Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH:20]4[O:22][CH2:21]4)=[CH:15][CH:16]=3)[C:11](=[O:23])[C:10](C)(C)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:26][NH:27][CH3:28].C(O)C>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH:20]([OH:22])[CH2:21][N:27]([CH3:28])[CH3:26])=[CH:15][CH:16]=3)[C:11](=[O:23])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(c2ccc(Cl)cc2)c2ccc(OCC3CO3)cc2C1=O
Reactant: CNC
Solvent: CCO
Product: CN(C)CC(O)COc1ccc2c(c1)C(=O)CCC2c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of 4-(4-chlorophenyl)-7-(2,3-epoxypropoxy)-2,2-dimethyl-1-tetralone (4.0 g) in ethanol (40 ml) was added to 40% ethanol dimethylamine solution (20 ml), and the mixture left to stand overnight. The solvent was removed and the residue shaken with ether-dilute hydrochloric acid. The aqueous layer was separated, basified, extracted with ether, and the extract dried (MgSO4). Evaporation gave 4-(4-chlorophenyl)-7-(2-hydroxy-3-dimethylaminopropoxy)-1-tetralone (3.2 g, 71%) as a gummy solid.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]1([C:18]2[CH:27]=[CH:26][C:21]3[NH:22][C:23](=[O:25])[O:24][C:20]=3[CH:19]=2)[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1>C1COCC1>[C:1]1([C:7]#[C:8][CH2:9][NH:10][C@H:14]2[CH2:15][CH2:16][C@H:11]([C:18]3[CH:27]=[CH:26][C:21]4[NH:22][C:23](=[O:25])[O:24][C:20]=4[CH:19]=3)[CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCC#Cc1ccccc1
Reactant: O=C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc([C@H]3CC[C@H](NCC#Cc4ccccc4)CC3)cc2o1

Procedure:
Condensation of 3-phenyl-prop-2-ynylamine (1.0 g, 7.6 mmol) and ketone 5 (1.7 g, 7.6 mmol), following the procedure described in Example 1, except THF was used as solvent gave compound 6-{trans-[4-(3-phenyl-prop-2-ynylamino)cyclohexyl]}-3H-benzoxazol-2-one (400 mg, 58%) as a white solid: 1H NMR (500 MHz, DMSO-d6): δ 7.45-7.35 (m, 5H), 7.19 (s, 1H), 7.50-6.94 (m, 2H), 3.59 (s, 2H), 3.30 (m, 2H), 2.75-2.61 (m, 1H), 2.06-2.00 (m, 2H), 1.85-1.80 (m, 2H), 1.58-1.41 (m, 2H), 1.25-1.10 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[NH:5][N:4]=1.Cl[C:13]([O:15][CH3:16])=[O:14]>O1CCOCC1>[C:8]([C:6]1[NH:5][N:4]=[C:3]([N:2]([CH3:1])[C:13](=[O:14])[O:15][CH3:16])[CH:7]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CNc1cc(C(C)(C)C)[nH]n1
Reactant: COC(=O)Cl
Solvent: C1COCCO1
Product: COC(=O)N(C)c1cc(C(C)(C)C)[nH]n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.7 %

Procedure:
15.5 g of 3-(N-methylamino)-5-t-butylpyrazole as prepared in Reference Example was dissolved in 50 ml of dioxane, and 11.3 g of methyl chloroformate was added to the solution. The mixture was then allowed to react at 100° C. for 5 hours. After the reaction was completed, the solvent was distilled off and the residue was dissolved in an alcohol. The solution was added in 200 ml of a 5% aqueous solution of sodium hydroxide and the mixture was stirred at room temperature for 30 minutes. After neutralization, the mixture was extracted with methylene chloride, and the methylene chloride layer was dried over anhydrous sodium sulfate, followed by distilling off the methylene chloride. The residue was recrystallized from a mixture of toluene and hexane, whereby 4 g of methyl N-(5-t-butyl-3-pyrazolyl)-N-methylcarbamate was obtained.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][O:6][CH2:7][CH2:8]Cl.[Cl:10][C:11]1[CH:12]=[C:13]([CH2:18][C:19]#[N:20])[CH:14]=[CH:15][C:16]=1[F:17]>CN1C(=O)CCC1.CCOCC>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2([C:19]#[N:20])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]2)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: N#CCc1ccc(F)c(Cl)c1
Reactant: ClCCOCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: N#CC1(c2ccc(F)c(Cl)c2)CCOCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
NaH (60% in mineral oil, 14.3 g, 357 mmol) was suspended in NMP (143 mL) and cooled to 0° C. A solution of 1-chloro-2-(2-chloroethoxy)ethane (20.4 g, 143 mmol) and 3-chloro-4-fluorophenylacetonitrile (24.23 g, 143 mmol) in ether was then added dropwise via addition funnel. The resulting reaction mixture was stirred at 0° C. for 3 hours and then quenched with water, acidified with 5N HCl, diluted with 400 mL of diethyl ether, added to a separatory funnel, partitioned with water, washed 3 times with 100 mL of water, separated, dried over Na2SO4, and concentrated in vacuo to give the title (16.99 g) after flash chromatography. MS m/e=240 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@H:14]([C:15]#[C:16][S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:13][C:12]1=[O:24])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].FC(F)(F)C(O)=[O:28].C(=O)(O)[O-].[Na+].[Cl-].[Na+]>C(Cl)Cl.C(OCC)(=O)C.O>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([S:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:28])[NH:13][C:12]1=[O:24])[CH3:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@H]1C#CSc1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)Sc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
To a solution of 3.28 g of (3S, 4R)-3-[(R)-1-t-butyldimethylsilyloxyethyl]-4-[(phenylthio)ethynyl]-2-azetidinone in 75.0 ml of anhydrous methylene chloride were added, under an atmosphere of nitrogen gas, 3.5 ml of trifluoroacetic acid, with stirring and ice-cooling. The mixture was then stirred for 30 minutes under ice-cooling and for a further 1.5 hours at room temperature. The reaction mixture was then poured into a mixture of 1.14 g of sodium bicarbonate, 75 ml of water and 300 ml of ethyl acetate. The mixture was saturated with sodium chloride and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate. The organic layer and the ethyl acetate extracts were combined, and the combined solution was washed successively with an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulphate. The solvent was distilled off under reduced pressure and the residue was subjected to column chromatography through silica gel, eluted with a 3:1 by volume mixture of cyclohexane and ethyl acetate, to give 3.09 g (yield 89.9%) of the title thioester compound, melting at 94°-95° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([CH:17]=[O:18])=[CH:7]1.CC(N=NC(C#N)(C)C)(C#N)C.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:16][O:15][C:11]1[CH:12]=[CH:13][C:14]2[N:6]3[C:7]([CH2:2][CH2:3][CH2:4][CH2:5]3)=[C:8]([CH:17]=[O:18])[C:9]=2[N:10]=1
Reactant: COc1ccc2c(n1)c(C=O)cn2CCCCBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc2c(n1)c(C=O)c1n2CCCC1
Reaction time: 0.33 h

Procedure:
Under argon, a solution containing 2.70 g (8.67 mmol) of the compound obtained in Step B and 1.45 g (8.67 mmol) of AIBN in 80 ml of toluene is brought to reflux. After stirring for 20 minutes, 4.67 ml (17.35 mmol) of tributyltin hydride in 100 ml of toluene are added to the reaction mixture, which is maintained at reflux for 24 hours. After returning to room temperature and evaporation to dryness, the residue is then hydrolysed and subsequently extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, concentrated and purified by flash chromatography over silica gel. (eluant: petroleum ether/ethyl acetate, 95:5) to yield the title product in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:25])=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:10]3[CH2:9][C:8](=O)[NH:7][C:6]=2[CH:24]=1.B.CO>O1CCCC1>[Cl:1][C:2]1[C:3]([Cl:25])=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:15][CH:10]3[CH2:9][CH2:8][NH:7][C:6]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN2c3cc(Cl)c(Cl)cc3NC(=O)CC2C1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN2c3cc(Cl)c(Cl)cc3NCCC2C1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of Example 15B (168 mg, 0.435 mmol) in tetrahydrofuran (1.5 mL) was added borane in tetrahydrofuran (1.74 mL, 1 M solution). The resulting mixture was heated to 80° C. overnight. Methanol was then added, and the mixture was heated at 80° C. for 1 hour to destroy excess borane. The reaction was then cooled to room temperature and 1 M HCl was added. The mixture was allowed to stir for another 30 minutes. Aqueous sodium bicarbonate was slowly added to the mixture until the solution was basic (pH=8). Ethyl acetate was then added, and the water layer was separated and washed two times with additional ethyl acetate. The organic layers thus obtained were combined and concentrated. The crude material was purified by silica gel chromatography eluting with a gradient of 0% to 30% ethyl acetate in hexane to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 6.88 (s, 1H), 6.70 (s, 1H), 5.75 (d, J=5.55 Hz, 1H), 3.61-3.79 (m, 1H), 3.36-3.58 (m, 2H), 2.95-3.23 (m, 5H), 2.82-2.94 (m, 1H), 1.80-1.97 (m, 1H), 1.56-1.74 (m, 1H), 1.41 (s, 9H); MS (DCI+) m/z 372.2 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[CH:11]([NH:13][C:14](=[O:29])[C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=2)([CH3:17])[CH3:16])[CH3:12])[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:49][CH2:50][F:51])(=O)=O>CN(C)C=O.CCOCC>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:49][CH2:50][F:51])=[CH:33][CH:32]=2)[CH:11]([NH:13][C:14](=[O:29])[C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=2)([CH3:17])[CH3:16])[CH3:12])[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2]
Reactant: CC(NC(=O)C(C)(C)Oc1ccc(C(F)(F)F)cn1)C(Cc1ccc(O)cc1)c1cc(F)cc(C#N)c1
Reactant: CS(=O)(=O)OCCF
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(NC(=O)C(C)(C)Oc1ccc(C(F)(F)F)cn1)C(Cc1ccc(OCCF)cc1)c1cc(F)cc(C#N)c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-[2-(3-cyano-5-fluorophenyl)-3-(4-hydroxyphenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide from Example 7, Step B (15 mg, 0.039 mmol) in 2 mL of dimethylformamide was added cesium carbonate (15 mg, 0.046 mmol) and 2-fluoroethyl methanesulfonate (20 uL, 0.16 mmol), and the reaction was stirred at 70° C. for 0.5 h. The resulting mixture was diluted with ether (20 mL), washed with water and brine and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 10 to 40% ethyl acetate in hexane to give N-{2-(3-cyano-5-fluorophenyl)-3-[4-(2-fluoroethoxy)phenyl]-1-methylpropyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide. 1H NMR (500 MHz, CD3OD): PL 87 δ 8.27 (br s, 1H), 7.94 (dd, 1H), 7.48 (d, 1H), 7.73-7.32 (m, 3H), 7.04 (s, 1H), 6.64 (s, 4H) 4.68 (m, 1H), 4.59 (m, 1H), 4.25 (m, 1H), 4.11 (m, 1H), 4.04 (m, 1H), 3.02 (dd, 1H), 2.84 (m, 1H), 2.57 (dd, 1H), 1.75 (s, 3H), 1.73 (s, 3H), 0.80 (d, 3H). LC-MS: m/e 544 (M+H)+ (3.8 min).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O=[C:8]1[CH2:19][S:18][CH2:17][C:16](=O)[NH:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][NH:9]1>O1CCCC1>[O:12]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:19][S:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: O=C1CSCC(=O)NCCOCCN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C1COCCNCCSCCN1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
To a suspension of lithium aluminum hydride (3.12 g, 82.2 mmol) in refluxing tetrahydrofuran under argon was added diamide 6 (3.50 g, 16.0 mmol) in small portions over 1 hour period. The mixture was refluxed for 3 days. After cooling to room temperature the excess reagent was destroyed by adding a mixture of water (2.7 ml) and THF (6.2 ml), then 15% aqueous NaOH (3.4 ml) and another mixture of water (5.6 ml) and THF (3.4 ml). The solid was filtered and washed extensively with pure THF. The filtrate and washings were combined, the solvent was removed in vacuo and the residue was chromatographed through a short alumina column with chloroform and the product was recrystallized from a chloroform-hexane mixture to give 1.88 g (62%) of 1-oxa-7-thia-4,10-diazacyclododecane (7) as a white solid mp 74°-76° C. Analysis calculated for C8H18N2OS: C, 50.49; H, 9.53. Found: C, 50.18; H, 9.72%.
Reaction SMILES: [C:1]1(=[O:21])[N:5]([CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7](O)=[O:8])[C:4](=[O:16])[C:3]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:2]12.C(N1C=CN=C1)([N:24]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1.CN(C)C1C=CN=CC=1.O>[C:1]1(=[O:21])[N:5]([CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([NH2:24])=[O:8])[C:4](=[O:16])[C:3]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:2]12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)C(c1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: CN(C)c1ccncc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)C(c1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
To a stirred mixture of α-phthalimidophenylacetic acid (2.50 g, 8.89 mmoL) in tetrahydrofuran (50 mL) is added carbonyldiimidazole (1.50 g, 9.25 mmoL) and a few crystals of 4-dimethylaminopyridine. The reaction is then heated to 50° C. for 45 minutes. After the reaction mixture cools to room temperature, 1 mL of concentrated ammonium hydroxide is added via syringe. The reaction is stirred for 1 hour, then diluted with 50 mL of water and partially concentrated to remove the majority of the tetrahydrofuran. The resulting slurry is filtered and the solid washed with copious amounts of water. The solid is dried in vacuo (60° C., <1 mm) to afford 1.9 g (76%) of α-phthalimidophenylacetamide, which may be alternatively named as N-phthaloylphenylglycinamide, as an off-white powder: mp 218°-220° C.; 1H NMR (DMSO-d6) δ9.00-7.75 (m, 4H, Ar), 7.61 (br s, 1H, CONH2), 7.55-7.20 (m, 6H, Ar, CONH2), 5.82 (s, 1H, CHCO2); 13C NMR (DMSO-d6) δ168.2, 167.1, 135.6, 134.5, 131.4, 129.4, 127.9, 127.7, 123.1, 56.3. Anal (C16H12N2O3), C, H, N.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([C:14]2[C:19]([O:20]C)=[CH:18][CH:17]=[CH:16][C:15]=2[O:22][CH3:23])=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.NN.[OH-].[K+]>C(O)COCCO>[NH2:1][C:2]1[C:11]([CH2:12][C:14]2[C:15]([O:22][CH3:23])=[CH:16][CH:17]=[CH:18][C:19]=2[OH:20])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1cccc(OC)c1C(=O)c1cc2ccccc2nc1N
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: COc1cccc(O)c1Cc1cc2ccccc2nc1N
Temperature: 160 °C

Procedure:
(2-Aminoquinolin-3-yl)(2,6-dimethoxyphenyl)methanone (0.19 g, 0.6 mmol) was dissolved in diethylene glycol (10 mL), mixed with hydrazine hydrate (0.19 mL, 6.1 mmol) and pulverized potassium hydroxide (0.27 g, 6.7 mmol) and heated for 2 hours at 160° C. The same amounts of hydrazine hydrate and potassium hydroxide were added two more times and the reaction mixture was stirred for two more hours each time at 160° C.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:15]=[C:14]([O:16]C)[C:13]([Cl:18])=[C:12]2[C:7]=1[CH2:8][CH2:9][N:10](C(OC(C)(C)C)=O)[C:11]2=[O:19].O>ClCCl>[Cl:5][C:6]1[CH:15]=[C:14]([OH:16])[C:13]([Cl:18])=[C:12]2[C:7]=1[CH2:8][CH2:9][NH:10][C:11]2=[O:19]
Reactant: COc1cc(Cl)c2c(c1Cl)C(=O)N(C(=O)OC(C)(C)C)CC2
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C1NCCc2c(Cl)cc(O)c(Cl)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
Boron tribromide (10 mL) was added to a cooled (0° C.) solution of tert-butyl 5,8-dichloro-7-methoxy-1-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate (296f, 14.5 g, 45.4 mmol) in dry dichloromethane (100 mL). The mixture was stirred at room temperature overnight, then water (10 mL) was added, causing a precipitate to form. The precipitate was collected by filtration, washed with water (500 mL), and dried to give 5,8-dichloro-7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (296g, 9.2 g, 95% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.58 (s, 1H), 8.17 (s, 1H), 7.13 (s, 1H), 3.25-3.23 (m, 2H), 2.83-2.80 (t, J=6.2 Hz, 2H). MS: 232 [M+1].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:6]=[CH:7][CH2:8]Cl.[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23][C:24]=2[N:25]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][N:21]([CH2:8][CH:7]=[CH:6][C:5]3[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:22][CH2:23][C:24]=2[N:25]=1
Reactant: COc1ccc(C=CCCl)cc1OC
Reactant: Nc1nc2c(s1)CCNCC2
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COc1ccc(C=CCN2CCc3nc(N)sc3CC2)cc1OC
Yield: 7.7 %

Procedure:
Prepared from 3,4-dimethoxy-cinnamyl chloride (prepared at -5° C. for 10 minutes) and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 7.7% of theory, Melting point: 122°-126° C. (ether).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([O:7][CH:8]([F:10])[F:9])[N:4]([CH3:11])[N:3]=1.[N:12]([O-])=O.[Na+].[Sn](Cl)Cl.[OH-].[Na+]>O.Cl.C(OCC)(=O)C>[F:9][CH:8]([F:10])[O:7][C:5]1[N:4]([CH3:11])[N:3]=[C:2]([NH:1][NH2:12])[CH:6]=1
Reactant: Cn1nc(N)cc1OC(F)F
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1nc(NN)cc1OC(F)F
Temperature: -10 °C
Reaction time: 1 h

Procedure:
39.8 g (0.25 mol) 3-Amino-5-difluoromethoxy-1-methyl-pyrazole was dissolved in 224 ml water and 450 ml concentrated hydrochloric acid. At -10° C., 18.55 g (0.27 mol) sodium nitrite in 80 ml water was added dropwise. After stirring for 1 hour at -10° C., 137.6 g tin(II)chloride, dissolved in 180 ml concentrated hydrochloric acid, was added, dropwise, at this temperature. After a further hour stirring at -10° C., 805 ml 32% caustic soda was added dropwise at this temperature. The reaction mixture was shaken 8 times with ethyl acetate, the combined organic phases washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated.
Reaction SMILES: Cl.[F:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH2:21][CH:20]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[O:19][N:18]=3)[N:14]=[C:13]([CH3:28])[N:12]=2)=[O:10])=[CH:5][C:4]=1[O:31][CH3:32].[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>C(Cl)Cl>[CH3:33][N:34]([CH3:38])[C:35]([N:25]1[CH2:24][CH2:23][CH:22]([CH:20]2[O:19][N:18]=[C:17]([C:15]3[N:14]=[C:13]([CH3:28])[N:12]=[C:11]([C:9]([NH:8][CH2:7][C:6]4[CH:29]=[CH:30][C:3]([F:2])=[C:4]([O:31][CH3:32])[CH:5]=4)=[O:10])[CH:16]=3)[CH2:21]2)[CH2:27][CH2:26]1)=[O:36]
Reactant: CN(C)C(=O)Cl
Reactant: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCNCC4)C3)nc(C)n2)ccc1F
Agent: Cl
Solvent: ClCCl
Product: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCN(C(=O)N(C)C)CC4)C3)nc(C)n2)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold solution of N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide hydrochloride (0.12 g, 0.25 mmol, Preparation #K.1) and TEA (0.091 g, 0.9 mmol, Sd Fine Chem) in DCM (15 mL) was added dimethyl carbamoyl chloride (0.033 g, 0.31 mmol, Aldrich). The reaction mixture was slowly warmed to RT and stirred for about 1 h. The reaction mixture was diluted with DCM (20 mL) and washed with water (2×15 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The crude material obtained was purified using silica gel column chromatography eluted with 2-3% methanol in DCM. Relevant fractions containing the required compound were combined and evaporated to dryness under reduced pressure to afford 6-(5-(1-(dimethylcarbamoyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide as an off white solid 0.064 g (50%): LC/MS (Table 1, Method c) Rt=1.83 min; MS m/z: 499.3 (M+H)+.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][C:6]([F:9])([F:8])[F:7].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1>C1COCC1>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]([OH:16])[CH2:3][CH2:4][CH2:5][C:6]([F:9])([F:8])[F:7])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: FC(F)(F)CCCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: OC(CCCC(F)(F)F)c1ccc(Br)cc1
Temperature: 24 °C
Reaction time: 18 h
Yield: 82.2 %

Procedure:
Magnesium (0.636 g, 26.2 mmol) was added to a solution of 4-bromo-1,1,1-trifluorobutane (5 g, 26.2 mmol) in THF (100 mL) and under nitrogen. The solution was stirred for 18 h at 24° C., and the Grignard reagent was transferred via cannula to a solution of 4-bromobenzaldehyde (4.85 g, 26.2 mmol) in THF (50 mL) at −78° C. under nitrogen. The cold bath was removed and the reaction allowed to warm and stirred 18 h, diluted with Et2O (1 vol), quenched with sat'd NH4Cl soln, and washed with brine. Concentrate, take up in CH2Cl2 and charged to a 40M Biotage® silica gel cartridge. Gradient elution was performed from 15% to 100% B over 1 L (A/B Hexanes/EtOAc) to give 1-(4-bromophenyl)-5,5,5-trifluoropentan-1-ol 6.4 g (82%).
Reaction SMILES: [OH:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]=1[C:17]([NH:19][CH2:20][C:21]([O:23]CC)=[O:22])=[O:18].[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)C=O>[OH:1][C:2]1[N:7]([CH2:32][C:31]2[CH:34]=[CH:35][C:28]([C:27]([F:37])([F:36])[F:26])=[CH:29][CH:30]=2)[C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]=1[C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)CNC(=O)c1c(O)[nH]c(=O)n(Cc2ccccc2)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CNC(=O)c1c(O)n(Cc2ccc(C(F)(F)F)cc2)c(=O)n(Cc2ccccc2)c1=O
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 30.5 %

Procedure:
A mixture of ethyl N-{[6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycinate (example 11a, 356 mg, 1.03 mmoles), 4-trifluoromethylbenzyl bromide (175 uL, 1.13 mmoles) and sodium carbonate (330 mg, 3.1 mmoles) in dimethylformamide (6.0 mL) was stirred under argon at 100° C. for 2.5 hours. The mixture was cooled, poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The ester was hydrolysed by stirring in a mixture of ethanol (3 mL) and 1 molar sodium hydroxide solution (3 mL) for 3 hours. The mixture was acidified and extracted with ethyl acetate. Purification by preparative HPLC (acetonitrile-water-0.1% TFA, 20-100%) and crystallization from ethanol-water gave the title compound (150 mg, 30%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.12 (s, 1 H), 10.12 (t, J=5.56 Hz, 1 H), 7.69 (d, J=8.08 Hz, 2 H), 7.53 (d, J=8.08 Hz, 2 H), 7.24-7.35 (m, 5 H), 5.11 (s, 2 H), 5.03 (s, 2 H), 4.14 (d, J=5.81 Hz, 2 H).