Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C1C=CC(CC2C=CC(N=C=O)=CC=2)=CC=1)=C=O.[C:20]([O-:33])(=[O:32])[CH2:21][CH2:22]CCCCCCCCC.[C:34]([O-])(=[O:46])[CH2:35]CCCCCCCCCC.C([Sn+2]CCCC)CCC.[N-:57]=[C:58]=[O:59]>C(C(C)=O)C>[C:20]([OH:33])(=[O:32])[CH:21]=[CH2:22].[NH2:57][C:58]([O:46][CH2:34][CH3:35])=[O:59]
Reactant: CCCCCCCCCCCC(=O)[O-]
Reactant: [N-]=C=O
Agent: CCCC[Sn+2]CCCC
Agent: O=C=Nc1ccc(Cc2ccc(N=C=O)cc2)cc1
Solvent: CCC(C)=O
Product: C=CC(=O)O
Product: CCOC(N)=O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Into a one liter 3-neck flask equipped with a mechanical stirrer, reflux condenser and drying tube, thermometer, and oil bath with temperature control, 130 g (0.1 mole) Sulfoester Polyol A (prepared as described below), was added to 50 g (0.2 mole) bis(4-isocyanatophenyl)methane, 0.03 g dibutyltin dilaurate, and 150 g methyl ethyl ketone. As stirring was initiated, the temperature began to rise. Additional heat was applied to raise the temperature of the contents of the flask to 60° C. and held at this temperature until analysis indicated the disappearance of hydroxyl and formation of isocyanate-terminated sulfopolyester (4 hours). There was then added 65 g pentaerythritol triacrylate and 500 ppm (with respect to the acrylate) of p-methoxy phenol. Stirring and heating was continued for an additional 4 hours at 60° C. The polymer was readily soluble in water from which it could be coated as a film and dried to a non-tacky coating that could be redissolved in water, sodium hydroxide solution, methanol, aqueous methanol, acetone, methylene chloride and other common organic solvents. The dried film had a calculated average molecular weight of 2400 and an acrylic group equivalent weight of about 400.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][NH:6][CH2:5]2)[CH2:3][N:2]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[N:20][CH:21]=1.CS(C)=O>O>[C:11]([O:10][C:8]([N:2]1[CH2:3][C:4]2([CH2:7][N:6]([C:16]3[CH:21]=[N:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[CH2:5]2)[CH2:1]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC2(CNC2)C1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC2(C1)CN(c1ccc([N+](=O)[O-])nc1)C2
Temperature: 90 °C
Reaction time: 40 h

Procedure:
In a 25 mL pear-shaped flask, tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (2.81 g, 14.2 mmol), 5-bromo-2-nitropyridine (2.88 g, 14.2 mmol), and TEA (1.58 g, 2.17 ml, 15.6 mmol) were combined with DMSO (12 ml) to give a light yellow solution. The reaction mixture was heated to 90° C. and stirred for 40 h. Cooled to 25° C. and the reaction mixture was diluted with 50 mL H2O and extracted with EtOAc (3×50 mL). The organic layers were combined, washed with sat NaCl (1×50 mL), dried over Na2SO4 and concentrated in vacuo. The purple oil was used crude in the subsequent reduction. (M+H)+=321 m/e.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][CH2:20][C:21](N)=[O:22])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.[Na].[OH-:32].[Na+].Cl>O.C(O)C>[CH:8]1[C:7]([CH:10]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][O:19][CH2:20][C:21]([OH:32])=[O:22])[CH2:15][CH2:16]2)[C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)=[CH:6][CH:5]=[C:4]([F:3])[CH:9]=1
Reactant: NC(=O)COCCN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: O=C(O)COCCN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
In a round-bottomed flask fitted with a mechanical stirrer, a Nitrogen inlet and a condenser, 30 g (0.065 mole) of 2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxyacetamide dihydrochloride are added to a mixture of 325 ml of ethanol, 130 ml of a 1 N aqueous sodium hydroxyde solution and 62 ml of a 6.3 N aqueous sodium hydroxide solution. The mixture is heated under reflux and under a Nitrogen atmosphere for 1.5 hours. The reaction mixture is then cooled down to room temperature and its pH is adjusted to 5 with 78 ml of a 5 N aqueous hydrochloric acid solution. Water is added, and ethanol is evaporated off under vacuum using a rotary evaporator. The resulting aqueous phase is extracted with dichloromethane. The organic phase is dried over anhydrous sodium sulphate and evaporated to dryness to give 25 g of crude efletirizine as an amorphous solid, 5 g of which are recrystallized in acetonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]I)=[CH:14][CH:13]=3)[CH:10]([CH2:28][CH2:29][CH:30]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[OH:31])[C:9]2=[O:39])=[CH:4][CH:3]=1.[CH3:40][NH:41][CH2:42][CH:43]([OH:52])[CH:44]([OH:51])[CH:45]([OH:50])[CH:46]([OH:49])[CH2:47][OH:48]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:41]([CH3:40])[CH2:42][CH:43]([OH:52])[CH:44]([OH:51])[CH:45]([OH:50])[CH:46]([OH:49])[CH2:47][OH:48])=[CH:14][CH:13]=3)[CH:10]([CH2:28][CH2:29][CH:30]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[OH:31])[C:9]2=[O:39])=[CH:4][CH:3]=1
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCCCCCCCCI)cc2)N1c1ccc(F)cc1
Reactant: CNCC(O)C(O)C(O)C(O)CO
Solvent: CN(C)C=O
Product: CN(CCCCCCCCOc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)CC(O)C(O)C(O)C(O)CO
Temperature: 50 °C
Reaction time: 2 h

Procedure:
150 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-(8-iodooctyloxy)phenyl]azetidin-2-one are dissolved in 5 ml of absolute dimethylformamide. 180 mg of 6-methylaminohexane-1,2,3,4,5-pentaol are then added, and the reaction solution is stirred at 50° C. for 2 h. After concentration using a rotary evaporator and oil pump vacuum at 40° C., the residue is purified by preparative HPLC. The product is obtained as an oil. C39H52F2N2O8 (714) MS (ESI): M+
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6][C:7]=1[CH3:8].S(Cl)([Cl:19])=O>>[Cl:19][CH2:2][C:3]1[N:4]=[C:5]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6][C:7]=1[CH3:8]
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(C=Cc2ccccc2)nc1CO
Product: Cc1oc(C=Cc2ccccc2)nc1CCl
Reaction time: 0.5 h

Procedure:
4-Hydroxymethyl-5-methyl-2-styryloxazole (1.0 g) was added to thionyl chloride (3 ml) and the mixture was allowed to stand at room temperature for 30 minutes. The thionyl chloride was distilled off under reduced pressure. The residue was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off and isopropyl ether was added to the residue to give 4-chloromethyl-5-methyl-2-styryloxazole as crystals; yield 0.98 g (90.7%). Recrystallization from ether gave light-yellow plates melting at 108°-109° C.
Reaction SMILES: [C@@H]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)O[C@H](CO)[C@@H](O)[C@H]1O.[Cl:20]C1C=C(C=CC=1)C(OO)=O.C1(C)C=CC=CC=1>CC(N(C)C)=O.Cl>[Cl:20][C:11]1[NH:12][C:13]2[C:19](=[N:18][CH:17]=[N:16][C:14]=2[NH2:15])[N:10]=1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: Nc1ncnc2nc(Cl)[nH]c12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.9 %

Procedure:
To a solution of adenosine (2.67 g, 10 mmol) in DMA/HCl (0.5M, 45 mL) was added m-chloroperoxybenzoic acid (MCPBA, 3.22 g, 16 mmol 87%) and stirred at room temperature for 2.5 h. An additional portion of MCPBA (0.9 g, 5 mmol) was added and stirring continued for another 1 h. Toluene (50 mL) was added to the reaction mixture and the solvents evaporated at 60° C. under vacuo to dryness. The residue was dissolved in water (50 mL) and extracted with ether (3×50 mL). The pH of the aqueous phase was adjusted to 5 with 2N NaOH and then diluted with EtOH (100 mL). The solution was stored in the refrigerator overnight. The light yellow solid that separated was collected, washed with cold EtOH (2×25 mL) and dried to give 1.44 g (85.2%) of 1: mp 305°-310° C. (dec.) [Lit. mp>300° C. (dec.)]: IR (KBr): 630 (C-C1), 3100-3300 (NH2) cm-1 : UV: λmax (pH 1) 262 nm (ε 8,700): λmax (pH 7) 268 nm (ε 7,900): λmax (pH 11) 269 nm (ε 8,300): 1H NMR (Me2SO-d6): δ 7.48 (br s, 2, NH2), 8.10 (s, 1, C2H) and 13.60 (br s, 1, N9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([N:9]=[CH:10][N:11](C)C)=O)[S:5][CH:6]=1.[CH3:14][NH:15]N>CC(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]2[N:15]([CH3:14])[N:11]=[CH:10][N:9]=2)[S:5][CH:6]=1
Reactant: CN(C)C=NC(=O)c1cc(Cl)cs1
Reactant: CNN
Solvent: CC(=O)O
Product: Cn1ncnc1-c1cc(Cl)cs1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
Equip a 3-L reaction flask with a cooling bath, air stirrer, and thermometer probe and charge with 4-chloro-N-dimethylaminomethylene-2-thiophene carboxamide. (155 g, 0.715 moles) and HOAc (1500 mL) to form a solution. Using an ice-water cooling bath to maintain the temperature at ≦30° C., add methylhydrazine (33.2 g, 0.721 moles) dropwise using an addition funnel over 15-20 min to form a light yellow slurry. Heat the reaction gradually to 90° C. and hold at 90° C. for 30 min. Analyze the mixture by GC, then cool the reaction to about 70° C., and concentrate to a thick oil/slurry. Add water (1.67 L) slowly to precipitate solids, cool the mixture to <30° C., filter, and wash with water (1.67 L). Dissolve the wet solids (125.8 g) in warm t-butyl methyl ether (1.64 L), dry over Na2SO4, filter, and concentrate to dryness to provide the title compound as a pale yellow solid (85.8 g, 60%).
Reaction SMILES: C([O:5][C:6](=[O:22])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([C:19](=[O:21])[NH2:20])=[CH:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.CO>C(Cl)Cl>[C:19]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:8]([CH2:7][C:6]([OH:22])=[O:5])[CH:9]=1)(=[O:21])[NH2:20]
Reactant: COc1ccc2c(c1)c(C(N)=O)cn2CC(=O)OC(C)(C)C
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)c(C(N)=O)cn2CC(=O)O
Reaction time: 3 h

Procedure:
To a solution of (3-carbamoyl-5-methoxy-indol-1-yl)-acetic acid tert-butyl ester (45.0 mg, 0.118 mmol) in CH2Cl2 (2.0 mL) was added TFA (1.0 mL) at RT, and stirring was continued for 3 h. Methanol was then added to the reaction mixture and volatiles were removed in vacuo. The residue was taken up in methanol and concentrated again under reduced pressure to afford the title compound as a beige solid: MS (LC/MS): 249 [M+H]+, 277 [M+Na]+; tR (HPLC conditions c): 2.93 min. The material thus obtained was used in the next reaction step without further purification.
Reaction SMILES: C1(C[N:8]([CH2:23][C@@H:24]([C@H:26]2[CH2:31][CH2:30][C:29]3[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:28]=3[O:27]2)[OH:25])[CH2:9][C@@H:10]([C@@H:12]2[CH2:17][CH2:16][C:15]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:14]=3[O:13]2)[OH:11])C=CC=CC=1.C([O-])=O.[NH4+].O>CO.[Pd]>[NH:8]([CH2:23][C@@H:24]([C@H:26]1[CH2:31][CH2:30][C:29]2[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:28]=2[O:27]1)[OH:25])[CH2:9][C@@H:10]([C@@H:12]1[CH2:17][CH2:16][C:15]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:14]=2[O:13]1)[OH:11]
Reactant: O[C@@H](CN(Cc1ccccc1)C[C@H](O)[C@H]1CCc2cc(F)ccc2O1)[C@@H]1CCc2cc(F)ccc2O1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: O[C@@H](CNC[C@H](O)[C@H]1CCc2cc(F)ccc2O1)[C@@H]1CCc2cc(F)ccc2O1
Temperature: 65 °C
Reaction time: 11 h
Yield: 85.5 %

Procedure:
(±)[R*,S*,S*,S*]-α,α′-[(phenylmethyl)imino-bis (methylene)] bis [6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] (5.0 g; 0.0101 mol) was dissolved in methanol (343.9 g). Ammonium formate (4.8 g; 0.0761 mol) was added to the reaction mixture followed by catalytic Palladium on carbon 5 wt. % wet (contains ˜50% water) (0.5 g). The reaction mixture was heated at reflux (about 65° C.) under stirring for about 11 hours then cooled to 45° C. filtered on a celite pad, washing with methanol, and finally concentrated under vacuum. The crude residue (6.2 g) was diluted with 2-butanol (65.2 g) then a solution of aq. 30% sodium hydroxide (2.0 g) and water (29.8 g) was added under stirring. The resulting suspension was heated to 70±2° C. until complete dissolution obtaining a clear two-phase mixture. The aqueous layer was separated and the resulting organic phase was washed with aq. sodium hydrogen carbonate (1.7 g dissolved in 22.6 g of water) and then with water (2×21.5 g). Toluene (5.0 g) was also added to improve the aqueous-organic separation. The organic phase was concentrated two-times under reduced pressure while adding fresh 2-butanol (total 32.9 g) to the resulting residues. The final organic solution (about 60 ml) was further diluted with 2-butanol (9.5 g) heated to 85-90° C. until complete dissolution and then gradually cooled to 20° C. obtaining the product precipitation. The solid was isolated by filtration, washing with 2-butanol (3×2.7 g), and dried under vacuum at 60° C. to give the title compound as a white solid (3.5 g, 96.6% w/w assay (HPLC); 82.6% molar yield). Purity Profile (HPLC): Sum of Impurities=0.284% w/w; Max Single Impurity (“de-F” Nebivolol)=0.196% w/w.
Reaction SMILES: [CH:1]1[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=2[CH:4]=[C:3]2[C:12]([O:14][C:15](=[O:16])[C:2]=12)=[O:13])=[O:8].C(N(CC)CC)C.[Cl:24][C:25]1[CH:49]=[CH:48][C:28]([O:29][C:30]2[CH:31]=[C:32]([CH:45]=[CH:46][CH:47]=2)[CH2:33][NH:34][C@@H:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38][CH2:37][CH2:36]2)=[CH:27][CH:26]=1.C([O-])([O-])=[O:51].[Na+].[Na+].Cl>C1COCC1>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([O:29][C:30]2[CH:31]=[C:32]([CH:45]=[CH:46][CH:47]=2)[CH2:33][N:34]([C@@H:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38][CH2:37][CH2:36]2)[C:7]([C:6]2[CH:1]=[C:2]([C:15]([OH:14])=[O:16])[C:3]([C:12]([OH:51])=[O:13])=[CH:4][C:5]=2[C:10]([OH:9])=[O:11])=[O:8])=[CH:48][CH:49]=1
Reactant: O=c1oc(=O)c2cc3c(=O)oc(=O)c3cc12
Reactant: Clc1ccc(Oc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(Oc3ccc(Cl)cc3)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
1,2,4,5-Benzenetetracarboxylic dianhydride (2.70 g, 12.4 mmol) and triethylamine (2.15 mL, 15.5 mmol) in THF (60 mL)were treated dropwise with the product from Example 1A (2.25 g, 6.18 mmol) in THF (10 mL) at −78° C. The reaction mixture was allowed to stir for 16 hours gradually warming to ambient temperature. The mixture was treated with saturated aqueous Na2CO3 solution, stirred vigorously for 30 minutes and then carefully acidified using 12M HCl. The acidified solution was extracted with ethyl acetate. The organic extracts were combined, washed with 1N HCl, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 100:1:1 ethyl acetate:HCO2H:H2O) to provide the title compound as a white solid (1.92 g, 52% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10]3[N:18]=[CH:19][CH:20]=[CH:21][C:9]=3[N:8]=2)[CH:2]=1.[H-].[Na+].[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][CH2:28]Cl>>[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][CH2:28][N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:8][C:9]2[CH:21]=[CH:20][CH:19]=[N:18][C:10]1=2
Reactant: c1cncc(C2=Nc3cccnc3Nc3ccccc32)c1
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCCN1c2ccccc2C(c2cccnc2)=Nc2cccnc21

Procedure:
Following the procedure of Example 23, 6-(3-pyridinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine is reacted with sodium hydride followed by reaction with 3-dimethylaminopropyl chloride to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]([N:9]([CH3:16])[C:10](=O)[C:11]([F:14])([F:13])[F:12])[C:7]#N)=[CH:4][CH:3]=1.ClC(=C)[C:21]#[N:22].[C:24](OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[N:9]([CH3:16])[C:10]([C:11]([F:12])([F:13])[F:14])=[CH:24][C:7]=2[C:21]#[N:22])=[CH:17][CH:18]=1
Reactant: CCOC(C)=O
Reactant: CN(C(=O)C(F)(F)F)C(C#N)c1ccc(Cl)cc1
Reactant: C=C(Cl)C#N
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: Cn1c(C(F)(F)F)cc(C#N)c1-c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 2.25 h
Yield: 22 %

Procedure:
A solution of N-(p-chloro-α-cyanobenzyl)-2,2,2-trifluoro-N-methylacetamide (13.8 g, 0.05 mol) in toluene is treated with tetrafluoroboric acid-diethyl etherate (10.5 g as is, 8.9 g real, 0.055 mol) at room temperature, heated to 60° C., treated with 2-chloroacrylonitrile (6.9 g, 0.075 mol) over a 25 minute period, held for 2 to 2.5 hours at 60° C., cooled and treated with ethyl acetate. The resultant solution is washed with water and concentrated to give a waxy residue. Flash column chromatography of the residue on silica gel packed with 15% ethyl acetate in heptane and eluted with 20% ethyl acetate in heptane gives the title product as pale yellow crystals, 3.1 g (22% yield), mp 129°-130° C., identified by 1H, 13C, and 19F NMR analyses.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[Si]([O:29][CH2:30][CH:31]1[CH:35]([CH2:36][O:37][Si](C(C)(C)C)(C)C)[CH2:34][C:33]([CH2:45]Br)=[CH:32]1)(C(C)(C)C)(C)C>>[OH:29][CH2:30][CH:31]1[CH:35]([CH2:36][OH:37])[CH2:34][C:33]([CH2:45][N:8]2[C:9]([C:10](=[O:19])[C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]2=[O:20])=[CH:32]1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: CC(C)(C)[Si](C)(C)OCC1C=C(CBr)CC1CO[Si](C)(C)C(C)(C)C
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2CC2=CC(CO)C(CO)C2)c1
Yield: 26.3 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and [3,4-di(t-butyldimethylsilyloxymethyl)cyclopent-1-en-1-yl]methyl bromide were reacted by the same method with example 28 to obtain the titled compound (74 mg).
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][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[C:37]1([CH2:43][CH2:44]CO)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[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][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][CH2:44][CH2:43][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: OCCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCCCc4ccccc4)cc3C)c2cc1OC
Yield: 102.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-phenyl-1-propanol (31 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (77 mg, yield 98%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([CH3:18])([S:14]([CH3:17])(=[O:16])=[O:15])[C:11]([OH:13])=O)=[C:4]([CH3:19])[CH:3]=1.[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][NH2:27].O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([CH3:18])([S:14]([CH3:17])(=[O:16])=[O:15])[C:11]([NH:27][O:26][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][O:20]2)=[O:13])=[C:4]([CH3:19])[CH:3]=1
Reactant: Cc1cc(Br)ccc1CCC(C)(C(=O)O)S(C)(=O)=O
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(Br)ccc1CCC(C)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
4-(4-Bromo-2-methylphenyl)-2-methyl-2-(methylsulfonyl)butanoic acid (3.28 g, 9.39 mmol), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (2.19 g, 18.7 mmol), 1-hydroxy benzotriazole monohydrate (3.68 g, 24 mmol), triethylamine (3.35 mL, 24 mmol) and (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.59 g, 18.7 mmol) were combined followed by the addition 60 mL of dichloromethane. The reaction was allowed to stir at room temperature overnight. The reaction mixture was diluted with 20 mL of dichloromethane and 60 mL of water. The aqueous layer was extracted with dichloromethane (2×40 mL). The organics were combined, dried over magnesium sulfate, filtered and concentrated onto silica gel. Silica chromatography (30% ethyl acetate 70% heptane for 10 minutes, then 30% ethyl acetate 70% heptane to 60% ethyl acetate 40% heptane for 40 minutes) afforded the title compound as a white solid (2.11 g, 50.1%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=1.[F:15][C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:18][CH:17]=1>>[F:15][C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=3)[CH2:24][CH2:23]2)[CH:19]=[CH:18][CH:17]=1
Reactant: Fc1cccc(N2CCNCC2)n1
Reactant: CC(=O)N[C@@H](C)c1ccc(CCl)cc1
Product: CC(=O)N[C@@H](C)c1ccc(CN2CCN(c3cccc(F)n3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using (S)-N-(1-(4-chloromethylphenyl)ethyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(6-fluoropyridin-2-yl)piperazine obtained in Example 85(2) instead of phenylpiperazine, the title compound was obtained as a pale-yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH:15][C:16](=[O:32])[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[N:27][CH:28]=[N:29][CH:30]=2)[CH:20]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:26]=[N:27][CH:28]=[N:29][CH:30]=4)[CH:20]=3)[CH2:17][C:16](=[O:32])[NH:15][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1NC(=O)CC(=O)c1cccc(-c2cncnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3cncnc3)c2)=Nc2ccc(Cl)cc2N1

Procedure:
The title compound was prepared from {4-chloro-2-[3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M86) (0.35 g, 0.75 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (230 mg, 88%).