Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].N1C=CC=CC=1.OC1[C:19]2([CH2:21][CH2:20]2)[CH2:18][N:17]([C@@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])C1>C(OCC)(=O)C>[C:5]([O:4][CH:1]1[C:19]2([CH2:20][CH2:21]2)[CH2:18][N:17]([C@@H:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH3:23])[CH2:2]1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](c1ccccc1)N1CC(O)C2(CC2)C1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1CN([C@H](C)c2ccccc2)CC12CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 1.5 g of compound 12 and 500 mg of lithium aluminum hydride in 30 ml of tetrahydrofuran was refluxed for 16 hours. 0.5 ml of water, 0.5 ml of 15% aqueous sodium hydroxide and 1.5 ml of water were added to the mixture in the mentioned order, and the mixture was stirred at room temperature for 30 minutes. The insoluble material was removed by filtration and the filtrate was concentrated to dryness to yield 1.4 g of 7-hydroxy-5-[1-(R)-phenylethyl]-5-azaspiro[2,4]heptane as a pale yellow oil. 5 ml of acetic anhydride and 5 ml of pyridine were added to 1.4 g of 7-hydroxy-5-[1-(R)-phenylethyl]-5-azaspiro[2,4]heptane which was cooled on an ice-bath. The mixture was stirred at room temperature for 3 hours. Ethyl acetate was added thereto and the solution was washed with saturated aqueous sodium bicarbonate and water, then, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to yield 1.6 g of 7-acetoxy-5-[1-(R)-phenylethyl]-5-azaspiro[2,4]heptane as a yellow oil. A mixture of 1.6 g of 7-acetoxy-5-[1-(R)-phenylethyl]-5-azaspiro[2,4]heptane and 1.2 g of palladium-on-carbon (50% water wet) in 20 ml of ethanol was shaken under 3.8 atm of pressured hydrogen atmosphere for 5 hours. During the reduction reaction, the reaction vessel was warmed by a tungsten lamp. The catalyst was removed by filtration and the solvent was removed under reduced pressure to give 880 mg of title compound 69 as an oil.
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][CH2:8][C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][C@H:9]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:8][CH2:7][C:6]([OH:17])=[O:5]
Reactant: CC(C)CCC[C@@H](C)CCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CCC[C@@H](C)CCC(=O)O
Reaction time: 8 h

Procedure:
(4R)-4,8-dimethyl nonanoic acid t-butyl ester in 25 mL CH2Cl2 at 0° C. was treated with TFA (6 mL). The mixture was allowed to reach ambient temperature and stir overnight. The solvent was removed by rotary evaporation, and the mixture was purified by silica gel chromatography (95/5 hexane/EtOAc) to give 0.962 g (4R)-4,8-dimethyl nonanoic acid. m/z 185 (M−).
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([CH3:28])=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].O>CN(C)C=O>[CH3:20]/[C:21](/[CH2:28][O:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH:2]([CH3:1])[CH2:3][CH3:4])=[CH:11][CH:10]=1)=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCC(C)Oc1ccc(O)cc1
Reactant: CCOC(=O)C=C(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C(/C)COc1ccc(OC(C)CC)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 4-(1-methylpropoxy)phenol (0.84 g, 5.06 mmol) and potassium carbonate (0.66 g, 0.48 mmol) in 10 ml of dimethylformamide (DMF) at 5° is added ethyl 4-bromo-3-methyl-2-butenoate (1.0 g, 0.48 mmol). The mixture is allowed to warm to RT and is stirred at RT for 20 hours. The reaction mixture is poured into water and extracted with ether. The organic layer is washed with 10% sodium hydroxide to remove any starting phenol, dried and the solvent removed. The product is purified by preparative thin layer chromatography (prep. TLC). The second main band is collected to give ethyl (Z)-3-methyl-4-[4-(1-methylpropoxy)phenoxyl]-2-butenoate, MS m/e 292 (M+).
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:14])([F:13])[F:15])=[CH:8][N:7]=1.[Cl:3][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: Oc1ccc(C(F)(F)F)cn1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc(Cl)nc1
Temperature: 60 °C

Procedure:
30 g of thionyl chloride was added to 12 g of 2-hydroxy-5-trifluoromethylpyridine dissolved in 20 g of dimethylformamide. The 2-hydroxy-5-trifluoromethylpyridine was prepared as disclosed in Examples 4 and 5 of applicant's copending application earlier referred to and incorporated herein by reference. The solution was then heated to 60° C. for 24 hours, cooled to 20° C. and diluted with 200 cc of water and the pH adjusted to 5.5 with sodium carbonate. The acid solution was extracted three times with 100 cc of chloroform each time and the extracts washed three times with 20 cc of water each time. The chloroform solution was evaporated at reduced pressure to give 2-chloro-5-trifluoromethylpyridine.
Reaction SMILES: Cl.C([O:4][C:5](=[O:26])[CH2:6][CH2:7][N:8]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2=[CH:18][C:19]([C:21]([O:23]CC)=[O:22])=[CH:20][N:10]2[CH2:9]1)C.[OH-].[K+]>CO.O>[C:21]([C:19]1[CH:18]=[C:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[N:8]([CH2:7][CH2:6][C:5]([OH:26])=[O:4])[CH2:9][N:10]2[CH:20]=1)([OH:23])=[O:22]
Reactant: CCOC(=O)CCN1Cn2cc(C(=O)OCC)cc2-c2ccccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCN1Cn2cc(C(=O)O)cc2-c2ccccc21

Procedure:
A solution of the product of Example VI (2.75 g, 0.008 m) and KOH (4.0 g, 0.072 m) in MeOH (40 ml) and H2O (40 ml) was refluxed for 4 hr. The methanol was removed under vacuum and the resulting aqueous solution was acidified with HCl (10% aqueous). When the solution became acidic, a greenish solid formed. It was filtered and washed with H2O and dried, to yield 2.2 g of crude product. Crystallization from MeOH afforded the desired product; m.p. 234°-236°.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[CH2:10][CH2:11][C@H:12]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:13](=[O:24])[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:35][OH:36].CCN(C(C)C)C(C)C>C(O)C>[CH2:1]([O:8][C:9](=[O:33])[CH2:10][CH2:11][C@H:12]([NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[C:13](=[O:24])[NH:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22](=[NH:23])[NH:35][OH:36])=[CH:20][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)NCc1ccc(C#N)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)NCc1ccc(C(=N)NO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 152.7 %

Procedure:
A solution of compound Q (9.65 g, 20.0 mmol), hydroxylamine hydrochloride (2.10 g, 30.0 mmol) and DIEA (5.22 ml, 30.0 mmol) in ethanol (abs., 150 ml) was refluxed for 6 h. The reaction mixture was allowed to cool to room temperature and stirred for additional 16 h, then the solvents were evaporated in vacuo. The resultant residue was dried in vacuo to provide compound R (14.8 g, yield exceeded quantitative) as yellowish oil. LC-MS [M+H] 485.5 (C25H32N4O6+H, calc: 485.8). Compound R was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N+:4]([O-])[C:5]2[CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1.O=P(Cl)(Cl)[Cl:14].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([Cl:14])[CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: [O-][n+]1cc(Br)cc2c1CCC2
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ClC1CCc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-bromo-6,7-dihydro-5H-[1]pyrindine N-Oxide (250 mg, 1.17 mM) in 3 mL of CH2Cl2 at room temperature was added POCl3 (0.131 mL, 1.4 mM) and triethylamine (0.202 mL, 1.4 mM). The reaction was stirred at room temperature for 2 hours then was extracted from saturated NaHCO3 solution into ethyl acetate, washed with saturated NaCl, dried over MgSO4, filtered, and concentrated to dryness. The product was used crude in the next step. 1H NMR (CDCl3): d 8.60 (s, 1 H), 7.80 (s, 1 H), 5.40 (d, 1 H), 3.00 (m, 2 H), 2.20 (m, 2 H)
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[C:5]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[S:8][C:6]=2[N:7]=1.S(=O)(=O)(O)O.O.[CH2:29](O)[CH3:30]>>[CH2:29]([O:12][C:11]([C:9]1[S:8][C:6]2[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][CH:15]=3)[C:5]=2[CH:10]=1)=[O:13])[CH3:30]
Reactant: Nc1nc(-c2c[nH]c3ccccc23)c2cc(C(=O)O)sc2n1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1cc2c(-c3c[nH]c4ccccc34)nc(N)nc2s1

Procedure:
The crude 2-amino-4-(1H-indol-3-yl)-thieno[2,3-d]pyrimidine-6-carboxylic acid was dissolved in ethanol (2 ml) and conc. sulphuric acid was added (5 drops). The solution was refluxed overnight before water was added and the volatiles were removed in vacuo. The aqueous solution was partitioned with 1M sodium hydrogen carbonate solution and ethyl acetate. The organics were combined, dried over sodium sulphate and evaporated to dryness. The pure compounds was obtained after preparative TLC as an off white coloured powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[F:12].[CH3:13][C:14]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])[CH3:15].CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C1(C)C=CC=CC=1>[C:14]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[F:12])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:13])[CH3:15]
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)cc2F)CC1
Temperature: 80 °C

Procedure:
A mixture of 20 mmol 1-bromo-2-fluoro-4-trifluoromethyl-benzene, 24.7 mmol n-Boc-piperazine, 0.1 mmol Tris(dibenzylideneacetone) dipalladium chloroform complex, 28.8 mmol sodium-t-butoxide and 0.4 mmol 2-(dicyclohexylphosphino)biphenyl in 50 ml toluene was heated for 16 h at 80° C. After cooling to RT the mixture was treated with 15 g Isolute HM—N and all volatiles were removed under vacuum. The residue was purified on silica eluting with a gradient of heptane/EtOAc to yield after evaporation the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][CH2:48][O:49]S(C)(=O)=O)=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:56]O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][CH2:48][O:49][CH3:56])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCOS(C)(=O)=O)CCC3)cc1
Agent: [H-]
Agent: [Na+]
Product: COCCCN1CCCc2ccc(CO[C@H]3CN(C(=O)OC(C)(C)C)CC[C@@H]3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21
Temperature: 50 °C
Reaction time: 6 h
Yield: 65.2 %

Procedure:
To an ice cooled solution of 0.240 g (0.319 mmol) of crude (3R,4R)-3-[1-(3-methanesulfonyloxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester [example 10(a)] in 3 ml of absolute methanol was added 0.0 17 g (0.383, 1.2 equiv.) of sodium hydride (55% suspension in mineral oil). The reaction was then stirred for 6 h at 50° C., allowed to cool to room temperature, poured into 50 ml of an ice/water mixture and extracted three times with 50 ml of ethyl acetate. The combined organic phases were washed twice with 20 ml of water, evaporated under reduced pressure and dried in a high vacuum. The thus obtained crude product was purified by chromatography on silica gel using a 2:1 v/v mixture of hexane and ethyl acetate as eluent to yield 0.143 g (0.208 mmol, 65.2% of theory) of (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-[1-(3-methoxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil; MS: 689 (M+H)+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][N+:4]([O-:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.B(F)(F)[F:11].[F:14][B-:15]([F:18])([F:17])[F:16].[H+].FF>C(#N)C>[F:14][B-:15]([F:18])([F:17])[F:16].[F:14][B-:15]([F:18])([F:17])[F:16].[OH:9][N+:4]12[CH2:7][CH2:8][N+:1]([F:11])([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: FB(F)F
Reactant: [O-][N+]12CCN(CC1)CC2
Agent: FF
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CC#N
Product: O[N+]12CC[N+](F)(CC1)CC2
Yield: 130.5 %

Procedure:
A solution of 1,4-diazabicyclo[2.2.2]octane N-oxide (12.8 g, 0.1 mole), boron trifluoride gas (6.8 g 0.1 mole), and tetrafluoroboric acid (50% solution, 12 g, 0.1 mole) in acetonitrile (200 mL) was cooled to 8° C. and treated with a mixture of fluorine in nitrogen (10% V/V, 0.15 mole). The reaction was evaporated, the remaining solid washed with acetone and dried to afford 21 grams of 1-hydroxyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (65% yield).
Reaction SMILES: [Na].[N+:2]([NH:5][C:6]([NH2:8])=[NH:7])([O-:4])=[O:3].[CH:9]([CH:11]([CH2:17][C:18]1[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][CH2:26][CH3:27])[C:20](=[O:28])[CH:19]=1)[C:12](OCC)=O)=[O:10]>CO.O>[N+:2]([NH:5][C:6]1[NH:8][C:9](=[O:10])[C:11]([CH2:17][C:18]2[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][CH2:26][CH3:27])[C:20](=[O:28])[CH:19]=2)=[CH:12][N:7]=1)([O-:4])=[O:3]
Reactant: N=C(N)N[N+](=O)[O-]
Reactant: CCCCn1ccc(CC(C=O)C(=O)OCC)cc1=O
Agent: [Na]
Solvent: O
Solvent: CO
Product: CCCCn1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cc1=O
Temperature: 0 °C

Procedure:
To a stirred solution of sodium (6.77 g) in methanol (120 ml) was added nitroguanidine (27.25 g. containing 25% water) and methanol (30 ml). The mixture was refluxed for 45 minutes and then was added dropwise ethyl α-formyl-β-(N-n-butyl-2-oxo-4-pyridyl)propionate (54.85 g) in methanol (150 ml) over 90 minutes. The reaction mixture was refluxed for 23 hours and evaporated under reduced pressure to give an oil. This oil was dissolved in water (200 ml) and extracted with chloroform (3×65 ml). The combined chloroform extracts were washed with water (2×35 ml). The combined aqueous layer and aqueous washings were taken to pH 5 with glacial acetic acid whereupon a brown oil came out of solution. This was dissolved with warming in isopropanol (75 ml) and cooled at 0° C. overnight to yield after filtration, washing and drying in vacuo 2-nitroamino-5-(1-n-butyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one as a solid (19.46 g), recrystallisation from aqueous acetic acid gave material with m.p. 198°-201° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][N:3]=[C:2]1[C:7]1[CH:8]=[C:9]([NH2:13])[CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C.[CH3:21][C:22]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:23]=1[O:24][CH2:25][CH2:26][CH2:27][C:28]([CH3:33])([CH3:32])[C:29](Cl)=[O:30]>ClCCl>[O:1]1[CH2:6][CH2:5][CH2:4][N:3]=[C:2]1[C:7]1[CH:8]=[C:9]([NH:13][C:29](=[O:30])[C:28]([CH3:32])([CH3:33])[CH2:27][CH2:26][CH2:25][O:24][C:23]2[CH:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:22]=2[CH3:21])[CH:10]=[CH:11][CH:12]=1
Reactant: Nc1cccc(C2=NCCCO2)c1
Reactant: Cc1ccc(C)c(OCCCC(C)(C)C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C)c(OCCCC(C)(C)C(=O)Nc2cccc(C3=NCCCO3)c2)c1
Temperature: 0 °C

Procedure:
To an ice cold solution of 3-(5,6-dihydro-4H-1,3-oxazin-2-yl)benzenamine, 8.8 g (0.05 mol), (Journal of the American Chemical Society, Vol. 59, pp. 2259-2261, (1937)) and triethylamine, 10 ml, in dichloromethane, 300 ml, is added 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride, 13.4 g (0.05 mol), (U.S. Pat. No. 4,285,951). The mixture is worked up to give 18.8 g of N-[3-(5,6-dihydro-4H-1,3-oxazin-2-yl)phenyl]-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide after recrystallization from diisopropyl ether; mp 114°-115° C.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CS(C)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>[C:4]([CH:3]([C:2](=[O:7])[CH3:1])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:6])[CH3:5]
Reactant: CCOC(=O)CCCCCCBr
Reactant: CC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CC#N
Solvent: CS(C)=O
Product: CCOC(=O)CCCCCCC(C(C)=O)C(C)=O
Temperature: 20 °C
Reaction time: 8 h
Yield: 458.4 %

Procedure:
A mixture of pentane-2,4-dione (5.0 g), ethyl 7-bromoheptanoate (11.1 g), potassium carbonate (13.8 g), and cesium carbonate (1.63 g) in a mixture of acetonitrile (150 ml) and dimethylsulfoxide (30 ml) was stirred at 20° C. overnight, then pentane-2,4-dione (5 g) was added. After stirring at 20° C. overnight, the mixture was partitioned between ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give ethyl 8-acetyl-9-oxodecanoate (55 g) as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:13][CH:14]=2)[N:3]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:8][C:6]1[CH:7]=[C:2]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:13][CH:14]=2)[N:5]=1
Reactant: C1COCCN1
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2nc(Cl)cc(Cl)n2)cn1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(C)(C)C(=O)Nc1ccc(-c2nc(Cl)cc(N3CCOCC3)n2)cn1

Procedure:
N-(5-(4,6-dichloropyrimidin-2-yl)pyridine-2-yl)pivalamide (975 mg, 3.0 mmol), morpholine (0.262 mL, 3.0 mmol) and triethylamine (502 mL, 3.6 mmol) are stirred in NMP (10 mL) for 2 hours at 85° C. At this time the reaction mixture is partitioned between EtOAc (200 mL) and NaHCO3(sat.) (50 mL). The organic layer is separated, washed with water (30 mL), then brine (30 mL), dried over Na2SO4, filtered, concentrated, obtaining the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH:21]C(=O)OC(C)(C)C)[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.C(Cl)Cl.Cl.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:17]4([NH2:21])[CH2:18][CH2:19][CH2:20]4)=[CH:15][CH:16]=3)[N:10]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(Cl)nn4c3-c3ccccc3)cc2)CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: NC1(c2ccc(-c3nc4ccc(Cl)nn4c3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 68 %

Procedure:
To a solution of tert-butyl {1-[4-(6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-6.2 (0.075 g, 0.15 mmol) in MeOH (0.65 mL) and DCM (1.0 mL) was added hydrogen chloride (4 M in dioxane, 0.8 mL, 3.2 mmol, 20.0 eq), and the resulting mixture was stirred at room temperature for 19 h. The resulting mixture was added to ice water (50 mL), made alkaline with aqueous sodium hydroxide (2 N), and extracted with EtOAc (2×50 mL). The combined organic phases were dried (Na2SO4 anh.) and concentrated under reduced pressure. The resulting material was recrystallized using diisopropyl ether to give 1-[4-(6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine (0.040 g, 68%):
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:24])=[N:5]1)([CH3:3])[CH3:2].[CH2:25]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([CH:41](O)[CH2:42][CH3:43])[CH2:37][CH2:36]1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCOCC1.CCOC(C)=O>[CH2:25]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([CH:41]([O:23][C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:11]([CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[CH:10]=[C:9]([C:8]2[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]([CH3:24])[N:7]=2)[N:18]=4)[CH2:42][CH3:43])[CH2:37][CH2:36]1)=[O:34])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCC(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(O)cc2OCC3)n(C(C)C)n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.1 %

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol (300 mg, 0.92 mmol), 4-(1-hydroxypropyl)piperidine-1-carboxylic acid benzyl ester (308 mg, 1.11 mmol) and triphenylphosphine (411 mg, 1.38 mmol) in dioxane (5 mL) was added dropwise DEAD (217 ul, 1.38 mmol) and the reaction mixture was stirred at RT for 4 h. The mixture was then diluted with EtOAc and washed with NaOH aq. (1N). The organic phase was washed with brine, then dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in EtOAc) affording 4-{1-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]propyl}piperidine-1-carboxylic acid benzylester (280 mg, 51%). 1H NMR (CDCl3, 400 MHz): δ 8.40 (1H, d, J=8.97 Hz), 7.59 (1H, s), 7.37-7.28 (5H, m), 6.73 (1H, dd, J=8.99, 2.56 Hz), 6.54 (1H, d, J=2.52 Hz), 5.98-5.87 (1H, m), 5.14 (2H, s), 4.51-4.45 (2H, m), 4.44-4.37 (2H, m), 4.34-4.19 (2H, bs), 4.09-4.03 (1H, m), 2.83-2.68 (2H, m), 2.43 (3H, s), 1.88-1.78 (1H, m), 1.75-1.61 (5H, m), 1.58 (6H, d, J=6.65 Hz), 1.38-1.30 (1H, m), 0.97 (3H, t, J=7.37 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[C:15]([O:21][C@H:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](Cl)=[O:24])(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].CN(C)C1C=CC=CC=1.Cl>ClCCl>[C:15]([O:21][C@H:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=[O:14])[C:10]([F:13])([F:11])[F:12])=[O:24])(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: Nc1ccc(Cl)cc1C(=O)C(F)(F)F
Reactant: CC(C)(C)C(=O)O[C@@H](C(=O)Cl)c1ccccc1
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)O[C@@H](C(=O)Nc1ccc(Cl)cc1C(=O)C(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone (2, 5.0 g, 22.4 mmol) was dissolved in dichloromethane (50 mL) and (R)-2-chloro-2-oxo-1-phenylethyl pivalate (8.54 g, 33.5 mmol) was added. To this mixture N,N-dimethylaniline (2.8 mL, 22.4 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with dichloromethane (50 mL), treated with 1N HCl, washed with brine and the organic layer was separated and evaporated to give (R)-2-(4-chloro-2-(2,2,2-trifluoroacetyl)-phenylamino)-2-oxo-1-phenylethyl pivalate (12) as an brown oil.