Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5](=[NH:14])[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[NH:7].C([Li])CCC.CCCCCC.[C:28]1([Sb:34](Cl)Cl)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CCOCC>[C:28]1([Sb:34]2[N:14]=[C:5]([O:4][CH2:3][C:2]([F:15])([F:16])[F:1])[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[N:7]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cl[Sb](Cl)c1ccccc1
Reactant: N=C(OCC(F)(F)F)C(=N)OCC(F)(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: FC(F)(F)COC1=N[Sb](c2ccccc2)N=C1OCC(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
The compound 1,2-di(2,2,2-trifluoroethoxy)ethanediimine (1.2 g, 5 mmol) was placed into a 50 mL Schlenk flask and the flask was flushed with nitrogen. Approximately 20 mL anhydrous diethyl ether was added, and the solution was cooled to approximately -70° to -80° C. (dry ice/isopropanol). Ten mmol (4.9 mL, 2.03M) n-butyllithium/hexane was then added dropwise via syringe; the solution was stirred at -78° C. for approximately 30 minutes. A solution of 1.35 g (5.0 mmol) of phenylantimony dichloride [(C6H5)SbCl2 ] in 25 mL of ether was then added dropwise via syringe. The reaction mixture was allowed to warm to room temperature while stirring. After stirring at room temperature for approximately 1-2 hours, the mixture was filtered through a fritted funnel, and the filtrate evaporated in vacuo. The solid residue was sublimed (1 torr, room temperature) to yield the white crystalline product 2-phenyl-4,5-di(2,2,2-trifluoroethoxy)-1,3,2-diazastibole in 45% yield (1.01 g, 2.25 mmol). 13C[1H]NMR (δ; CD2Cl2) 156.0 ppm (>C=N--; s), 152.2, 132.2, 131.5, and 129.3 ppm (phenyl C), 124.8 ppm (--CF3, t, J1 =278.0 Hz), 63.7 ppm (q, J2 =34.9Hz). Elemental analysis was carried out: calcd (found) for C12H9N2O2F6Sb: C, 32.10% (32.17%), H, 2.02% (2.09%), N, 6.24% (6.31%), F, 25.39% (25.43%), Sb 27.12% (27.20%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[I-].[Na+].[OH-].[Na+].Cl[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>C(O)(CC)(C)C.C1(C)C=CC=CC=1>[C:14]1([C:12](=[O:13])[CH2:11][N:1]2[CH:5]=[CH:4][N:3]=[N:2]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1c[nH]nn1
Reactant: O=C(CCl)c1ccccc1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)(C)O
Solvent: Cc1ccccc1
Product: O=C(Cn1ccnn1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
1,2,3-Triazole (1689 mg, 24.45 mmol), sodium iodide (2443 mg, 16.3 mmol) and sodium hydroxide (978 mg, 24.45 mmol) were added to t-amyl alcohol (6.5 ml), and the mixture was refluxed under stirring for 1 hour. 2-Chloro-1-phenylethanone (2520 mg, 16.3 mmol) was dissolved in t-amyl alcohol (13 ml) and added dropwise over 1 hour. The mixture was refluxed under stirring for 1 hour. The mixture was cooled to room temperature, toluene (50 ml) was added. The mixture was washed with water (50 ml×2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/2→1/4) to give 1-phenyl-2-(1H-1,2,3-triazol-1-yl)ethanone (1.38 g) as brown crystals (yield 45%). 1-Phenyl-2-(2H-1,2,3-triazol-2-yl)ethanone (550 mg) was obtained as yellow crystals (yield 18%). 1-phenyl-2-(1H-1,2,3-triazol-1-yl)ethanone
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])[CH:4]=1.[C:21]1([P:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[Br-:1].[F:18][C:17]([F:20])([F:19])[S:14]([O:13][C:5]1[CH:4]=[C:3]([CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])[CH2:2][P+:27]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)(=[O:16])=[O:15]
Reactant: COC(=O)c1ccc(CBr)cc1OS(=O)(=O)C(F)(F)F
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1OS(=O)(=O)C(F)(F)F
Product: [Br-]
Yield: 100 %

Procedure:
A solution of methyl 4-bromomethyl-2-trifluoromethylsulfonyloxybenzoate (23.12 g; 61 mmol) and triphenylphosphine (16 g; 61 mmol) in toluene (240 ml) was refluxed for 5 hours. The resulting solid was filtered and washed with ether to give 3-trifluoromethylsulfonyloxy-4-methoxycarbonylbenzyl triphenylphosphonium bromide. Yield=100%.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]2/[C:18](=[CH:28]/[C:29]([OH:31])=[O:30])/[C:19]3[S:20][CH:21]=[CH:22][C:23]=3[C:24]([O:26][CH3:27])=[N:25][C:16]=2[CH:15]=1.[Cl:34]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1.O>[Cl:34][C:21]1[S:20][C:19]2/[C:18](=[CH:28]\[C:29]([OH:31])=[O:30])/[C:17]3[CH:32]=[CH:33][C:14]([Cl:13])=[CH:15][C:16]=3[N:25]=[C:24]([O:26][CH3:27])[C:23]=2[CH:22]=1
Reactant: COC1=Nc2cc(Cl)ccc2/C(=C/C(=O)O)c2sccc21
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC1=Nc2cc(Cl)ccc2/C(=C/C(=O)O)c2sc(Cl)cc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A round-bottomed flask, equipped with a magnetic stirrer, digital thermometer, addition funnel and a condenser with nitrogen inlet-outlet, is charged with diisopropylamine (462.9 mL) and tetrahydrofuran (4.2 L). The solution is cooled to −78° C. and n-butyl lithium (1.71 L, 1.6 M in hexane) is added over a period of 1 hour. After addition the reaction mixture is stirred for 1 hour and [7-Chloro-10-methoxy-3-thia-9-aza-benzo[f]azulen-(4Z)-ylidene]-acetic acid (350 g), dissolved in tetrahydrofuran (1.4 L), is added dropwise over 1 hour while maintaining the temperature at −70° C. Stirring is maintained for 1 hour at −78° C. Afterwards the yellow solution is transferred through a cold tube to a solution of hexachloroethane (779 g), dissolved in tetrahydrofuran (4.2 L), over a period of 45 min while maintaining the temperature at −25° C. The yellow solution is then allowed to slowly warm up to 0° C. over 30 min and kept at this temperature for 30 min. Then, deionized water (2.26 kg) is added over 5 min and the resulting emulsion concentrated under vacuum to remove the solvent. Then tert-butylmethylether (5.25 L) and water (3 L) are added. After vigorous stirring the organic phase is removed and replaced with isopropyl acetate (7 L). Then the mixture is acidified with phosphoric acid (339 L) to get a pH value of 2-3. Afterwards, the organic phase is separated and concentrated to 1/10, methanol (6.2 L) is added and the temperature raised to 65° C. over 40 min. The solution is distilled to a volume of 3.4 L, the resulting suspension cooled to −15° C. and stirred for 1 hour. The crystalline precipitation is collected by filtration, washed with cold methanol (500 mL) and dried under vacuum (50° C., 20-50 mmbar) to yield [2,7-Dichloro-10-methoxy-3-thia-9-aza-benzo[f]azulen-(4Z)-ylidene]-acetic acid with a melting point of 195-197° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.[CH3:14][C@H:15]1[CH2:17][O:16]1.O>O1CCCC1.CCOCC>[Cl:3][C:4]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:14][C@@H:15]([OH:16])[CH3:17]
Reactant: Fc1ccc2[nH]ccc2c1Cl
Reactant: C[C@H]1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: C[C@H](O)Cn1ccc2c(Cl)c(F)ccc21
Reaction time: 1 h
Yield: 78.9 %

Procedure:
A suspension of 0.11 g of sodium hydride dispersion in 15 ml of tetrahydrofuran was treated with 0.5 g of 4-chloro-5-fluoroindole at 0° and stirred at this temperature for 1 hour. After the addition of 0.4 ml of (S)-methyloxirane the reaction mixture was stirred at s room temperature for 48 hours and subsequently treated with water. The mixture was diluted with ether, washed with water and with saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 30 g of silica gel with toluene-ethyl acetate (33:1). There was obtained 0.53 g (78.9%) of (S)-1-(4-chloro-5-fluoro-indol-1-yl)-propan-2-ol as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.Cl[CH2:10][CH:11]=O.C(=O)(O)[O-].[Na+]>C(#N)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[CH:11][N:1]=2)[CH:4]=1
Reactant: O=CCCl
Reactant: Nc1ccc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Brc1ccc2nccn2c1
Yield: 83.4 %

Procedure:
Reflux a solution of 2-amino-5-bromo-pyridine (Maybridge; 1.0 g, 5.78 mmol), 50% aqueous chloroacetaldehyde (2 mL, 12.7 mmol) in acetonitrile (100 mL) for 14 h. Dilute the reaction with saturated aqueous sodium bicarbonate and extract into ethyl acetate. Flash chromatography using appropriate ethyl acetate/hexane mixtures gives 0.95 g (83%) of the subtitled compound as a tan solid. MS (electrospray, m/z) 196.7, 198.7 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.9 (d, J=1.5 Hz, 1H), 7.90 (s, 1H), 7.58 (d, J=1.5 Hz, 1H), 7.53 (d, J=9.2 Hz, 1H), 7.29 (dd, J=9.2, 2 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[CH2:5][CH2:6][C:7]([OH:9])=O.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=1>C1COCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][C:7]([NH:29][C:30]2[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=2)=[O:9])[CH:10]=[CH:11][C:12]=1[OH:13]
Reactant: O=C(O)CCc1ccc(O)c(O)c1
Reactant: COC(=O)c1ccc(N)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)CCc2ccc(O)c(O)c2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 22 %

Procedure:
To a solution of 3,4-dihydroxyhydrocinnamic acid (723 mg, 3.97 mmol) in anhydrous THF (20 mL) were added N-methylmorpholine (0.44 mL, 3.97 mmol) and isobutylchloroformate (0.52 mL,3.97 mmol) at 0° C. After 45 min, at 0° C., a solution of methyl 4-aminobenzoate (500 mg, 3.31 mmol) in anhydrous THF (4 mL) was added to the reaction mixture. After 5 min the temperature was allowed to warm up to rt and stir overnight. After extraction with EtOAc (100 mL), washing with HCl (0.1N, 50 mL) and a saturated aqueous solution of NaHCO3 (50 mL), the organic layer was dryed over sodium sulfate and evaporated under vacuo to give a yellow oil. Purification by flash chromatography using DCM/MeOH (95/5) as eluant gave the title compound as a colourless oil (22%) in a 94.8% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[CH:4]([CH3:17])[N:5]1[CH:9]=[C:8]([CH3:10])[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6]1.[CH3:20]I.[CH2:22](I)[CH3:23]>>[CH3:19][N:2]([CH3:1])[C:3](=[O:18])[C:4]([CH3:20])([CH3:17])[N:5]1[CH:9]=[C:8]([CH2:10][CH2:22][CH3:23])[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6]1
Reactant: CI
Reactant: CCI
Reactant: Cc1cn(C(C)C(=O)N(C)C)nc1-c1ccccc1
Product: CCCc1cn(C(C)(C)C(=O)N(C)C)nc1-c1ccccc1

Procedure:
Following the procedure of Example 95, but substituting N,N,α-trimethyl-3-phenyl-4-propylpyrazole-1-acetamide for N,N,α,4-tetramethyl-3-phenypyrazole-1-acetamide and methyl iodide for ethyl iodide, there was obtained N,N,α,α-tetramethyl-3-phenyl-4-propylpyrazole-1-acetamide, m.p. 98.5°-101° C.
Reaction SMILES: [NH:1]([C:3]1[CH:21]=[CH:20][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1)[NH2:2].[C:22]([NH:25][CH:26]([C:32](=O)[CH3:33])[C:27](OCC)=[O:28])(=[O:24])[CH3:23]>C(O)C>[C:22]([NH:25][C:26]1[C:27](=[O:28])[N:1]([C:3]2[CH:21]=[CH:20][C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=3)=[O:8])=[CH:5][N:4]=2)[NH:2][C:32]=1[CH3:33])(=[O:24])[CH3:23]
Reactant: NNc1ccc(C(=O)Nc2ccc(C(F)(F)F)cc2)cn1
Reactant: CCOC(=O)C(NC(C)=O)C(C)=O
Solvent: CCO
Product: CC(=O)Nc1c(C)[nH]n(-c2ccc(C(=O)Nc3ccc(C(F)(F)F)cc3)cn2)c1=O
Temperature: 25 °C
Yield: 45.6 %

Procedure:
6-Hydrazino-N-[4-(trifluoromethyl)phenyl]nicotinamide (0.31 g) and ethyl 2-acetamido-3-oxobutanoate (0.24 g) were suspended in ethanol (25 mL), and the suspension was heated to reflux for 23 hours. The reaction solution was cooled to room temperature, and the obtained solid was collected by filtration and washed with ethanol. The solid was dried under reduced pressure to obtain the title compound (0.20 g) as a white solid (yield: 46%).
Reaction SMILES: N.[Na].[CH3:3][N:4]([CH2:6][C:7]#[CH:8])[CH3:5].Cl.Br[CH2:11][CH2:12][CH2:13][NH2:14]>C(OCC)C>[CH3:3][N:4]([CH3:5])[CH2:6][C:7]#[C:8][CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: C#CCN(C)C
Reactant: NCCCBr
Agent: Cl
Agent: N
Agent: [Na]
Solvent: CCOCC
Product: CN(C)CC#CCCCN
Reaction time: 1 h
Yield: 16 %

Procedure:
A flask fitted with a dry ice condenser was charged with liquid ammonia (250 ml). To this was added sodium (0.24 mol) in portions together with a few grains of ferric nitrate; subsequently dimethylaminoprop-2-yne (0.24 mol) was added. The reaction mixture was stirred for one hour, 3-bromopropylamine hydrochloride (0.24 mol) was added in portions and the mixture stirred for a further two hours. Anhydrous diethyl ether (150 ml) was added and excess ammonia was allowed to evaporate overnight. The reaction mixture wws dissolved in methanol and evaporated under reduced pressure to afford a residue, which was partitioned between chloroform and water. The aqueous layer was washed with chloroform (5×150 ml). The chloroform extracts were combined, dried over MgSO4, filtered and evaporated under reduced pressure to give 6-dimethylaminohex-4-ynylamine as an oil (5.4 g).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].CC(C)C[C@H](N[C:40]([C@@H:42]1[O:44][C@H:43]1[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[O:41])C(N1CCN(C2C=CC=CN=2)CC1)=O>>[CH3:5][CH:4]([CH3:6])[CH2:3][C@H:2]([NH:1][C:40]([C@@H:42]1[O:44][C@H:43]1[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[O:41])[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:16]=[CH:17][CH:18]=[CH:19][N:20]=2)[CH2:11][CH2:10]1)=[O:8]
Reactant: CC(C)C[C@H](N)C(=O)N1CCN(c2ncccn2)CC1
Reactant: CCOC(=O)[C@@H]1O[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N1CCN(c2ccccn2)CC1
Product: CCOC(=O)[C@@H]1O[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N1CCN(c2ncccn2)CC1
Yield: 92.1 %

Procedure:
Monoethyl trans-epoxy succinate (3.52 g) and 1-L-leucyl-4-(2-pyrimidinyl)piperazine (6.10 g) were condensed in the same manner as employed in the preparation of ethyl trans-3-[(s)-3-methyl-1-{4-(2-pyridyl)piperazine-1-yl carbonyl}butylcarbamoyl]oxirane-2-carboxylate to yield 8.50 g of ethyl trans-3-[(s)-3-methyl-1-{4-(2-pyrimidinyl)piperazine-1-yl carbonyl}butylcarbamoyl]oxirane-2-carboxylate (yield: 92.1%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>>[CH:25]1([C:28]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([C:11]4[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH2:15][CH:16]=4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:29])[CH2:27][CH2:26]1
Reactant: Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1
Reactant: O=C(Cl)C1CC1
Product: O=C(Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1)C1CC1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.006 mL (0.061 mMol) cyclopropylcarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: CC(OC[C:6]1[C:19]2[C:14](=CC=CC=2)[C:13]([CH2:20][O:21][C:22]([CH3:24])=[O:23])=C2C=1C=CC=C2)=O.C([O:27][C:28](=[O:30])[CH3:29])C.[CH3:31]CCCCC>CN(C1C=CN=CC=1)C>[C:22]([O:21][C@@H:20]([CH2:13][CH2:14][C@H:19]([O:30][C:28](=[O:27])[CH3:29])[CH3:6])[CH3:31])(=[O:23])[CH3:24]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: CCOC(C)=O
Reactant: CCCCCC
Agent: CN(C)c1ccncc1
Product: CC(=O)O[C@H](C)CC[C@@H](C)OC(C)=O
Yield: 80 %

Procedure:
A solution of prolinol complex 10 (779 mg, 4.0 mmol) in THF (20 mL) was oxidized as above with ethylene glycol (0.44 mL, 7.9 mmol), 2M methanolic sodium hydroxide (12 mL, 24 mmol) and 30% H2O2 (2 mL, 20 mmol). Ether (50 mL) was added and the solution was washed with brine (2×10 mL). The aqueous phase was extracted with ether (2×10 mL). The combined organic layers were dried (K2CO3) and evaporated. Chromatography (ethyl acetate) of the residue afforded (R,R)-2,5-dihydroxyhexane (356 mg, 75% yield). The idol was acetylated with acetic anhdride (1.5 mL) and DMAP (30 mg) at 20° C. for 12 h. Standard workup followed by chromatography (ethylacetate/hexane, 1:9) gave (R,R)-2,5-diacetoxyhexane (482 mg, 80% yield). Bulb-to-bulb distillation gave pure diacetate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:18]3[C:13](=[C:14]([F:20])[C:15]([F:19])=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][N:3]=1.Cl.[NH:22]1[C:27]2[N:28]=[CH:29][CH:30]=[CH:31][C:26]=2[C:25]2([CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[O:24][C:23]1=[O:37].C(=O)([O-])[O-].[K+].[K+].O.C(#N)C>CN1C(=O)CCC1>[F:20][C:14]1[C:15]([F:19])=[CH:16][CH:17]=[C:18]2[C:13]=1[CH2:12][CH2:11][N:10]2[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:34]2[CH2:33][CH2:32][C:25]3([O:24][C:23](=[O:37])[NH:22][C:27]4[N:28]=[CH:29][CH:30]=[CH:31][C:26]3=4)[CH2:36][CH2:35]2)[CH:7]=1)=[O:9]
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Reactant: O=C(c1ccnc(Cl)c1)N1CCc2c1ccc(F)c2F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CN1CCCC1=O
Product: O=C1Nc2ncccc2C2(CCN(c3cc(C(=O)N4CCc5c4ccc(F)c5F)ccn3)CC2)O1
Temperature: 130 °C
Reaction time: 10 h

Procedure:
0.23 g (0.78 mmol) (2-chloro-pyridin-4-yl)-(4,5-difluoro-2,3-dihydro-indol-1-yl)-methanone were added to 0.20 g (0.78 mmol) spiro[piperidine-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one-hydrochloride and 0.11 g (0.78 mmol) potassium carbonate in 3.0 mL NMP. The reaction mixture was first of all stirred for 10 h at 130° C., then cooled to RT and then stirred overnight at RT. The crude product was combined with water/acetonitrile and purified by preparative HPLC-MS. The product fractions were combined and evaporated down. The residue was triturated with diisopropylether, suction filtered and dried in the air.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][CH2:12][CH3:13])[N:3]=1.[CH:14]([NH2:17])([CH3:16])[CH3:15]>CC(C)=O>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:17][CH:14]([CH3:16])[CH3:15])[N:3]=[C:4]([NH:11][CH2:12][CH3:13])[N:5]=1
Reactant: CC(C)N
Reactant: CCNc1nc(Cl)c(C#N)c(Cl)n1
Solvent: CC(C)=O
Product: CCNc1nc(Cl)c(C#N)c(NC(C)C)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.7 %

Procedure:
To a stirred solution of 6.5 grams of 4,6-dichloro-2-ethylamino-5-pyrimidinecarbonitrile in 100 ml of acetone was added dropwise 7.4 grams of isopropylamine in 30 ml of acetone. Upon complete addition, the reaction mixture was stirred at room temperature for 16 hours. The acetone was removed by evaporation under reduced pressure, and the solid residue was washed with water. The resultant solid was collected by filtration to give 6.8 grams of 4-chloro-2-ethylamino-6-isopropylamino-5-pyrimidinecarbonitrile; mp 160°-165°. Recrystallization from a mixture of benzene and methylcyclohexane gave purified product; mp, 163°-165°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5](Br)=[C:4]([CH3:11])[N:3]=1.[F:12][C:13]([F:28])([F:27])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:16]2[CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=[C:14]([C:13]([F:12])([F:28])[F:27])[CH:15]=2)=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1nc(N)c(C#N)nc1Br
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1nc(N)c(C#N)nc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
This compound is prepared in a manner analogous to that of Step A of Example 4, using 1.7 grams (0.008 mole) of 2-amino-3-cyano-5-bromo-6-methylpyrazine, 3.2 grams (0.012 mole) of 3,5-di(trifluoromethyl)phenylboronic acid, 4.3 grams (0.031 mole) of potassium carbonate and 0.3 gram of tetrakis(triphenylphosphine)palladium(0) in 150 mL of toluene, yielding 2-amino-3-cyano-5-[3,5-di(trifluoro-methyl)phenyl]-6-methylpyrazine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@@H:4]([N:12]1[CH:17]=[C:16](Br)[CH:15]=[C:14]([NH:19][C:20](=[O:31])[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[C:13]1=[O:32])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.B(O)(O)[C:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][CH:36]=1.[F-].[Cs+]>O1CCCC1.C(OCC)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:1][O:2][C:3](=[O:33])[C@@H:4]([N:12]1[CH:17]=[C:16]([C:43]2[C:44]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:40]=[CH:41][CH:42]=2)[CH:15]=[C:14]([NH:19][C:20](=[O:31])[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[C:13]1=[O:32])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)n1cc(Br)cc(NC(=O)c2ccc(C(F)(F)F)cc2)c1=O
Reactant: OB(O)c1cccc2ccccc12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccccc1)n1cc(-c2cccc3ccccc23)cc(NC(=O)c2ccc(C(F)(F)F)cc2)c1=O
Temperature: 25 °C
Yield: 80.8 %

Procedure:
A mixture of (S)-2-[5-bromo-2-oxo-3-(4-trifluoromethylbenzoylamino)-2H-pyridin-1-yl]-3-phenylpropionic acid methyl ester from Step E (66.8 mg, 0.128 mmol), 1-naphthyleneboronic acid (44.0 mg, 0.256 mmol), cesium fluoride (97 mg, 0.64 mmol), tris(dibenzylideneacetone)dipalladium(0) chloroform complex (13.0 mg, 0.013 mmol) and bis(tri-t-butylphosphine)palladium(0) (16.0 mg, 0.031 mmol) in tetrahydrofuran (2.0 mL) was heated to reflux for 15 h. The reaction mixture was cooled to room temperature, diluted with diethyl ether (100 mL), washed with saturated ammonium chloride solution and brine. The organic layer was separated, dried with sodium sulfate, filtered and concentrated. Purification by medium pressure liquid chromatography on silica gel (1:5 ethyl acetate/hexanes) gave 59 mg (81%) of the title compound as a semisolid. MS 571.2 (M+H)+.
Reaction SMILES: O[CH:2]1O[C:5](=[O:7])[C:4]2[CH:8]=[C:9]3[C:14](=[C:15]([O:16][CH3:17])[C:3]1=2)[CH:13]=[CH:12][CH:11]=[CH:10]3.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][C:22]1[CH:21]=[CH:20][C:19]([N:18]2[C:5](=[O:7])[C:4]3[CH:8]=[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]4=[C:15]([O:16][CH3:17])[C:3]=3[CH2:2]2)=[CH:24][CH:23]=1)[CH3:30]
Reactant: COc1c2c(cc3ccccc13)C(=O)OC2O
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(N2Cc3c(cc4ccccc4c3OC)C2=O)cc1
Reaction time: 24 h
Yield: 54.5 %

Procedure:
3-Hydroxy-4-methoxynaphtho[2,3-c]furan-1(3H)-one (50 mg, 0.22 mmol) and ethyl 4-aminophenylacetate (47 mg, 0.26 mmol) in dichloromethane (5 ml) were stirred at room temperature under nitrogen for 1 hour. Sodium triacetoxyborohydride (138 mg, 0.66 mmol) was added and stirring continued for 24 h. The reaction was adjusted to pH14 with sodium hydroxide solution (2N) and extracted with dichloromethane (3×5 ml). The combined extracts were evaporated under vacuum and the residue triturated with cyclohexane/ether to give ethyl[4-(4-methoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetate as a white solid (45 mg, 54%).