Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.[Li]CCCC.O>O1CCCC1.CCCCCC>[N:18]1([C:4]2[CH:5]=[C:6]([S:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)(=[O:10])=[O:9])[CH:7]=[CH:2][N:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(S(=O)(=O)c2ccnc(N3CCCC3)c2)cc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
10.0 g (0.026 Mol) 4-(2-Bromo-6-pyrrolidin-1-yl-pyridine-4-sulfonyl)-phenylamine were dissolved in tetrahydrofuran (200 ml), cooled at -40° C. and 33 ml (0.053 Mol) nBuLi in hexane were added. The reaction mixture was stirred at -15° C. for 1 h. Then water (10 ml) was added, the mixture was extracted with ethylacetate, the organic phase was washed with water and brine and dried over Na2SO4. After chromatography on SiO2 with ethyl acetate hexan 1:1 and drying in a high vacuum, it was obtained 3.6 g (45%) of 4-(2-pyrrolidin-1-yl-pyridine-4-sulfonyl) -phenylamine as light yellow cristals; mp.: 186-187° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[O:19][CH2:18][CH:17]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][O:15]3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[BH4-].[Na+].O>C(O)C>[OH:1][CH:2]1[CH2:3][CH2:4][CH:5]([CH:8]2[CH2:9][CH2:10][CH:11]([CH:14]3[O:15][CH2:16][CH:17]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18][O:19]3)[CH2:12][CH2:13]2)[CH2:6][CH2:7]1
Reactant: CCCCC1COC(C2CCC(C3CCC(=O)CC3)CC2)OC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCC1COC(C2CCC(C3CCC(O)CC3)CC2)OC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.4 %

Procedure:
In 50 ml of ethanol was dissolved 3.2 g (9.9 mmol) of the 2-(4-(4-oxocyclohexyl)cyclohexyl)-5-n-butyl-1,3-dioxane, and the solution was cooled down to 0° C. To this solution was added gradually 0.19 g (5.0 mmol) of sodium borohydride such that the liquid temperature did not exceed 15° C., and the mixture was stirred for 1 hour. Water in an amount of 50 ml was added to the reaction mixture, the product thus formed was extracted with ether, the extract was washed with 1N-hydrochloric acid and water in this turn, and the solvent was distilled off. After the residue was purified by column chromatography on silica gel (eluent: heptane/ethyl acetate=2/1), the solvent was distilled off. The residue was recrystallized from ethanol to give 1.2 g (3.7 mmol) of 2-(4-(4-hydroxy-cyclohexyl)cyclohexyl)-5-n-butyl-1,3-dioxane. Yield of this compound based on 2-(4-(4-oxocyclohexyl)cyclohexyl-5-n-butyl-1,3-dioxane was 37%.
Reaction SMILES: [Cl:1][C:2]([F:6])=[C:3]([F:5])[F:4].[CH2:7]=[CH:8][CH:9]=[CH:10][CH3:11]>>[Cl:1][C:2]1([F:6])[C:3]([F:5])([F:4])[CH2:7][CH:8]=[CH:9][CH:10]1[CH3:11]
Reactant: C=CC=CC
Reactant: FC(F)=C(F)Cl
Product: CC1C=CCC(F)(F)C1(F)Cl
Reaction time: 1 h
Yield: 52 %

Procedure:
A flow reactor equipped with dual tubes having 20 mm of inner diameter of the outer tube, 16 mm of outer diameter of the inner tube, and 60 cm of length of the tubes was employed. The temperature in the reactor was kept at 520° C. Chlorotrifluoroethylene (CTFE), 1,3-pentadiene and nitrogen gas were continuously injected into the flow reactor at the rates of 36.1 g/hr, 20.4 g/hr, and 0.4 mol/hr, respectively, and the vapor phase condensation was carried out for 1 hour. Then, 4.7 g of unreacted chlorotrifluoroethylene (CTFE) was recovered. The resultant was purified by steam distillation, and then the water layer was removed to give 32.1 g of the mixture (GC%=52%).
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>CO>[C:8]([C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:12][N:13]([CH3:15])[CH3:14])#[N:9]
Reactant: COC(OC)N(C)C
Reactant: N#CCc1ccccc1
Solvent: CO
Product: CN(C)C=C(C#N)c1ccccc1
Reaction time: 24 h
Yield: 77.9 %

Procedure:
A stirred solution of 5.1 grams (0.044 mole) of benzyl cyanide and 8.7 grams (0.065 mole) of N,N-dimethylformamide dimethyl acetal in 150 mL of methanol was heated at reflux for about 20 hours. After this time gas chromatographic analysis of the reaction mixture indicated that the reaction was not complete. An additional 3.0 mL of the intermediate acetal (total--0.088 mole) was added, and the heating at reflux was continued an additional 24 hours. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was triturated with 25% methylene chloride in petroleum ether, yielding 5.9 grams of 1-cyano-1-phenyl-2-(N,N-dimethylamino)ethene. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH2:15][CH2:14][CH:13]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][C:11]=2[CH:25]=1)C.[OH-].[NH4+:28]>CO>[CH2:18]([NH:17][CH:13]1[CH2:12][C:11]2[CH:25]=[C:7]([O:6][CH2:5][C:4]([NH2:28])=[O:3])[CH:8]=[CH:9][C:10]=2[CH2:16][CH2:15][CH2:14]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)COc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)COc1ccc2c(c1)CC(NCc1ccccc1)CCC2

Procedure:
A solution of 2-(8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)acetic acid ethyl ester (320 mg) and 28% ammonium hydroxide (1 ml) in methanol (3 ml) was stirred at room temperature for 12 hours. The mixture was evaporated in vacuo to give 2-(8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)acetamide (270 mg).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)(=O)C.O>CO>[CH2:14]([O:13][N:12]=[C:11]([C:8]1[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=1)[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)Oc1ccc(C(=NOCc2ccccc2)OCc2ccccc2)cc1
Solvent: CO
Solvent: O
Product: Oc1ccc(C(=NOCc2ccccc2)OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
To a solution of 4-{(benzyloxy)[(benzyloxy)imino]methyl}phenyl acetate (19) (1.671 g, 4.45 mmol) in dry methanol (30 ml) 3.43 N sodium methoxide solution in methanol (1.3 ml, 4.46 mmol) was added and the reaction mixture was stirred at ambient temperature until the starting material disappeared (ca. 1 hour). The mixture was poured into a mixture of water (60 ml) and saturated NaH2PO4 (30 ml), and extracted with ethyl acetate (2×25 ml). The extract was washed with brine (30 ml) and dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silicagel (50 g) with benzene-ethyl acetate (9:1) as eluent to give benzyl N-(benzyloxy)-4-hydroxybenzenecarboximidoate (15) (1.428 g, 96%) as an interchangeable mixture (2D TLC) of 2 isomers with Rf 0.62 and Rf 0.49 (toluene-ethyl acetate, 9:1). Major (less polar) isomer of 15: 1H NMR (DMSO-d6, HMDSO) δ: 4.99 (2H, s); 5.09 (2H, s); 6.80 (2H, d, J=8.7 Hz); 7.27-7.53 (10H, m); 7.67 (2H, d, J=8.7 Hz); 9.96 (1H, s). Minor (more polar) isomer of 15: 1H NMR (DMSO-d6, HMDSO) δ: 5.06 (2H, s); 5.24 (2H, s); 6.75 (2H, d, J=8.6 Hz); 7.27-7.53 (10H, m); 7.67 (2H, d, J=8.6 Hz); 9.84 (1H, s).
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:21])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:3][CH2:4]O.[C:22]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:27]=1[OH:36])([CH3:25])([CH3:24])[CH3:23].B(F)(F)F.CCOCC.O>O1CCOCC1>[C:32]([C:28]1[CH:29]=[C:30]([CH2:4][CH:3]=[C:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:21])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH:31]=[C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:27]=1[OH:36])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: CC(=CCO)CCCC(C)CCCC(C)CCCC(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: O
Solvent: C1COCCO1
Product: CC(=CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CCCC(C)CCCC(C)CCCC(C)C
Yield: 9.1 %

Procedure:
A solution of 3,7,11,15-tetramethyl-2-hexadecen-1-ol (2.97 g;10.0 mmole) in dioxane (8 ml) was dropwise added to a solution of 2,6-di-tert-butyl phenol (4.13 g;200 mmole) and boron trifluoride ethyl etherate (0.86 g;6.0 mmole) in dioxane (20 ml) at 40° C. over one hour. After stirring the resultant solution at that temperature for 2.5 hours, the reaction solution was poured into water (30 ml) and was then extracted once with ethyl acetate (20 ml). The extract was successively washed with 30 ml of 5% (w/v) aqueous sodium hydroxide solution containing 3% (w/v) sodium hydrosulfite (once), 30 ml of water (twice) and then 30 ml of saturated aqueous sodium chloride (once) and was dried over anhydrous magnesium sulfate. Then, the solvent and the unreacted 2,6-di-tert-butyl-phenol were distilled off and the resultant residue was subjected to silica gel column chromatography to obtain 440 mg (0.91 mmole) of 2,6,di-tert-butyl-4-(3,7,11,15,tetramethyl-2 -hexadecenyl)-phenol from the fractions eluted through the column with hexane-ethyl acetate (50:1). Yield=9.1%.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]([O:11]CC2C=CC=CC=2)=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1>CO.[Pd].O>[CH3:1][C:2]1[C:7]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1CC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: Cc1ncccc1CC(=O)O
Reaction time: 3 h

Procedure:
The residue including benzyl 2-(2-methyl-3-pyridyl)acetate obtained in Preparation 29-(2) was dissolved in methanol (5 ml), and 10% palladium on carbon was added thereto. The mixture was stirred under hydrogen atmosphere for 3 hours. The reaction mixture was diluted with water and washed with ethyl acetate. The solvent was removed in vacuo to give 2-(2-methyl-3-pyridyl)acetic acid (90 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([O:35][C:36]([CH:38]1[CH2:43][CH2:42][CH2:41][NH:40][CH2:39]1)=[O:37])[CH3:34]>>[CH2:33]([O:35][C:36]([CH:38]1[CH2:43][CH2:42][CH2:41][N:40]([C:30]([C@@H:9]2[CH2:10][C@H:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[CH2:12][N:8]2[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:31])[CH2:39]1)=[O:37])[CH3:34]
Reactant: CCOC(=O)C1CCCNC1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Product: CCOC(=O)C1CCCN(C(=O)[C@@H]2C[C@H](NCc3ccc(F)cc3F)CN2Cc2ccccc2)C1
Yield: 16 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using piperidine-3-carboxylic acid ethyl ester instead of 2-piperazin-1-yl-benzonitrile, to the title product [(2S,4S)-1-benzyl-4-(2,4-difluoro-benzylamino)-pyrrolidine-2-carbonyl]-piperidine-3-carboxylic acid ethyl ester (9.7 mg, 16% yield) as colorless oil. MS m/e=486.6 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].[H-].[Na+].I[CH2:18][CH3:19].O>CN(C=O)C>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6])[CH3:19]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.2 %

Procedure:
Step A To a solution of methyl 3-hydroxy-4-nitrobenzoate (Aldrich) (3 g, 15.2 mmol) in anhydrous DMF (25 mL) were added NaH (Aldrich, 60%) (0.91 g, 22.8 mmol) and iodoethane (2.61 g, 16.7 mmol) sequentially. The reaction mixture was stirred at room temperature for 2 h. Water was added. The mixture was extracted with ethyl acetate. The organic extract was washed with water, brine, dried over MgSO4, and concentrated to give methyl 3-ethoxy-4-nitrobenzoate as a light yellow solid (1.0 g, 29%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:14]1[N:15]=[C:16]([CH2:20][C:21](OCC)=[O:22])[O:17][C:18]=1[CH3:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>C(OCC)C>[CH2:7]([C:14]1[N:15]=[C:16]([CH2:20][CH2:21][OH:22])[O:17][C:18]=1[CH3:19])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)Cc1nc(Cc2ccccc2)c(C)o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: Cc1oc(CCO)nc1Cc1ccccc1
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a suspension of lithium aluminum hydride (LiAlH4) (0.7 g) in ethyl ether (40 ml), a solution of ethyl 2-(4-benzyl-5-methyl-2-oxazolyl)acetate (4.76 g) in ethyl ether (60 ml) was added dropwise under ice cooling conditions, followed by stirring for 1 hour. After water (5 ml) was added dropwise to the reaction mixture, the insoluble substances were filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography. From the fraction eluted with chloroform-ethyl acetate (2:1, v/v), 2-(4-benzyl-5-methyl-2-oxazolyl)ethanol (3.0 g, 75%) was obtained as an oily substance.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].C(OC(=O)C)(=O)C.O[C@@H:13]1[CH2:17][C:16](=[O:18])[C:15]([CH2:19][C:20]#[CH:21])=[C:14]1[CH3:22]>C(Cl)(Cl)Cl>[CH3:22][C:14]1[C@H:13]([O:2][N+:1]([O-:4])=[O:3])[CH2:17][C:16](=[O:18])[C:15]=1[CH2:19][C:20]#[CH:21]
Reactant: C#CCC1=C(C)[C@H](O)CC1=O
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: C#CCC1=C(C)[C@H](O[N+](=O)[O-])CC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
Into a mixed solution of 8 g of fuming nitric acid and 24 g of acetic anhydride, kept at a temperature of -5° to 10° C., was added dropwise 6 g of (R)-4-hydroxy-3-methyl-2-(2-propynyl)-2-cyclopenten-1-one ([α]D23 ; -19.5° (C=1.36, in chloroform), (R)-isomer/(S)-isomer=96.7/3.3). Then, the mixture was stirred for 30 minutes at the same temperature. Thereafter, the reaction mixture was poured into 200 ml of ice water, and then subjected to a toluene extraction. The toluene layer was separated and washed with an aqueous 5% sodium hydrogencarbonate solution and then with water. The extract was dried over anhydrous magnesium sulfate and, then, concentrated to give 7.56 g of crude (R)-3-methyl-4-nitroxy-2-(2-propynyl)-2-cyclopenten-1-one.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH:19]=[O:20])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:21])[CH:3]=1.[CH3:22][O:23][CH2:24][Li]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19](=[O:20])[CH2:22][O:23][CH3:24])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:21])[CH:3]=1
Reactant: [Li]COC
Reactant: O=Cc1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Product: COCC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl

Procedure:
1-[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-methoxy-ethanone 10p is prepared from 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carbaldehyde 10f and lithiomethyl methyl ether by the procedures described in Example 44. MS APCI (+) m/z 412, 414 (M+, Br pattern) detected.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH:9]1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:16][OH:17].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=[N:16][OH:17])[CH:9]1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1C(=O)CCN1Cc1ccccc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC1C(=NO)CCN1Cc1ccccc1
Yield: 63.7 %

Procedure:
To 80 ml of ethanol solution containing 16 g of 1-benzyl-2-methyl-3-pyrrolidone was added 80 ml of aqueous solution containing 13 g of hydroxylamine hydrochloride. After adding 18 g of sodium carbonate to the solution, the mixture was warmed to 35°-40° C. for 30 minutes. The reaction mixture was condensed under reduced pressure to half volume, and the product was extracted twice each time with 80 ml of ether. The extracts were combined and dried over anhydrous magnesium sulfate. The extracts were condensed under reduced pressure to provide 11 g of oily crude 1-benzyl-3-hydroxyimino-2-methylpyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH2:9]([C:13]1[O:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[CH2:10][C:11]#[CH:12]>>[Cl:1][C:2]1[N:7]=[C:6]([C:12]#[C:11][CH2:10][CH2:9][C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C#CCCc1nc2ccccc2o1
Product: Clc1nccc(C#CCCc2nc3ccccc3o2)n1
Yield: 9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2,4-dichloropyrimidine (200 mg, 1.34 mmol) and 2-(but-3-ynyl)benzo[d]oxazole (230 mg, 1.34 mmol, Example 8(A)) at room temperature. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 35 mg (0.12 mmol, 9%) of 2-(4-(2-chloropyrimidin-4-yl)but-3-ynyl)benzo[d]oxazole as a yellow solid.
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH:12][C:13]2[N:14]([CH3:21])[N:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)=[CH:10][CH:9]=[C:8]([CH3:22])[N:7]=1)=[O:5])C.[NH2:23][C:24]1[S:25][CH:26]=[C:27]([CH3:29])[N:28]=1>>[CH3:29][C:27]1[N:28]=[C:24]([NH:23][C:4]([C:6]2[C:11]([NH:12][C:13]3[N:14]([CH3:21])[N:15]=[C:16]([CH:18]4[CH2:19][CH2:20]4)[CH:17]=3)=[CH:10][CH:9]=[C:8]([CH3:22])[N:7]=2)=[O:5])[S:25][CH:26]=1
Reactant: Cc1csc(N)n1
Reactant: CCOC(=O)c1nc(C)ccc1Nc1cc(C2CC2)nn1C
Product: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cc(C3CC3)nn2C)n1

Procedure:
The tide compound, was prepared from 3-(5-Cyclopropyl-2-methyl-2H-pyrazol-3-ylamino)-6-methyl-pyridine-2-carboxylic acid ethyl ester and 2-Amino-4-methylthiazole in accordance with the general method of Example 78, step 2 to yield the final compound as a yellow solid, MS (ISP): m/e=369.0 (M+H+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[CH3:12][N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[N:3]=[C:4]([N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CNc1ccccc1
Reactant: Clc1nc(Cl)c2sccc2n1
Solvent: ClCCl
Product: CN(c1ccccc1)c1nc(N(C)c2ccccc2)c2sccc2n1

Procedure:
2,4-Dichlorothieno[3,2-d]pyrimidine (1 g, 0.0048 mol) and N-methylaniline (5 ml) were heated at 130° for 1 hour. The reaction mixture was diluted with dichloromethane (200 ml) and extracted with 2N hydrochloric acid (3×150 ml). The organic phase was then washed with sodium carbonate, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give a brown solid. Recrystallization from methanol gave the title compound, (1.08 g), m.p. 120°-122°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])[CH3:2].[C:35]1([OH:41])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C>CN1CCCC1=O.[Cu]Cl>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:15]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3[O:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:17]=[C:18]([CH3:20])[CH:19]=2)=[CH:9][C:8]=1[CH3:33])[CH3:2]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Oc3ccccc3)c2)cc1C
Temperature: 120 °C
Yield: 54.6 %

Procedure:
A mixture of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester (0.309 g, 0.576 mmol), phenol (0.163 g, 1.73 mmol), cesium carbonate (0.56 g, 1.72 mmol), copper (I) chloride (0.029 g, 0.293 mmol) and 2,2,6,6-tetramethyl-3,5-heptanedione (0.027 g, 0.147 mmol) in 1-methyl-2-pyrrolidinone (10 mL) is heated to 120° C. for 20 hours under N2. The reaction is cooled and quenched with 1 N HCl (20 mL). The mixture is then diluted with Et2O and extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 9/1 hexanes/ethyl acetate to afford 0.173 g (43%) of the title compound. Rf=0.55 (4/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) M/z mass calculated for C32H29O35F3 550, found 551 (M+1, 100%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:17]=[C:16]3[C:12]([NH:13][C:14](=[O:26])[N:15]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[C:11]([C:27]([O:29]CC)=O)[N:10]=2)[CH2:4][CH2:3]1.[NH2:32]C1C(C(OCC)=O)=NC(N[C@H]2CC[C@H](O)CC2)=NC=1NC1C=CC=CC=1OC>ClCCl>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:17]=[C:16]3[C:12]([NH:13][C:14](=[O:26])[N:15]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[C:11]([C:27]([NH2:32])=[O:29])[N:10]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1nc(N[C@H]2CC[C@H](O)CC2)nc(Nc2ccccc2OC)c1N
Reactant: CCOC(=O)c1nc(N[C@H]2CC[C@H](O)CC2)nc2c1[nH]c(=O)n2-c1ccccc1OC
Solvent: ClCCl
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(N[C@H]3CC[C@H](O)CC3)nc21

Procedure:
Ethyl 2-(trans-4-hydroxycyclohexylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate and the imidazole ester. Ethyl 5-amino-2-(trans-4-hydroxy-cyclohexylamino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate (0.240 g, 0.598 mmol) and 1,1′-1,1′-carbonyldiimidazole (0.968 g, 5.98 mmol) in dichloromethane (20 mL) were reacted according to general procedure F. A mixture of the title compound and the imidazole ester were formed and were taken on without further purification. MS (ESI) m/z 399 [M+1]+ (title compound), 522 [M+1]+ (imidazole urea).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:28])[NH:14][C:13](=[O:15])[C:12]3([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[N:11]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C([O-])(O)=O.[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:28])[N:14]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:13](=[O:15])[C:12]3([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[N:11]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1C[C@@](C)(c2cc(F)cc(F)c2)NC(=O)C12CCCCC2
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)C2(CCCCC2)N(C(=O)OC(C)(C)C)C[C@@]1(C)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of tert-butyl (3R)-3-(3,5-difluorophenyl)-3-methyl-5-oxo-1,4-diazaspiro[5.5]undecane-1-carboxylate from Step H (60 mg, 0.152 mmol) in THF (0.5 mL) at 0° C. was added NaH (12 mg of a 60% dispersion in oil, 0.30 mmol). After 5 min, ethyl bromoacetate (437 mg, 2.62 mmol) was added and the mixture was allowed to warm to ambient temperature and stirring was continued for 1 h. Saturated aqueous NaHCO3 (2 mL) was added and the mixture was extracted with EtOAc (2×5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—95:5 to 60:40, to give the title compound. MS: m/z=425 (M−C4H7).