Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH3:15])[N:14]=1)[C:9]([OH:11])=O)[CH:3]([CH3:5])[CH3:4].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:47]([C:49]1[CH:50]=[C:51]([CH:56]=[C:57]([CH2:60]C)[C:58]=1[OH:59])[C:52]([NH:54]O)=[NH:53])[CH3:48]>C(Cl)Cl>[CH2:47]([C:49]1[CH:50]=[C:51]([C:52]2[N:54]=[C:9]([C:8]3[CH:12]=[C:13]([CH3:15])[N:14]=[C:6]([CH2:2][CH:3]([CH3:4])[CH3:5])[CH:7]=3)[O:11][N:53]=2)[CH:56]=[C:57]([CH3:60])[C:58]=1[OH:59])[CH3:48]
Reactant: CCc1cc(C(=N)NO)cc(CC)c1O
Reactant: Cc1cc(C(=O)O)cc(CC(C)C)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(-c2noc(-c3cc(C)nc(CC(C)C)c3)n2)cc(C)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To a solution of 2-isobutyl-6-methyl-isonicotinic acid hydrochloride (2.18 g, 9.53 mmol) and DIPEA (3.69 g, 28.6 mmol) in DCM (10 mL), TBTU (3.67 g, 11.44 mmol) is added. The mixture is stirred for 5 min before 3,5-diethyl-4,N-dihydroxy-benzamidine (1.85 g, 9.53 mmol) is added. The mixture is stirred at rt for 1 h. The mixture is diluted with DCM, washed with sat. aq. NaHCO3 solution, dried over MgSO4, filtered and concentrated. The crude 2-isobutyl-6-methyl-isonicotinic acid (3-ethyl-4,N-dihydroxy-5-methyl-benzamidine) ester (LC-MS: tR=0.79 min, [M+1]+=370.06) is dissolved in dioxane (50 mL) and heated to 100° C. for 4 h. The solvent is evaporated and the crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 2-ethyl-4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenol (1.97 g) as a colourless oil; LC-MS: tR=0.93 min; [M+1]+=352.16; 1H NMR (CDCl3): δ 7.85 (s, 2 H), 7.75 (s, 1 H), 7.70 (s, 1 H), 5.05 (s br, 1H), 2.78 (d, J=7.5 Hz, 2H), 2.74 (q, J=7.5 Hz, 2H), 2.69 (s, 3H), 2.37 8 s, 3H), 2.19 (hept, J=7.5 Hz, 1H), 1.34 (t, J=7.5 Hz, 3H), 1.00 (d, J=6.5 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])=[CH:12][CH:11]=1)=[O:8].[NH:25]1[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]1>>[Br:1][C:2]1[C:3]([N:25]2[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]2)=[N:4][CH:5]=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)C(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: O[C@@H]1CCNC1
Product: O=C(Nc1ccc(OC(F)(F)C(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 33.1 using 5-bromo-6-chloro-N-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)nicotinamide (Stage 212.2) and (R)-pyrrolidin-3-ol to afford a solid. UPLC-MS (Condition 3) tR=1.05 min, m/z=478.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[Cl:11][C:12]1[C:13](F)=[CH:14][C:15]2[O:20][CH:19]([C:21]([F:24])([F:23])[F:22])[C:18]([C:25]([O:27]CC)=[O:26])=[CH:17][C:16]=2[CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:5]([C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][CH:8]=1)[O:1][C:13]1[C:12]([Cl:11])=[CH:30][C:16]2[CH:17]=[C:18]([C:25]([OH:27])=[O:26])[CH:19]([C:21]([F:23])([F:24])[F:22])[O:20][C:15]=2[CH:14]=1)([OH:7])=[O:6]
Reactant: O=C(O)c1cccc(O)c1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3cccc(C(=O)O)c3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 3-hydroxybenzoic acid and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4. (Note: In the step similar to step 3, an additional equivalent of potassium carbonate was added.) mp 288.1-289.2° C. 1H NMR (acetone-d6 /300 MHz) 7.92 (m, 2H), 7.75 (s, 1H), 7.68 (d, 1H, J=1.4 Hz), 7.62 (t, 1H, J=7.9 Hz), 7.41 (m, 1H), 6.72 (s, 1H), 5.85 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6 /282 MHz) -79.4 (d, J=6.5 Hz). ESHRMS m/z 413.0027 (M-H, Calc'd 113.0040). Anal. Calc'd for C18H10ClF3O6 : C, 52.13; H, 2.43; Cl, 8.55. Found: C, 51.88; H, 2.48; Cl, 8.65.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1.[CH2:19]([N:25]([CH3:29])[C:26](Cl)=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].N1C=CC=CC=1>C1(C)C=CC=CC=1>[F:18][C:2]([F:1])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:26](=[O:27])[N:25]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH3:29])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1
Reactant: CCCCCCN(C)C(=O)Cl
Reactant: CN1CCC(O)N(c2nnc(C(F)(F)F)s2)C1=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCN(C)C(=O)OC1CCN(C)C(=O)N1c1nnc(C(F)(F)F)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), N-hexyl-N-methylcarbamoyl chloride (0.06 mole), pyridine (0.06 mole) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 3 hours. After this time the reaction mixture is cooled to room temperature and is filtered to remove pyridine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvent leaving a residue. The residue is recrystallized to yield the desired product tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-(N-hexyl-N-methylcarbamoyloxy)-2(1H)-pyrimidinone.
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:13]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=[O:15])[CH3:14].[OH-].[Na+].CCCCCC.C(OCC)(=O)C>CO>[C:1]1([CH:11]=[CH:14][C:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: CC(=O)c1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: O=C(C=Cc1cccc2ccccc12)c1cccs1
Yield: 80 %

Procedure:
3.12 g (20 mmol) of 1-naphthaldehyde and 2.52 g (20 mmol) of 2-acetylthiophene were dissolved in 20ml of methanol and 800 mg (20 mmol) of sodium hydroxide was slowly added thereto. The mixture was reacted at room temperature for 8 hours and then the solid thus produced was filtered and dried. The filtrate was adjusted to pH 4-6 using 1N hydrochloric acid solution and extracted with ethyl acetate. The organic solvent was removed under reduced pressure and the residue was subjected to column chromatography(eluent: hexane/ethyl acetate=4/1, v/v) to give 4.23 g (16 mmol, Yield 80%) of the title compound together with the filtered solid.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH2:10])=[N:7][C:6]=1[CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH3:12][O:13][CH2:14][CH2:15]Br>C(Cl)Cl.CO>[C:1]([C:5]1[S:9][C:8](=[NH:10])[N:7]([CH2:15][CH2:14][O:13][CH3:12])[C:6]=1[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(N)sc1C(C)(C)C
Reactant: COCCBr
Solvent: CO
Solvent: ClCCl
Product: COCCn1c(C)c(C(C)(C)C)sc1=N
Temperature: 85 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
A mixture of 5-tert-butyl-4-methylthiazole-2-ylamine (1.5 g, 8.8 mmol) and 2-bromoethyl methyl ether (0.91 mL, 9.7 mmol) was warmed to 85° C. and allowed to stir for 24 hours. The crude material was dissolved in ˜5 mL of a 1:1 mixture of CH2Cl2 and CH3OH and a small amount of silica gel was added. This mixture was concentrated to dryness and the residue was purified via flash column chromatography (SiO2, 9:1:0.1 CH2Cl2:CH3OH:NH4OH) to afford the title compound (1.0 g, 4.4 mmol, 50% yield). 1H NMR (300 MHz, CD3OD) δ ppm 1.41 (s, 9H) 2.38 (s, 3H) 3.35 (s, 3H) 3.66 (t, J=4.70 Hz, 2H) 4.16 (t, J=4.70 Hz, 2H); MS (DCI/NH3) m/z 229 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[N:14]1[CH:19]=[C:18](B(O)O)[CH:17]=[N:16][CH:15]=1.[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([NH2:29])=[N:25]1>>[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([NH:29][C:2]2[N:3]=[CH:4][C:5]([C:18]3[CH:19]=[N:14][CH:15]=[N:16][CH:17]=3)=[C:6]3[C:11]=2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]3)=[N:25]1
Reactant: OB(O)c1cncnc1
Reactant: Cn1ccc(N)n1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Product: Cc1ccc2c(-c3cncnc3)cnc(Nc3ccn(C)n3)c2n1

Procedure:
The title compound, MS: m/e=318.2 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 5-pyrimidineboronic acid and 1-methyl-1H-pyrazol-3-ylamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH3:12])[CH2:6][C:5]2=[O:13].C([O:16][CH:17]=[C:18]([C:24](OCC)=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>>[O:16]=[C:17]1[C:10]2=[CH:11][C:2]([F:1])=[CH:3][C:4]3=[C:9]2[N:8]([CH:7]([CH3:12])[CH2:6][C:5]3=[O:13])[CH:24]=[C:18]1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC1CC(=O)c2cc(F)ccc2N1
Product: CCOC(=O)c1cn2c3c(cc(F)cc3c1=O)C(=O)CC2C
Temperature: 170 °C

Procedure:
A stirred mixture of 12 g (0.067 mole) of 6-fluoro-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline from example 4 and 14.8 g (0.070 mole) of diethyl ethoxymethylenemalonate was heated gradually to 160 to 180° C. while removing the ethanol generated by distillation. After 0.5 hour the mixture was cooled to 60°C., and 30 g of polyphosphoric acid was added. This mixture was heated gradually to 150 to 160°C. and maintained at 155° to 160°C. for 5 to 10 minutes. Following cooling, water was added, and the mixture was kneaded to produce an orange powder which was separated by filtration. Recrystallization from a mixture of 500 ml of 95% ethanol and 100 ml of glacial acetic acid gave a yellow product, ethyl 6,7-dihydro-1,7-dioxo-9-fluoro-5-methyl-1H,5H-benzo[ij]-quinolizine2-carboxylate, m.p. 262-265°C.
Reaction SMILES: [CH3:1][O:2][NH:3][CH:4]([CH3:24])[CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[CH2:21][CH2:22][CH3:23].[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[CH2:21]([C:9]1[N:8]([CH2:7][CH2:6][CH2:5][CH:4]([N:3]([O:2][CH3:1])[C:32]([NH:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:33])[CH3:24])[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=1)[CH2:22][CH3:23]
Reactant: O=C=Nc1ccccc1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(C)NOC
Solvent: C1CCOC1
Product: CCCc1nc2cnc3ccccc3c2n1CCCC(C)N(OC)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The preparation of O-methyl-N-[1-methyl-4-(2-propyl-1H-imidazo-[4,5-c]quinolin-1-yl)butyl]hydroxylamine is described in parts A-D of Example 10. Phenyl isocyanate (0.49 mL, 4.59 mmol) was added to a solution of O-methyl-N-[1-methyl-4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]hydroxylamine (1.0 g, 3.06 mmol) in tetrahydrofuran (THF) (20 mL) and stirred for 4 hours at ambient temperature. The reaction mixture was concentrated under reduced pressure to afford 1.02 g of 1-[4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-methylbutyl]-1-methoxy-3-phenylurea which was used without any further purification.
Reaction SMILES: [CH:1]([C@H:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:2].[CH2:17]([Mg]Br)[CH3:18].[Cl-].[NH4+]>C1COCC1>[OH:2][CH:1]([C@H:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:17][CH3:18]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
A solution of tert-butyl (4R)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (14.0 g) in THF (250 mL) was cooled in a dry ice/acetone bath under nitrogen atmosphere, and ethyl magnesium bromide (24 mL, 3M solution in diethyl ether) was added dropwise thereto. The resulting mixture was stirred for 3 hr while elevating the temperature gradually to 0° C., and saturated aqueous ammonium chloride solution was added thereto. The mixture was separated into phases, the aqueous layer was then extracted with ethyl acetate, and the organic layer was washed with water and brine. After drying over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate=92:8-37:63) to afford tert-butyl (4R)-4-(1-hydroxypropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (11.14 g).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].BrC1C=CC(F)=CC=1[CH2:22][O:23][CH2:24]OC>>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:3]=1[CH2:4][O:5][CH2:22][O:23][CH3:24]
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Reactant: COCOCc1cc(F)ccc1Br
Product: COCOCc1cc(C(F)(F)F)ccc1Br

Procedure:
This compound was made from 2-bromo-5-trifluoromethylbenzaldehyde in the same manner as compound 5b and used for the next step without purification.
Reaction SMILES: [OH-].[Na+].[CH2:3]([CH:5]1[O:7][CH2:6]1)Cl.[OH:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[O:11][CH2:12][CH2:13][OH:14]>O1CCOCC1>[O:7]1[CH:5]([CH2:3][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][CH2:13][OH:14])[CH2:6]1
Reactant: OCCOc1ccccc1O
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: OCCOc1ccccc1OCC1CO1
Temperature: 50 °C
Yield: 41.7 %

Procedure:
69 ml of 1 N sodium hydroxide and 7.3 ml of epichlorohydrin were added to a solution of 7.2 g of 2-(2-hydroxyphenoxy)ethanol in 50 ml of dioxane, and the mixture was heated at 50° C. for 2 hours with stirring. The reaction solution was extracted with chloroform, washed with water and dried. The solvent was distilled off under reduced pressure. The residue was chromatographed on a silica gel column to afford 4.1 g (yield 41.7%) of 1,2-epoxy-3-[2-(2-hydroxyethoxy)phenoxy]propane as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[C:18]([C:27]2[O:28][CH:29]=[CH:30][N:31]=2)=[N:19][N:20]([CH2:23][C:24](O)=[O:25])[C:21]=1[CH3:22].F[P-](F)(F)(F)(F)F.N1([PH+](N2CCCC2)N2CCCC2)CCCC1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.CCOC(C)=O>[Cl:16][C:17]1[C:18]([C:27]2[O:28][CH:29]=[CH:30][N:31]=2)=[N:19][N:20]([CH2:23][C:24]([N:10]2[CH2:9][CH2:8][C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:15][CH:14]=3)([OH:13])[CH2:12][CH2:11]2)=[O:25])[C:21]=1[CH3:22]
Reactant: Cc1c(Cl)c(-c2ncco2)nn1CC(=O)O
Reactant: OC1(Cc2ccc(F)cc2)CCNCC1
Agent: C1CCN([PH+](N2CCCC2)N2CCCC2)C1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)c(-c2ncco2)nn1CC(=O)N1CCC(O)(Cc2ccc(F)cc2)CC1
Reaction time: 14 h
Yield: 30.2 %

Procedure:
To a 20 mL vial equipped with a magnetic stirring bar was added 63 mg of 4-(4-Fluoro-benzyl)-piperidin-4-ol (0.3 mmol, 1.2 equiv.), 62 mg of (4-Chloro-5-methyl-3-oxazol-2-yl-pyrazol-1-yl)-acetic acid (0.26 mmol, 1.0 equiv), and 138 mg of benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.27 mmol, 1.0 equiv). The reagents were dissolved in 0.6 mL of DMA and to the resultant solution was added 0.18 mL of DIPEA (1.0 mmol, 3.8 equiv.). The reaction solution was stirred for 14 h and then poured into 50 mL of EtOAc. The organic extracts were washed with saturated aq. NaCl (5×10 mL), 1% aq NaOH (1×10 mL), and 0.1 N HCl (1×10 mL). The organic extracts were dried over MgSO4 and concentrated in vacuo to afford a yellow oil, which was purified by preparative HPLC to afford 34 mg of 2-(4-Chloro-5-methyl-3-oxazol-2-yl-pyrazol-1-yl)-1-[4-(4-fluoro-benzyl)-4-hydroxy-piperidin-1-yl]-ethanone (30% yield): MS (ES) M+H expected=413.2, found 413.2. 1H NMR (CDCl3, 400 MHz, 23° C.) δ 7.69 (s, 1H), 7.27 (s, 1H), 7.11-7.14 (m, 2H), 6.98-7.03 (m, 2H), 5.06 (d, J=16.0 Hz, 1H), 4.93 (d, J=16.0 Hz, 1H), 4.32-4.35 (m, 1H), 3.66-3.69 (m, 1H), 3.43-3.50 (m, 1H), 2.96-3.03 (m, 1H), 2.74 (s, 2H), 2.30 (s, 3H), 1.55-1.63 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:19])[CH2:11][CH:12]([CH3:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C=O)C>[CH2:22]([N:9]([C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[C:10](=[O:19])[CH2:11][CH:12]([CH3:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)CC(C)CC(=O)Nc1ccc(C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC(C)CC(=O)N(Cc1ccccc1)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.1 %

Procedure:
To a solution of the compound obtained in Step 1 (228 mg, 0.88 mmol) in DMF (6 mL) was added sodium hydride (60% in oil, 126 mg, 2.63 mmol) at 0° C. The reaction mixture was stirred at room temperature for 30 min, and benzyl bromide (0.156 mL, 1.31 mmol) was added thereto at 0° C. The reaction mixture was stirred at room temperature for 14 hr, to the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5 to 85% ethyl acetate/hexane) to give methyl 5-(benzyl(4-cyanophenyl)amino)-3-methyl-5-oxopentanoate (81 mg, 0.230 mmol, 26.3%) as a colorless oil.
Reaction SMILES: [H-].[Na+].[C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[CH:21][N:20]=1>CN(C=O)C.O>[C:3]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[CH:21][N:20]=2)=[CH:7][CH:8]=1
Reactant: Clc1ncnc2ccccc12
Reactant: OCCc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(-c2ccc(CCOc3ncnc4ccccc34)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
To a solution of 0.53 g of sodium hydride in 200 ml of DMF was added 2.2 g of 2-[(1,1'-biphenyl)-4-yl]ethanol, and the mixture was stirred at room temperature for one hour. Then 1.8 g of 4-chloroquinazoline in 20 ml of DMF were added, and the mixture was stirred at room temperature for another three hours. The mixture was then poured into a mixture of ice in water. The solid phase was collected and washed with water. TLC showed two spots. The product was purified using HPLC (silica gel, CH2Cl2) giving 1.1 g of the title product. Yield: 30.6%. M.P. 72°-74° C.
Reaction SMILES: [O:1]([Si:3]([C:12]([CH3:15])([CH3:14])[CH3:13])([C:8]([CH3:11])([CH3:10])[CH3:9])[C:4]([CH3:7])([CH3:6])[CH3:5])[Na].[CH-:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1.[Cl:21][Ti+:22](Cl)Cl>C1(C)C=CC=CC=1>[Cl-:21].[Cl-:21].[CH:16]1([Ti+2:22][O:1][Si:3]([C:12]([CH3:15])([CH3:14])[CH3:13])([C:8]([CH3:11])([CH3:10])[CH3:9])[C:4]([CH3:7])([CH3:6])[CH3:5])[CH:20]=[CH:19][CH:18]=[CH:17]1
Reactant: c1cc[cH-]c1
Reactant: CC(C)(C)[Si](O[Na])(C(C)(C)C)C(C)(C)C
Reactant: Cl[Ti+](Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](O[Ti+2]C1C=CC=C1)(C(C)(C)C)C(C)(C)C
Product: [Cl-]
Temperature: 23 °C
Reaction time: 5 h

Procedure:
NaOSitBu3 (0.502 g, 2.106 mmol, prepared by reacting Na and tBu3SiOH in refluxing hexane) in toluene (20 mL) was added to a toluene solution (20 mL) of CpTiCl3 (0.462 g, 2.106 mmol) at −78° C. The solution was warmed to 23° C. and stirred for about 5 hours. The solution was pumped to dryness and the residue was extracted with hexane. The hexane solution was concentrated to ˜2 mL and the product crystallized as yellow-orange crystals at −70° C. Yield was 0.79g, 94%. 1H NMR (C7D8, δ): 6.22 (s, 5H), 1.17 (s, 27H).
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[N:5]=[N:6][C:7]=1[N:8]([CH3:10])[NH2:9].[CH:20](N(C(C)C)CC)(C)C.Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCOCC1>[CH3:10][N:8]([C:7]1[N:6]=[N:5][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[C:3]([CH3:20])[CH:2]=1)[NH:9][C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(-c2cccc([N+](=O)[O-])c2)nnc1N(C)N
Solvent: C1COCCO1
Product: CCOC(=O)NN(C)c1cc(C)c(-c2cccc([N+](=O)[O-])c2)nn1

Procedure:
A mixture of 1.6 g. of 5-methyl-3-(m-nitrophenyl)-6-(1-methylhydrazino)pyridazine, 1.03 g. of diisopropylethylamine and 40 ml. of dioxane in a 100 ml. round bottom flask is warmed slightly until solution takes place. A 0.75 g. portion of ethyl chloroformate is pipetted into the solution for one hour and then the dioxane is removed on a rotating evaporator. The product is obtained after recrystallization from acetone-petroleum ether, m.p. 142°-144° C.
Reaction SMILES: [CH:1](=[C:3]1[CH2:8][C:7]2[CH2:9][CH:4]1[CH2:5][CH:6]=2)[CH3:2].[CH2:10]=[CH:11][CH3:12].C=C.B(C1C(F)=C(F)C(F)=C(F)C=1F)(C1C(F)=C(F)C(F)=C(F)C=1F)C1C(F)=C(F)C(F)=C(F)C=1F>C1(C)C=CC=CC=1>[CH2:1]=[CH2:2].[CH2:10]=[CH:11][CH3:12].[CH:1](=[C:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2)[CH3:2]
Reactant: CC=C1CC2=CCC1C2
Agent: C=C
Agent: Fc1c(F)c(F)c(B(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Solvent: Cc1ccccc1
Solvent: C=CC
Product: CC=C1CC2C=CC1C2
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A 2 L batch reactor is charged with 500 mL of mixed alkanes, 75 mL of 5-ethylidene-1-norbornene, and 500 mL of liquefied propylene. The reactor is heated to 60° C., and is saturated with ethylene at 500 psig (3.4 MPa). In an inert atmosphere drybox, 10 μmol of a 0.005M solution in toluene of rac-[1,2-ethanediylbis(1-(2-methyl-4-phenyl)indenyl)]zirconium (trans,trans-1,4-diphenyl-1,3-butadiene) and 10 μmol of a 0.005 m solution of B(C6F5)3 in toluene are combined and the mixture is transferred to the reactor to initiate polymerization. After 15 minutes, the reactor is vented and the solution is drained from the reactor. The polymer solution is combined with 100 mg of antioxidant and the volatiles are removed under reduced pressure in order to isolate the rubbery terpolymer of ethylene/propylene/ethylidene norbornene.