Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.COC1C=CC=CC=1O.[CH:22]([Si:25]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])Cl)([CH3:24])[CH3:23]>C1(C)C(C)=CC=CC=1>[C:1]([O:5][Si:25]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:22]([CH3:24])[CH3:23])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)O
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: COc1ccccc1O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: C=CC(=O)O[Si](C(C)C)(C(C)C)C(C)C

Procedure:
72.1 g (1 mol) of glacial acrylic acid, 101.2 g (1 mol) of triethylamine 0.072 g of methoxyphenol and 300 ml of xylene is added to a four-neck, round bottom flask equipped with a stirrer, condenser, nitrogen inlet, thermometer and dropping funnel. Under a nitrogen blanket, a solution of 192.8 g (1 mol) of triisopropylchlorosilane in 100 ml of xylene is slowly added to the rapidly stirred reactants at room temperature. The temperature is permitted to rise to a maximum temperature of 55° C. and this temperature is maintained with cooling if necessary.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([Cl:25])[C:16]=1[N:26]1[C:30]([CH2:31][CH3:32])=[C:29]([CH2:33]O)[C:28]([CH2:35][CH3:36])=[N:27]1.C(N(CC)CC)C.CS(Cl)(=O)=O>CCOCC>[CH2:35]([C:28]1[C:29]([CH2:33][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][C:2]=2[OH:11])=[C:30]([CH2:31][CH3:32])[N:26]([C:16]2[C:15]([Cl:14])=[CH:20][C:19]([C:21]([F:22])([F:24])[F:23])=[CH:18][C:17]=2[Cl:25])[N:27]=1)[CH3:36]
Reactant: Oc1ccc2ccccc2c1
Reactant: CCc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(CC)c1CO
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(CC)c1Cc1c(O)ccc2ccccc12
Reaction time: 0.25 h
Yield: 29 %

Procedure:
A solution of 303 mg (2.1 mmol) of 2-naphthol in 5 mL of dry ether was treated with 50 mg (2.1 mmol) of sodium hydride and the mixture was stirred for 15 minutes. A solution of 368 mg (1.0 mmol) of the compound of step C in 5 mL of dry ether and 126 mg (0.174 mL, 1.22 mmol) of triethylamine was cooled to 0° C. and treated with 114 mg (0.077 mL, 1.0 mmol) of methanesulfonyl chloride. Triethylamine hydrochloride was removed by filtration and the filtrate was added to the above suspension of sodium 2-naphthoxide and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was then partitioned between water and ether and the organic extracts were dried and evaporated to give the desired product in 29% yield. 1H-NMR (CDCl3) δ1.00 (3H, t, J=7), 1.20 (3H, t, J=7), 2.44 (2H, q, J=7), 4.58 (2H, s), 6.96-7.84 (8H, m).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:14]([N:24]2[CH2:29][CH2:28][N:27]([S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])[CH2:26][CH2:25]2)=[N:13][C:12]=1[C:35]1[CH:36]=[C:37]([O:42][CH3:43])[C:38]([NH2:41])=[N:39][CH:40]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].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>[CH2:33]([S:30]([N:27]1[CH2:28][CH2:29][N:24]([C:14]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:11]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[C:12]([C:35]3[CH:36]=[C:37]([O:42][CH3:43])[C:38]([NH2:41])=[N:39][CH:40]=3)[N:13]=2)[CH2:25][CH2:26]1)(=[O:32])=[O:31])[CH3:34]
Reactant: CCS(=O)(=O)N1CCN(c2nc(-c3cnc(N)c(OC)c3)c(Br)n2COCC[Si](C)(C)C)CC1
Reactant: OB(O)c1ccncc1
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: [Na+]
Solvent: COCCOC
Product: CCS(=O)(=O)N1CCN(c2nc(-c3cnc(N)c(OC)c3)c(-c3ccncc3)n2COCC[Si](C)(C)C)CC1

Procedure:
A mixture of pyridin-4-ylboronic acid (17.0 mg, 0.14 mmol) and 5-(5-bromo-2-(4-(ethylsulfonyl)piperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-3-methoxypyridin-2-amine (26.5 mg, 0.05 mmol) in DME (1.5 mL) and 2.0 M aqueous Na2CO3 (0.5 mL) was sparged with Ar for 2 min. Tetrakis(triphenylphosphine)palladium(0) (10.6 mg, 9.2 μmol) was added. The mixture was sparged with Ar for an additional 2 min and was irradiated in a sealed tube in a microwave reactor at 115° C. for 15 min. The reaction mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with sat aqueous NaHCO3 (30 mL), brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The material purified by preparative TLC (SiO2, 0.25 mm, 95:5 DCM-MeOH) to afford 5-(2-(4-(ethylsulfonyl)piperazin-1-yl)-5-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-3-methoxypyridin-2-amine was isolated as colorless solid: LCMS (m/z): 574.3 (MH+), tR=0.68 min.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12].[NH2:13][C:14]1[CH:23]=[CH:22][C:17]2=[N:18][C:19](=[O:21])[N:20]=[C:16]2[CH:15]=1>C(O)C>[O:12]=[C:4]1[NH:5][C:6]2[C:11](/[C:3]/1=[CH:2]/[NH:13][C:14]1[CH:23]=[CH:22][C:17]3[NH:18][C:19](=[O:21])[NH:20][C:16]=3[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: Nc1ccc2c(c1)=NC(=O)N=2
Reactant: O=C1Nc2ccccc2C1=CO
Solvent: CCO
Product: O=C1Nc2ccccc2/C1=C/Nc1ccc2[nH]c(=O)[nH]c2c1
Yield: 51.3 %

Procedure:
A solution of 161 mg (1.00 mMol) of 3-(hydroxymethylene)-1,3-dihydro-2H-indol-2-one, 149 mg (1.00 mMol) of 5-aminobenzimidazolone, and 5 ml of ethanol was heated at 55° C. for 1.5 hr. The resulting solid was isolated by filtration and recrystallized from DMSO/methanol to yield 150 mg (51%) of a yellow solid, 1H NMR (DMSO-d6): δ6.80 (d, J=7.7 Hz, 1H), 6.85-6.98 (m, 4H), 7.00 (s, 1H), 7.54 (d, J=7.4 Hz, 1H), 8.50 (d, J=12.7 Hz, 1H), 10.39 (s, 1H), 10.56 (s, 1H), 10.72 (d, J=12.7 Hz, 1H), 10.74 (s, 1H); APCI-MS m/z291 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.[C:30](Cl)(Cl)=[S:31].[NH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:30]([NH:34][N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[S:31])=[CH:18][CH:17]=1
Reactant: NN1CCCCC1
Reactant: S=C(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NN4CCCCC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in N,N-dimethylformamide (2 ml) and triethylamine (1 ml) to prepare a solution. Thiophosgene (50 mg) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. Next, 1-aminopiperidine (50 mg) was added thereto, and the mixture was further stirred at room temperature for 13 hr. Ethyl acetate was added to the reaction solution, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (49 mg, yield 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:20])[CH2:10][N:9]=1.[OH-].[Na+].CO.Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>O>[N:29]1([CH2:28][CH2:27][S:20][C:11]2[CH2:10][N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=3[N:12]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: ClCCN1CCCCCC1
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCC(SCCN1CCCCCC1)=N2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 7.5 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in a solvent mixture comprising 30 ml of a 10% aqueous sodium hydroxide solution and 30 ml of methanol is added dropwise under ice cooling with stirring an aqueous solution of 7.0 g of 1-chloro-2-(perhydroazepin-1-yl)ethane hydrochloride over a period of about 10 minutes, and the resulting mixture is stirred at room temperature for 4 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is rinsed with a 5% aqueous sodium hydroxide solution, washed with water and dried. Thereafter the solvent is distilled off to obtain an oily residue of 2-(2-perhydroazepin-1-ylethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine. The oily product thus obtained is treated, according to usual procedure, with 2.74 g of fumaric acid and recrystallized from isopropyl alcohol to obtain 9.9 g of 2-(2-perhydroazepin-1-ylethylthio)-5-(2-chlorophenyl)-7 -chloro-3H-1,4-benzodiazepine fumarate, m.p. 170°-171° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][SH:5].[H-].[Na+].[F:10][C:11]1[CH:16]=[C:15]([C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])[CH:14]=[C:13](F)[CH:12]=1.O>CN(C=O)C>[F:10][C:11]1[CH:16]=[C:15]([C:17]([OH:26])([C:18]([F:19])([F:20])[F:21])[C:22]([F:24])([F:25])[F:23])[CH:14]=[C:13]([S:5][CH2:4][CH2:3][Si:2]([CH3:7])([CH3:6])[CH3:1])[CH:12]=1
Reactant: C[Si](C)(C)CCS
Reactant: OC(c1cc(F)cc(F)c1)(C(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCSc1cc(F)cc(C(O)(C(F)(F)F)C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 55 %

Procedure:
2-Trimethylsilylethane thiol (2.9 g, 21.9 mmol) was added dropwise to a suspension of NaH (1.8 g, 43.8 mmol) in dry DMF (60 mL) and stirred for 20 min. Then 1,3-difluoro-5-(hexafluoro-2-hydroxyprop2-yl)benzene (Step 1) was added in dry DMF and the resulting reaction mixture was heated at 70° C. for 16 h. The reaction mixture was then added carefully to H2O and extracted with EtOAc. The combined organic phases were washed with brine, dried and evaporated to give a residue which was chromatographed on silica gel, eluting with 95:5 mixture of hexane:EtOAc to afford the title compound (3.2 g, 55%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C@@H:19]([OH:23])[C:20]#[C:21][CH3:22])[CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].C(N(CC)CC)C.Cl[C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([C:42]([F:45])([F:44])[F:43])[CH:40]=2)[N:35]=[CH:34][N:33]=1>CCO>[OH:23][C@@H:19]([C:20]#[C:21][CH3:22])[C@@H:6]([NH:5][C:3](=[O:4])[CH2:2][NH:1][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([C:42]([F:44])([F:45])[F:43])[CH:40]=2)[N:35]=[CH:34][N:33]=1)[CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)CN
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)CNc1ncnc2ccc(C(F)(F)F)cc12
Temperature: 25 °C
Yield: 59.5 %

Procedure:
Benzyl (2S,3S)-2-(2-aminoacetamido)-3-hydroxyhex-4-ynylcarbamate (194 mg, see procedure 15a) was dissolved in EtOH (3 mL) and the resultant solution was charged with triethylamine (0.42 mL) and 4-chloro-6-(trifluoromethyl)quinazoline (141 mg). The mixture was heated at 80 C for 14 h, cooled to RT, and concentrated in vacuo to afford benzyl (2S,3S)-3-hydroxy-2-(2-(6-(trifluoromethyl)quinazolin-4-ylamino)acetamido)hex-4-ynylcarbamate (186 mg). MS found: (M+H)+=516.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:9][CH2:10][N:11]([CH3:17])[CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:4][CH:3]=1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25].[CH3:36][C:37]1[NH:41][CH:40]=[N:39][C:38]=1[CH2:42][S:43][CH2:44][CH2:45][NH2:46]>C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:24]([NH:46][CH2:45][CH2:44][S:43][CH2:42][C:38]2[N:39]=[CH:40][NH:41][C:37]=2[CH3:36])=[O:25])[CH3:17])=[CH:6][CH:7]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CN(CCCCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1[nH]cnc1CSCCNC(=O)NCCCCN(C)CCC(c1ccc(Cl)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 0.8 g (2.4 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,4-butanediamine, an equimolar amount of 1,1'-carbonyldiimidazole and 0.5 g (2.9 mmol) of 2-[[(5-methylimidazol-4-yl)methyl]thio]ethaneamine [R. W. Brimblecombe et al., J. Int. Med. Res. 3, 86 (1975)] as starting materials. Working up by chromatography (eluant: ethyl acetate/methanol 9+1) analogously to Example 63 yields the purified title compound in the form of a crystalline solid that is recrystallised from ether; m.p.: 97°-98° C.; MS (+FAB method): m/z (rel. int.[%])=529 ([M+H]+, 10), 230 (100); IR (KBr): 1643 cm-1 (C=O).
Reaction SMILES: ClC(Cl)(Cl)COC(=O)[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:27])[NH:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:16][C:15]=2[NH:28][C:29]2[C:30]3[CH:38]=[CH:37][C:36]([CH:39]([CH3:41])[CH3:40])=[N:35][C:31]=3[N:32]=[CH:33][N:34]=2)=[CH:9][CH:8]=1.[OH-].[Na+].Cl>O1CCOCC1.O.C(OCC)(=O)C>[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:27])=[CH:16][C:15]=2[NH:28][C:29]2[C:30]3[CH:38]=[CH:37][C:36]([CH:39]([CH3:41])[CH3:40])=[N:35][C:31]=3[N:32]=[CH:33][N:34]=2)=[CH:9][CH:8]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)NC4CCCC4)ccc3Sc3ccc(NC(=O)OCC(Cl)(Cl)Cl)cc3)ncnc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NC4CCCC4)ccc3Sc3ccc(N)cc3)ncnc2n1
Temperature: 60 °C
Yield: 64.4 %

Procedure:
A solution of the product of Example 155A (39.9 mg, 0.0592 mmol) in 1,4-dioxane (2 mL) was treated with a solution of sodium hydroxide (5.9 mg, 0.148 mmol) in water (1 mL), then heated at 60° C. for 1 hour. The reaction was then cooled to room temperature and diluted with ethyl acetate (50 mL) and water (25 mL). The aqueous pH was adjusted to 5 with 1N aqueous hydrochloric acid, the layers were separated, and the organic phase washed with water (2×25 mL) and brine (25 mL). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo. Purification of the residue by silica gel flash chromatography with 4% methanol/methylene chloride provided the title compound as a white solid (19 mg, 64%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (d, J=6.62 Hz, 6 H) 1.43-1.58 (m, 4 H) 1.59-1.75 (m, 2 H) 1.78-1.96 (m, 2 H) 3.12-3.32 (m, 1 H) 4.11-4.26 (m, 1 H) 5.57 (s, 2 H) 6.61 (d, J=8.46 Hz, 2 H), 6.81 (d, J=8.82 Hz, 1 H) 7.11 (d, J=8.46 Hz, 2 H) 7.64 (t, J=9.01 Hz, 1 H) 7.83 (s, 1 H) 8.21 (d, J=6.62 Hz, 1 H) 8.56 (s, 1 H) 8.86 (d, J=8.82 Hz, 1 H) 10.10 (s, 1 H); MS (ESI+) m/z 499 (M+)+, (ESI−) m/z 497 (M−H)−.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)[CH:22]=[C:21]3[C:16]=2[C:17]([NH:36][C:37]2[CH:41]=[C:40]([CH2:42][C:43]([OH:45])=O)[NH:39][N:38]=2)=[N:18][CH:19]=[N:20]3)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:46][C:47]1[CH:48]=[C:49]([CH:51]=[CH:52][CH:53]=1)[NH2:50].Cl.CN(C)CCCN=C=NCC.OC1C=CC=C[N+]=1[O-]>CN(C)C=O.ClCCl>[NH3:8].[C:1]([O:5][CH2:6][CH2:7][N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:24]=[C:23]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)[CH:22]=[C:21]3[C:16]=2[C:17]([NH:36][C:37]2[CH:41]=[C:40]([CH2:42][C:43]([NH:50][C:49]4[CH:51]=[CH:52][CH:53]=[C:47]([F:46])[CH:48]=4)=[O:45])[NH:39][N:38]=2)=[N:18][CH:19]=[N:20]3)[CH2:12][CH2:13]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1CCN(CCCOc2cc(OC3CCN(CCOC(C)(C)C)CC3)c3c(Nc4cc(CC(=O)O)[nH]n4)ncnc3c2)CC1
Reactant: Nc1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [O-][n+]1ccccc1O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCN(CCCOc2cc(OC3CCN(CCOC(C)(C)C)CC3)c3c(Nc4cc(CC(=O)Nc5cccc(F)c5)[nH]n4)ncnc3c2)CC1
Product: N
Yield: 138 %

Procedure:
[3-({5-{[1-(2-tert-butoxyethyl)piperidin-4-yl]oxy}-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazolin-4-yl}amino)-1H-pyrazol-5-yl]acetic acid (140 mg, 0.22 mmol) in dimethylformamide (1 ml) was reacted with 3-fluoroaniline (24 μl, 0.25 mmol) in the presence of 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (48 mg, 0.25 mmol) and 2-hydroxypyridin-1-oxide (27 mg, 0.24 mmol) at 50° C. for 45 minutes. The solvent was evaporated and the residue purified by chromatography on silica gel. Elution with dichloromethane:methanol (97:3) then dichloromethane:methanolic ammonia (95:5) yielded 2-[3-({5-{[1-(2-tert-butoxyethyl)piperidin-4-yl]oxy}-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazolin-4-yl}amino)-1H-pyrazol-5-yl]-N-(3-fluorophenyl)acetamide (109 mg, 58% yield):
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH:23][C:24](=[O:30])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:17][C:18]([O:20]CC)=[O:19])=[CH:11][CH:10]=1.[OH-].[Na+]>C1COCC1.CO>[C:18]([CH2:17][C@H:16]([NH:23][C:24](=[O:30])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:3]2[CH:2]=[CH:7][CH:6]=[C:5]([Cl:8])[CH:4]=2)=[CH:10][CH:11]=1)([OH:20])=[O:19]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(Cl)ccc2Cl)cc1)NC(=O)CCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCC(=O)N[C@@H](CC(=O)O)Cc1ccc(-c2cccc(Cl)c2)cc1
Reaction time: 4.5 h
Yield: 70.2 %

Procedure:
To a solution of (R)-4-(1-(2′,5′-dichlorobiphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acid (106 mg, 0.234 mmol) in THF (2 ml) and MeOH (0.1 ml), 1M aqueous NaOH solution (1.406 mL, 1.406 mmol) is added at room temperature. After stirring for 4.5 hours, the reaction is quenched with 0.1 M aqueous HCl (3 ml), and the products are extracted with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude is triturated in DCM. The precipitates are collected on a funnel, washed with DCM, and dried under reduced pressure to give (R)-4-(1-carboxy-3-(3′-chlorobiphenyl-4-yl)propan-2-ylamino)-4-oxobutanoic acid (64.0 mg) as white solid; HPLC retention time=1.24 minutes (condition A); MS (m+1)=424.07; 1H NMR (400 MHz, CD3OD) δ ppm 2.38-2.42 (m, 2 H) 2.45-2.57 (m, 4 H) 2.87 (A of ABX, Jab=13.6 Hz, Jax=7.6 Hz, 1 H) 2.95 (B of ABX, Jab=13.6 Hz, Jbx=6.1 Hz, 1 H) 4.44-4.51 (m, 1 H) 7.30-7.37 (m, 6 H) 7.47 (d, J=8.4 Hz, 1 H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[O:11][C:10]([CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29](N)=[CH:28][CH:27]=1)([CH3:23])[CH2:9][C:8]2=[O:33])(=[O:3])[CH3:2].N([O-])=O.[Na+].[ClH:38].[C:39]([O:43][CH2:44][CH3:45])(=[O:42])[CH:40]=[CH2:41]>O.CC(C)=O>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[O:11][C:10]([CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:41][CH:40]([Cl:38])[C:39]([O:43][CH2:44][CH3:45])=[O:42])=[CH:28][CH:27]=1)([CH3:23])[CH2:9][C:8]2=[O:33])(=[O:3])[CH3:2]
Reactant: Cl
Reactant: CC(=O)Oc1cc2c(cc1C(C)(C)CC(C)(C)C)OC(C)(COc1ccc(N)cc1)CC2=O
Reactant: C=CC(=O)OCC
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CC(=O)c3cc(OC(C)=O)c(C(C)(C)CC(C)(C)C)cc3O2)cc1

Procedure:
Following the same procedure as described in Preparation 18, 9 g of 6-acetoxy-2-(4-aminophenoxymethyl)-2-methyl-7-(1,1,3,3-tetramethylbutyl) chroman-4-one (prepared as described in Preparation 24), 1.8 g of sodium nitrite, 10 ml of concentrated hydrochloric acid, 20 g of ethyl acrylate, 0.3 g of cuprous oxide, 100 ml of acetone and about 8 ml of water were reacted, to give the title compound.
Reaction SMILES: F[C:2]1[CH:3]=CC(O[C@H]2CC[C@H](C(O)=O)CC2)=N[CH:7]=1.C(Cl)(=O)C(Cl)=O.COC(C1C=C(C=CC=1)O[C@H]1CC[C@H](C([N:40](C)[C:41]2[CH:61]=[CH:60][C:44]([CH2:45][N:46]3[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C@@H:48](C)[CH2:47]3)=[C:43]([CH3:62])[CH:42]=2)=O)CC1)=O.C(N(CC)CC)C>ClCCl.CN(C)C=O>[CH:2]([NH:40][C:41]1[CH:61]=[CH:60][C:44]([CH2:45][N:46]2[CH2:47][CH2:48][N:49]([C:52]([O:54][C:55]([CH3:56])([CH3:57])[CH3:58])=[O:53])[CH2:50][CH2:51]2)=[C:43]([CH3:62])[CH:42]=1)([CH3:3])[CH3:7]
Reactant: O=C(O)[C@H]1CC[C@H](Oc2ccc(F)cn2)CC1
Reactant: COC(=O)c1cccc(O[C@H]2CC[C@H](C(=O)N(C)c3ccc(CN4CCN(C(=O)OC(C)(C)C)[C@@H](C)C4)c(C)c3)CC2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(NC(C)C)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Tert-butyl trans-4-[(5-fluoropyridin-2-yl)oxy]cyclohexanecarboxylate (511 mg, 1.73 mmol) produced in (15B) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added thereto at 0° C., and then, the resulting mixture was stirred under a nitrogen atmosphere for 2 hours. After toluene (10 mL) was added to the reaction solution, the solvent was distilled off under reduced pressure, followed by drying, whereby trans-4-[(5-fluoropyridin-2-yl)oxy]cyclohexanecarboxylic acid was obtained as a colorless oil (310 mg, yield: 74%). The obtained trans-4-[(5-fluoropyridin-2-yl)oxy]cyclohexanecarboxylic acid (310 mg, 0.892 mmol) was dissolved in dichloromethane (5 mL), and oxalyl chloride (235 μL, 2.68 mmol) and a catalytic amount of dimethylformamide were added thereto at 0° C., and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 30 minutes. The residue obtained by distilling off the solvent in the reaction solution under reduced pressure was dissolved in dichloromethane (15 mL), and tert-butyl 4-[4-(isopropylamino)-2-methylbenzyl]piperazine-1-carboxylate (113 mg, 0.325 mmol) produced in (5A) and triethylamine (125 μL, 0.892 mmol) were added thereto at 0° C., and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour.
Reaction SMILES: [CH2:1]([O:3][P:4]([O-:8])[O:5][CH2:6][CH3:7])[CH3:2].CC(C)([O-])C.[Na+].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][C:17]=1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])=[CH:18][C:17]=1[O:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1.[O:24]1[CH2:25][CH2:30][CH2:29][CH2:28]1
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Reactant: CCOP([O-])OCC
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(Cc1ccc(F)c(Oc2ccccc2)c1)OCC
Temperature: 10 °C
Reaction time: 0.08 h

Procedure:
A mixture of diethylphosphite (6.9 g, 0.05 mol) in tetrahydrofuran is cooled to 10° C., treated portionwise with sodium t-butoxide (4.9 g, 0.05 mol) while maintaining the reaction mixture temperature below about 20° C., stirred at room temperature for 5 minutes, cooled, and treated dropwise with 4-fluoro-3-phenoxybenzyl bromide (14.05 g, 0.05 mol) at about 10-15° C. to give a solution of the title product in tetrahydrofuran (98% yield by gas chromatography).