27]2)=[O:25])[CH2:21][CH3:22])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CCOC(C)=O
Reactant: CC[C@H](NC(=O)C1(c2ccccc2)CCNCC1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CC[C@H](NC(=O)C1(c2ccccc2)CCN(C(=O)N2CCN(c3ccc(F)cc3)CC2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 66.4 mg (0.409 mmol) N,N′-carbonyldiimidazole in dry THF (4 mL) was added 74 mg (0.409 mmol) 1-(4-fluorophenyl)piperazine and the reaction mixture was stirred at room temperature for 3 h. 40 mg (0.124 mmol) 4-Phenyl-piperidine-4-carboxylic acid ((S)-1-phenyl-propyl)-amide dissolved THF (2 mL) was added. The mixture was heated under reflux for 12 h. The reaction mixture was subjected to flash chromatography with n-heptane and ethyl acetate over a 20 g silica gel column to yield 62 mg 1-[4-(4-fluoro-phenyl)-piperazine-1-carbonyl]-4-phenyl-piperidine-4-carboxylic acid ((S)-1-phenyl-propyl)-amide. MS ISP (m/e): 529.3 (100) [(M+H)+].