Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([CH3:13])[C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH2:14]([NH:1][C:2]1[C:11]([F:12])=[C:10]([CH3:13])[C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1c(F)c(N)cc2oc(=O)[nH]c12
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: Cc1c(F)c(NCc2ccccc2)cc2oc(=O)[nH]c12
Reaction time: 15 h
Yield: 85.7 %

Procedure:
A mixture of 6-amino-5-fluoro-4-methyl-2-benzoxazolone (Example 7 0.43 g, 2.40 mmoles) and benzaldehyde (0.26 g, 2.40 mmoles) in ethanol (2 ml) was refluxed for 2.5 hours. After cooling, the precipitated product was collected and washed with cold ethanol. To a mixture of the precipitate (0.63 g) and ethanol (8 ml) was added portionwise sodium borohydride (300 mg) at room temperature under stirring. Stirring continued for 15 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The aqueous phase was extracted twice with ethyl acetate. The combined ethyl acetate extracts were dried over sodium sulfate and evaporated to dryness. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate/hexane (1:4 by volume) to give the title compound (0.56 g). Recrystallization from methanol gave 0.44 g (68%) of the title compound as pale orange needles: m.p. 204°-206° C.
Reaction SMILES: [CH:1]([O:4][CH:5]([CH3:7])[CH3:6])(C)C.[Na].BrC1[S:11][CH:12]=[CH:13][N:14]=1>CC(O)C>[CH:5]([O:4][C:1]1[S:11][CH:12]=[CH:13][N:14]=1)([CH3:7])[CH3:6]
Reactant: CC(C)OC(C)C
Reactant: Brc1nccs1
Agent: [Na]
Solvent: CC(C)O
Product: CC(C)Oc1nccs1
Reaction time: 15 h
Yield: 73.2 %

Procedure:
To a solution of sodium isopropyloxide (10.0 g) in 2-propanol (100 mL) was added 2-bromothiazol (10.0 g) at 85° C. and the mixture was stirred for 15 hours. After cooling, the reaction mixture was concentrated in vacuo and thereto was added water. The mixture was extracted with diethylether and the extract was washed with water and a saturated brine, dried over magnesium sulfate and concentrated in vacuo to give 2-isopropyloxythiazol (6.39 g, yield: 73%). MS(APCI) m/z: 144 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[I-].C[N+]1C=CN([C:19](=[O:28])[N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)C=1.C(N(CC)CC)C>C(#N)C>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[O:1][C:19](=[O:28])[N:20]([CH3:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1ccc2ccccc2n1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C(=O)Oc1ccc2ccccc2n1)c1ccccc1
Temperature: 50 °C
Yield: 39.5 %

Procedure:
A solution of 2-hydroxyquinoline (0.44 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. More acetonitrile (60 ml) was added and the solution was heated at 50° C. for 3 days. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (40:60)) yielding the title compound (0.33 g, 40% yield) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[OH:12])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[OH:12]
Reactant: N#Cc1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: N#Cc1ccc(O)c(N)c1
Yield: 97.8 %

Procedure:
To a solution of 2-nitro-4-cyanophenol(10 g, 61 mmol) in methanol(250 mL) was added 10% Pd/C (1 g). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5% MeOH/CH2Cl2) gave the desired product(8.0 g, 97%). 1H NMR (CD3OD): δ 6.96 (d, 1H), 6.90 (dd, 1H), 6.77 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][C:9]2[CH:28]=[CH:27][C:12]([O:13][CH2:14][C:15]3[N:16]=[C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:18][C:19]=3[CH3:20])=[CH:11][CH:10]=2)[N:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:36]=[O:37]>O>[CH3:1][C:2]1[C:6]([CH:36]=[O:37])=[C:5]([CH3:7])[N:4]([CH2:8][C:9]2[CH:28]=[CH:27][C:12]([O:13][CH2:14][C:15]3[N:16]=[C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:18][C:19]=3[CH3:20])=[CH:11][CH:10]=2)[N:3]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(C)n(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c(C)c1C=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 55 %

Procedure:
A mixture of 4-[4-(3,5-dimethyl-1H-pyrazol-1-ylmethyl)phenoxymethyl]-5-methyl-2-phenyloxazole (1.62 g), phosphorus oxychloride (1.00 g), and N,N-dimethylformamide (20 ml) was stirred for 5 days at room temperature. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium bicarbonate and with saturated aqueous sodium chloride solution, then dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and 3,5-dimethyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazole-4-carbaldehyde (950 mg, yield: 55%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C:22]=3[CH2:27][CH:28]=[CH2:29])([CH3:20])[C@@H:18]([O:30]CC3C=CC=CC=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)C1C=CC=CC=1.[F:38][C:39]([F:66])([C:56]([F:65])([F:64])[C:57]([F:63])([F:62])[C:58]([F:61])([F:60])[F:59])[CH2:40][CH2:41][CH2:42][CH:43]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]C=C)[C:44]([O:46]CC)=[O:45]>>[OH:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C@@H:22]3[CH2:27][CH2:28][CH2:29][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH:43]([CH2:42][CH2:41][CH2:40][C:39]([F:38])([F:66])[C:56]([F:64])([F:65])[C:57]([F:63])([F:62])[C:58]([F:61])([F:59])[F:60])[C:44]([OH:46])=[O:45])([CH3:20])[C@@H:18]([OH:30])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: C=CCCCCCC(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Reactant: C=CCC1=C2c3ccc(OCc4ccccc4)cc3CC[C@H]2[C@@H]2CC[C@H](OCc3ccccc3)[C@@]2(C)C1
Product: C[C@]12C[C@H](CCCCCCCCC(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O

Procedure:
Starting with the 3,17β-bis(benzyloxy)-11-(2-propenyl)estra-1,3,5(10), 9(11)-tetraene prepared in Example 20 and ethyl 2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-8-nonenoate prepared separately, the same procedure as shown in Example 20 was repeated to give 10-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)decanoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[CH3:2].C(O)C>[Pd].O1CCCC1>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[CH3:2]
Reactant: CCOC(=O)CC1=C(c2cccc(OC)c2)CCCC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCCCC1c1cccc(OC)c1
Reaction time: 18 h
Yield: 89.4 %

Procedure:
Combine [2-(3-methoxy-phenyl)-cyclohex-1-enyl]-acetic acid ethyl ester (9.91 g, 36.0 mmol), 10% Pd on carbon (2.06 g, 14.4 mmol), and ethanol (90 mL) and tetrahydrofuran (5 mL), degas, and add 50 psi H2 at room temperature. After 18 hours, filter off the Pd catalyst over celite eluting with ethyl acetate. Concentrate and flash chromatograph with 0% to 20% ethyl acetate/hexanes to yield the titled compound (8.89 g, 89%) as a clear oil. TLC Rf=0.42 in 6:1 hexanes:ethyl acetate. 1H NMR (CDCl3):1H NMR (CDCl3): 7.21 (t, 1H, J=8.1 Hz), 6.78 (d, 2H, J=7.5 Hz), 6.72 (s, 1H), 3.98 (q, 2H, J=7.0 Hz), 3.80 (m, 3H), 2.89 (m, 1H), 2.51 (m, 1H), 2.31 (m, 1H), 1.97 (m, 1H), 1.88 (m, 1H), 1.72 (m, 4H), 1.44 (m, 3H), 1.16 (t, 3H, J=6.6 Hz).
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:11]([O-])=O)=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[C:7]#[N:8].CCOC(C)=O>CCO>[NH2:11][C:3]1[C:2]([OH:1])=[CH:9][C:6]([C:7]#[N:8])=[C:5]([CH3:10])[CH:4]=1
Reactant: Cc1cc([N+](=O)[O-])c(O)cc1C#N
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(N)c(O)cc1C#N
Yield: 98.6 %

Procedure:
5-hydroxy-2-methyl-4-nitrobenzonitrile (D91, 185 mg, 1.04 mmol) was dissolved in EtOH:EtOAc (24 mL, 1:1) and was reduced using an H-Cube (full H2 mode, 25° C., 1 mL/min). The reaction was concentrated by rotary evaporation to give 4-amino-5-hydroxy-2-methylbenzonitrile (D92, 152 mg, 95%) as a pale yellow solid.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7]O.C(O[CH:12]=[C:13]([C:30]([C:32]1([CH3:35])[CH2:34][CH2:33]1)=[O:31])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:17]=1[C:26]([F:29])([F:28])[F:27])=[O:15])C>>[CH3:25][S:22]([C:19]1[CH:20]=[CH:21][C:16]([C:14]([C:13]2[CH:12]=[N:7][O:31][C:30]=2[C:32]2([CH3:35])[CH2:34][CH2:33]2)=[O:15])=[C:17]([C:26]([F:29])([F:28])[F:27])[CH:18]=1)(=[O:24])=[O:23]
Reactant: CCOC=C(C(=O)c1ccc(S(C)(=O)=O)cc1C(F)(F)F)C(=O)C1(C)CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: CC1(c2oncc2C(=O)c2ccc(S(C)(=O)=O)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
Sodium acetate (1.0 g) was added to a stirring mixture of hydroxylamine hydrochloride (0.85 g) and 2-ethoxymethylene-1-(4-methylsulphonyl-2-trifluoromethylphenyl)-3-(1-methylcyclopropyl)-propane-1,3-dione (4.2 g) in industrial methylareal spirit (200 ml). The mixture was stirred at room temperature for 3 hours. The mixture was evaporated to dryness and then suspended in ethyl acetate (100 ml). The resultant suspension was washed with water (100 ml), dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 4-(4-methylsulphonyl-2-trifluoromethylbenzoyl)-5-(1-methylcyclopropyl) isoxazole (compound 99, 3.5 g) as a white Solid, m.p. 141°-142° C.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH2:14])[CH2:6]1)(=[O:3])[CH3:2].CO[CH:17]1[CH2:21][CH2:20][CH:19](OC)O1.C(Cl)(Cl)Cl.[Cl-].[Na+]>C(O)(=O)C>[C:1]([O:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:14]2[CH:17]=[CH:21][CH:20]=[CH:19]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1Cc2cccc(N)c2C1
Reactant: COC1CCC(OC)O1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)OC1Cc2cccc(-n3cccc3)c2C1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A stirred solution of 0.70 g (0.004 mole) of 4-amino-2-indanyl acetate and 0.56 g (0.004 mole) of 2,5-dimethoxytetrahydrofuran in 1.5 mL of acetic acid was heated under reflux for 3 hours. The reaction mixture was cooled to ambient temperature and poured into 30 mL of chloroform. The mixture was stirred with 30 mL of an aqueous saturated solution of sodium chloride. The organic layer was removed, and the aqueous layer extracted with two portions of 30 mL each of chloroform. The combined organic phases were washed with two portions of 30 mL each of an aqueous saturated solution of sodium chloride. The organic layer was dried over potassium carbonate, filtered, and the filtrate concentrated under reduced pressure to give 0.89 g of 4-(1-pyrrolyl)-2-indanyl acetate.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:9][C@@H:8]([O:10][CH3:11])[CH2:7][N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].O.O[Li].O>C(#N)C>[C:15]([O:14][C:12]([N:6]1[CH2:7][C@H:8]([O:10][CH3:11])[CH2:9][C@@H:5]1[C:3]([OH:4])=[O:2])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)[C@H]1C[C@@H](OC)CN1C(=O)OC(C)(C)C
Agent: [Li]O
Solvent: O
Solvent: CC#N
Product: CO[C@@H]1C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 28 h

Procedure:
Into a solution of 5 (2.54 g, 9.80 mmol) in acetonitrile (20 mL) was added water (20 mL) and LiOH.H2O (1.64 g, 39.2 mmol). The mixture was stirred at RT for 28 h before removing the acetonitrile under reduced pressure. EtOAc was added to the residue that was then washed with 1N HCl. The aqueous layer was extracted with additional EtOAc and the combined organic layers were washed with brine and dried over MgSO4. The solution was concentrated under reduced pressure to reveal 6 (2.16 g, 90%) as a white solid. MS: APCI (AP−): 244.1 (M)−.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:9]([C:10]([OH:12])=O)[C:8]=1[NH2:18].[O-:19][C:20]#[N:21].[K+].[OH-].[Na+]>O>[CH3:17][O:16][C:15]1[C:7]([O:6][CH3:5])=[C:8]2[C:9]([C:10](=[O:12])[NH:21][C:20](=[O:19])[NH:18]2)=[CH:13][CH:14]=1
Reactant: COc1ccc(C(=O)O)c(N)c1OC
Reactant: N#C[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(=O)[nH]c(=O)[nH]c2c1OC
Temperature: 40 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
Acetic acid (177.4 ml., 3.1 moles) was added to a vigorously stirred suspension of 3,4-dimethoxyanthranilic acid (436.5 g., 2.21 moles) in 10 liters of water. Then 2.24 liters of 20% potassium cyanate (5.53 moles) solution was gradually added and the mixture was stirred for one hour at 40° C. After cooling the reaction mixture to 20° C., 3.54 kg. sodium hydroxide pellets were added maintaining the temperature below 40° C. The reaction mixture was heated to 90° C. for 45 minutes and then slowly cooled in an ice bath. The sodium salt of the product was filtered, resuspended in 6 liters of water, acidified with concentrated hydrochloric acid (370 ml.), cooled and filtered to yield 404 grams (82%) of the product. Recrystallization from dimethylformamide gave colorless crystals, M.P. 314°-6° C.
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].C(N(CC)CC)C.[CH:22](=[O:26])[CH2:23][CH2:24][CH3:25]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:3][C@H:2]([C@@H:22]([OH:26])[CH2:23][CH2:24][CH3:25])[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: CCCC=O
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC[C@H](O)[C@@H](C)C(=O)n1c(=O)oc2ccccc21
Yield: 80 %

Procedure:
A solution of N-propionyl-2-benzoxazolone (100.0 g) in anhydrous CH2Cl2 (1100 mL) was cooled to 3° C. with mechanical stirring under N2 atmosphere. TiCl4 (58.4 mL) was added at a rate such that the internal temperature remained below 10° C. (ca. 10 minutes). The resulting yellow slurry was stirred vigorously for 40 minutes, then triethylamine (87.4 mL) was added at a rate such that the internal temperature remained below 10° C. (ca. 10 minutes). The resulting deep red solution was stirred for 80 minutes. Butyraldehyde (58.9 mL) was added at a rate such that the internal temperature remained below 10° C. (ca. 20 minutes), and the reaction was followed by thin-layer chromatography (4:1 hexanes/ethyl acetate). After stirring for 90 minutes, the reaction was quenched by addition of 450 mL of 2 N HCl. The phases were separated, and the aqueous phase was extracted 3 times with 750-mL portions of ether. The organic phases were combined and washed three times with 200-mL portions of 2 N HCl. The acidic washes were combined and back-extracted 3 times with 150-mL portions of ether. The combined organic extract was washed once with 300 mL of sat. aq. NaHCO3, and once with 300 mL of sat. aq. NaCl. The organic phase was then dried over MgSO4, filtered, and concentrated under vacuum to a yellow slurry. The product was collected by vacuum filtration and rinsed with hexanes to yield a colorless solid. Concentration of the filtrate yielded a second crop of product, which was collected in the same manner, giving a combined 103 g (80% yield) of crystalline product; mp=123–4° C. The mother liquor can be chromatographed (4:1 hexanes/ethyl acetate) to yield additional product. 1H-NMR (CDCl3, 400 MHz): δ 8.10 (1H,m), 7.23–7.32 (3H,m), 4.12 (1H,m), 3.98 (1H,dq,J=3, 7), 2.26 (1H, br s), 1.38–1.64 (4H,m), 1.34 (3H,d,J=7), 0.98 (3H,t,J=7). 13C-NMR (CDCl3, 100 MHz): δ 176.4, 151.1, 142.2, 127.8, 125.5, 124.9, 116.3, 109.9, 71.3, 43.7, 36.2, 19.2, 13.9, 10.1.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:16]=[CH:15][C:7]([C:8]([NH:10][CH:11]=[N:12][O:13][CH3:14])=[O:9])=[C:6]([CH3:17])[CH:5]=1.ClN1C(=O)CCC1=O.[Cl:26][C:27]1[CH:28]=[C:29]([C:37]([C:39]([F:42])([F:41])[F:40])=[CH2:38])[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1.C(=O)([O-])O.[K+]>COCCOC.O>[Cl:26][C:27]1[CH:28]=[C:29]([C:37]2([C:39]([F:40])([F:41])[F:42])[O:1][N:2]=[C:3]([C:4]3[CH:16]=[CH:15][C:7]([C:8]([NH:10][CH:11]=[N:12][O:13][CH3:14])=[O:9])=[C:6]([CH3:17])[CH:5]=3)[CH2:38]2)[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1
Reactant: CON=CNC(=O)c1ccc(C=NO)cc1C
Reactant: C=C(c1cc(Cl)cc(C(F)(F)F)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CON=CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 11.7 %

Procedure:
In a solution of 81 mg of 4-hydroxyiminomethyl-N-(methoxyiminomethyl)-2-methyl benzoic acid amide in 10 ml of 1,2-dimethoxyethane, 60 mg of N-chlorosuccinimide was added, and stirred at 70° C. for 45 minutes. Then, the reaction mixture was left and cooled to room temperature, and then 60 mg of 3-chloro-5-trifluoromethyl-1-(1-trifluoromethylethenyl)benzene, 40 mg of potassium hydrogen carbonate and 3 drops of water were added, and continued to stir at room temperature further for 15 hours. After the completion of the reaction, the reaction mixture was poured in 10 mL of water, and extracted with ethyl acetate (15 mL×2). The combined organic phases were dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that were eluated with ethyl acetate-hexane (gradient of 1:5 to 1:3) to obtain 13 mg of the aimed product as colorless resinous substance.
Reaction SMILES: C1(CO[C:9](=[O:27])[NH:10][C@H:11]2[CH2:14][N:13]([C:15]([NH:17][P:18]([N:23]([CH3:25])[CH3:24])([N:20]([CH3:22])[CH3:21])=[O:19])=[O:16])[C:12]2=[O:26])C=CC=CC=1.[C:28]1([CH2:34]C(Cl)=O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>[Pd].C(N(CC)CC)C>[CH3:25][N:23]([P:18]([NH:17][C:15]([N:13]1[CH2:14][C@H:11]([NH:10][C:9](=[O:27])[CH2:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:12]1=[O:26])=[O:16])([N:20]([CH3:21])[CH3:22])=[O:19])[CH3:24]
Reactant: CN(C)P(=O)(NC(=O)N1C[C@H](NC(=O)OCc2ccccc2)C1=O)N(C)C
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Pd]
Solvent: CCN(CC)CC
Product: CN(C)P(=O)(NC(=O)N1C[C@H](NC(=O)Cc2ccccc2)C1=O)N(C)C

Procedure:
By a procedure analogous to that used in the second part of Example IV, (S)-[1-[[[bis-(dimethylamino)phophinyl]amino]carbonyl]2-oxo-3-azetidinyl]carbamic acid phenylmethyl ester, produced as in the previous Example, is hydrogenated in the presence of 10% Pd on carbon catalyst, and the intermediate thus obtained is acylated by reaction with phenylacetyl chloride and triethylamine to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([O:21][CH3:22])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([OH:23])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:30]([O:34][C:35](=[O:39])[CH:36](Br)[CH3:37])([CH3:33])([CH3:32])[CH3:31]>C(#N)C>[CH3:22][O:21][C:19]([C:16]1[S:15][C:11]2[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[O:23][CH:36]([CH3:37])[C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:39])[C:10]=2[C:17]=1[CH3:18])=[O:20]
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O)c2c1C
Reactant: CC(Br)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(C)C(=O)OC(C)(C)C)c2c1C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Methyl 4-(4-fluoro-2-hydroxyphenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylate (100 mg) and Caesium carbonate (240 mg) was dissolved in acetonitrile (2 ml) and 2-bromopropionic acid tert-butylester (70 mg) was added. The reaction mixture was stirred at 60° C. for 2 h. Then the reaction was quenched with water and the precipitate was collected by filtration. The residue cake was washed with water and a few drops of methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.O[CH2:14][CH2:15][N:16]([CH2:29][CH2:30]O)[C:17](=[O:28])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1.P(=O)(O)(O)O.[OH-].[Na+]>O>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[O:24][CH3:25])[C:17]([N:16]1[CH2:15][CH2:14][N:1]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]3)[CH2:30][CH2:29]1)=[O:28]
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Reactant: COc1ccc(C(=O)N(CCO)CCO)cc1OC
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC
Yield: 71.4 %

Procedure:
A mixture of 2.7 g of 6-amino-3,4-dihydrocarbostyril, 5.9 g of N,N-bis(2-hydroxyethyl)-3,4-dimethoxybenzamide and 8.6 g of 85% phosphoric acid was reacted at 165° to 175° C. for 4.5 hours while stirring. After allowing to cool, to the reaction mixture was added dropwise about 50 ml of water to dissolve. The solution was neutralized with an aqueous 48% sodium hydroxide solution and extracted with chloroform. After drying the extract over potassium carbonate, chloroform was distilled off. Recrystallization of the residue from ethanol-chloroform gave 4.7 g of 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 238°-239.5° C., colorless granules.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH2:10][CH:11]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:22][C@@H:23]1[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25][CH2:24]1>>[CH3:22][C@@H:23]1[CH2:28][CH2:27][C@H:26]([NH:29][C:5]2[N:4]=[C:3]([O:9][CH2:10][CH:11]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]3)[C:2]([Br:1])=[CH:7][N:6]=2)[CH2:25][CH2:24]1
Reactant: C[C@H]1CC[C@@H](N)CC1
Reactant: CC(C)(C)OC(=O)N1CC(COc2nc(Cl)ncc2Br)C1
Product: CC(C)(C)OC(=O)N1CC(COc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2Br)C1

Procedure:
Using the procedure of Example 1 Step 2, tert-butyl 3-((5-bromo-2-chloropyrimidin-4-yloxy)methyl)azetidine-1-carboxylate was reacted with cis-4-methylcyclohexanamine to provide the title compound in 55% yield. 1H NMR (CDCl3, 300 MHz) 8.10 (s, 1H), 5.17 (m, 1H), 5.47 (d, 2H), 4.11-4.00 (m, 3H), 3.84-3.79 (m, 2H), 3.02-2.98 (m, 1H), 1.78-1.58 (m, 6H), 1.46 (s, 9H), 1.46-1.27 (m, 3H), 0.95 (d, 3H); MS (ESI) m/z: Calc: 454.2 (M+). Found. 456.1 (M+2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:17]=[C:16]([CH3:18])[C:15]([NH2:19])=[C:11]2[O:12][C:13]=1[CH3:14].C(N(CC)CC)C.[C:27](Cl)(=[O:30])[CH2:28][CH3:29]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:17]=[C:16]([CH3:18])[C:15]([NH:19][C:27](=[O:30])[CH2:28][CH3:29])=[C:11]2[O:12][C:13]=1[CH3:14]
Reactant: Cc1nn2c(-c3ccc(Cl)cc3Cl)c(C)oc2c1N
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1c(C)nn2c(-c3ccc(Cl)cc3Cl)c(C)oc12
Reaction time: 2 h

Procedure:
To a suspension of 3-(2,4-dichloro-phenyl)-2,6-dimethyl-pyrazolo[5,1-b]oxazol-7-ylamine (Intermediate ID) (500 mg, 1.503 mmol) in DCM (10 ml) under N2 is added triethylamine (0.461 ml, 3.31 mmol) followed by propionyl chloride (0.144 ml, 1.654 mmol) at 0° C. After 2 hr, the reaction mixture is diluted with DCM (50 ml) and washed with 1M HCl, NaHCO3, Brine, dried (MgSO4) and evaporated down to give a pink solid. This is then triturated with Et2O to give the title compound as an off white solid. MS: n/z 351.9[M+H]+