Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[CH:16])[CH2:10][C@H:9]1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([CH3:25])[CH:19]=1)=[O:7].Cl.[CH3:36][C:37]1([CH3:43])[CH2:42][O:41][CH2:40][CH2:39][NH:38]1.C=O.[CH:46](N(C(C)C)CC)(C)C>O1CCOCC1.[Cu]I>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:46][N:38]2[CH2:39][CH2:40][O:41][CH2:42][C:37]2([CH3:43])[CH3:36])[CH2:10][C@H:9]1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([CH3:25])[CH:19]=1)=[O:7]
Reactant: CC1(C)COCCN1
Reactant: CCN(C(C)C)C(C)C
Reactant: C#CCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc(C)c(C)c2)C1
Agent: [Cu]I
Agent: C=O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(C[C@@H]2CN(CC#CCN3CCOCC3(C)C)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(2-propynyl)piperazine (0.49 g), 3,3-dimethylmorpholine hydrochloride (0.185 g), paraformaldehyde (62 mg), diisopropylethylamine (0.21 ml), and copper (1) iodide (20 mg) in 1,4-dioxane (5 ml) was stirred at 70° C. for 1.5 hours. After removal of the solvent by evaporation, the residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (40:1). The fractions containing the objective compound was collected and evaporated under reduced pressure to give a syrup of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-(3,3-dimethylmorpholino)-2-butynyl]piperazine (0.45 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:27]=[C:26]4[C:22]([C:23]([CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:24][NH:25]4)=[CH:21][CH:20]=3)[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].I[CH3:38]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:27]=[C:26]4[C:22]([C:23]([CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])=[CH:24][N:25]4[CH3:38])=[CH:21][CH:20]=3)[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CI
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(CCC(=O)OC(C)(C)C)c[nH]c4c3)no2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(CCC(=O)OC(C)(C)C)cn(C)c4c3)no2)cc1Cl
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% in mineral oil, 7.47 mg) was added to a solution of 1,1-dimethylethyl 3-[6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D17) (150 mg) in dry DMF (4 mL) at RT. After stirring for 5 min, iodomethane (0.029 mL) was added. The resulting solution was stirred at RT for 1.2 hours. Another portion of sodium hydride (4 mg) was added. After stirring for 5 min, methyliodide (0.015 mL) was added, and the resulting solution was stirred for 1 hour. DMF was evaporated. EtOAc (50 mL) was added and the resulting solution was washed with aqueous HCl (40 mL), followed by water (100 mL). The organic fraction was dried over anhydrous magnesium sulfate. The dried solution was concentrated. The residue was purified by Biotage (25% EtOAc in hexane) to afford 1,1-dimethylethyl 3-[6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]propanoate (D18) (113 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.38 (15H, m), 2.58 (2H, t), 2.93 (2H, t), 3.85 (3H, s), 4.89 (1H, m), 7.32 (1H, br s), 7.45 (1H, d), 7.75 (2H, m), 8.15 (2H, m), 8.22 (1H, d). MS (ES): C27H30ClN3O4 requires 495; found 496.0 (M+H+).
Reaction SMILES: Cl[C:2]1C=CC(C2C3C(=O)N(C)C=CC=3C3C(C)=NOC=3CN=2)=CC=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]3[NH:46][C:45](=[O:47])[CH:44]=[CH:43][C:34]=3[C:35]3[C:41]([CH3:42])=[N:40][O:39][C:36]=3[CH2:37][N:38]=2)=[CH:28][CH:27]=1.ClC1C=CC(C2C3C(=O)NC=CC=3C3C(C)=NOC=3CN=2)=CC=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]3[N:46]([CH3:2])[C:45](=[O:47])[CH:44]=[CH:43][C:34]=3[C:35]3[C:41]([CH3:42])=[N:40][O:39][C:36]=3[CH2:37][N:38]=2)=[CH:28][CH:27]=1
Reactant: Cc1noc2c1-c1ccn(C)c(=O)c1C(c1ccc(Cl)cc1)=NC2
Reactant: Cc1noc2c1-c1ccc(=O)[nH]c1C(c1ccc(Cl)cc1)=NC2
Agent: Cc1noc2c1-c1cc[nH]c(=O)c1C(c1ccc(Cl)cc1)=NC2
Product: Cc1noc2c1-c1ccc(=O)n(C)c1C(c1ccc(Cl)cc1)=NC2

Procedure:
A procedure similar to 6-(4-chlorophenyl)-1,8-dimethyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7(8H)-one was followed, except that 6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[3,2-e]azepin-8(7H)-one was used as starting material instead of 6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7(8H)-one. LC/MS m/z 340 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J=9.56 Hz, 1H), 7.48 (d, J=8.93 Hz, 2H), 7.35 (d, J=8.52 Hz, 2H), 6.82 (d, J=9.35 Hz, 1H), 5.32 (d, J=12.46 Hz, 1H), 4.15 (d, J=12.7 Hz, 1H), 2.95 (s, 3H), 2.50 (s, 3H).
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].CCN(CC)CC.[ClH:24].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=1>CO>[ClH:24].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:9]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][C:2]([CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[N:34]2)=[CH:29][CH:28]=1
Reactant: O=C(O)CCC(=O)CC(=O)c1cccnc1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(-n2nc(CCC(=O)O)cc2-c2cccnc2)cc1
Yield: 52 %

Procedure:
Compound 29 (2.21 g, 10 mM) in methanol (150 ml) containing Et3N (2 ml) was treated with 4-methoxyphenylhydrazine hydrochloride (1.85 g, 10.6 mM) at RT for 4 hr. The solvent was removed in vacuo and the residue was partitioned between 5% NaOH and Et2O. The basic aqueous layer was separated and acidified with 10% HCl to pH 2. Saturated brine was added and the aqueous layer was exhaustively extracted with CH2Cl2. The combined CH2Cl2 layers were concentrated to give the title compound 31 as a tan crystalline solid (Recry. Acetone, 1.87 g, 52%) mp=226°-228° C., MS, m/e 323 (M+).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:20][N:21]1[C:27](=[O:28])[N:26]2[CH2:29][C@H:22]1[CH2:23][CH2:24][C@H:25]2[C:30]([OH:32])=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:33]([NH:35][NH2:36])=[O:34].CCOC(C)=O>C1COCC1.[Cl-].[Na+]>[CH2:13]([O:20][N:21]1[C:27](=[O:28])[N:26]2[CH2:29][C@H:22]1[CH2:23][CH2:24][C@H:25]2[C:30]([NH:36][NH:35][CH:33]=[O:34])=[O:32])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: NNC=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=CNNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 190.9 %

Procedure:
1,1′-Carbonyldiimidazole (5.8 g, 36.2 mmol) was added to a 0° C. solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (5.0 g, 18.1 mmol) in dry THF (200 mL). The reaction mixture was allowed to warm to rt then was stirred at rt for 3 hrs. Formohydrazide (5.4 g, 90.5 mmol) was added in one portion, and the reaction mixture was stirred for additional 3 hrs. The mixture was then diluted with saturated sodium chloride and exatracted with EtOAc (3×). The combined organic layer was washed with saturated sodium chloride (2×), dried over Na2SO4, and concentrated to afford crude (2S,5R)-6-(benzyloxy)-N′-formyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (˜11 g), which was directly used in the next step. ESI-MS (EI+, m/z): 319.1 [M+H]+.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[N:17][C:18]3[C:23]([N:24]=2)=[CH:22][C:21]([C:25]([O:27]C)=[O:26])=[CH:20][CH:19]=3)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)=[N:17][C:18]3[C:23]([N:24]=2)=[CH:22][C:21]([C:25]([OH:27])=[O:26])=[CH:20][CH:19]=3)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCN(C(=O)c4ccccc4)CC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCN(C(=O)c4ccccc4)CC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a solution of methyl 3-(4-benzoylpiperazin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (130 mg, 0.27 mmol) in methanol (15 ml) was added NaOH (37 mg, 0.93 mmol) in water (1 ml). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (15 ml) and adjusted to pH 5 with hydrochloric acid (1N). The solids were collected by filtration to afford 3-(4-benzoylpiperazin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a yellow solid (53.0 mg, 42%).
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>>[Cl:11][CH2:12][C:13]1[N:10]=[C:1]([CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[O:9][CH:15]=1
Reactant: CCOC(=O)CCC(N)=O
Reactant: O=C(CCl)CCl
Product: CCOC(=O)CCc1nc(CCl)co1
Yield: 7.2 %

Procedure:
In substantially the same manner as in Reference Example 31, ethyl succinamidate was allowed to react with 1,3-dichloroacetone to give ethyl 4-chloromethyl-2-oxazolepropionate as an oily product. The yield was 7.2%.
Reaction SMILES: [I:1][CH2:2][CH2:3][C:4]([F:7])([F:6])[F:5].[C:8]1([P:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[I-:1].[F:5][C:4]([F:7])([F:6])[CH2:3][CH2:2][P+:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: FC(F)(F)CCI
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: FC(F)(F)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [I-]
Temperature: 0 °C
Reaction time: 28 h
Yield: 79.8 %

Procedure:
To a solution of 1-iodo-3,3,3-trifluoropropane (19.3 g, 86.1 mmol) in toluene (50 mL) at 23° C. was added triphenylphosphine (25.8 g, 98.5 mmol). The reaction mixture was warmed to reflux and stirred for 28 h. The resulting mixture was cooled to 0° C. in an ice bath and filtered to collect the white solid product. The product was washed with toluene (3×) and air-dried to afford the pure product as white solid (33.4 g, 80%).
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](/[CH3:17])\[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:16])/[CH2:9][CH2:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13].[C:18]([O:22][CH3:23])(=[O:21])[CH2:19][SH:20].C(N(CC)CC)C>CO>[OH:1][CH2:2]/[CH:3]=[C:4](/[CH3:17])\[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:16])/[CH2:9][CH2:10][C:11](=[O:15])[CH:12]([CH3:14])[CH2:13][S:20][CH2:19][C:18]([O:22][CH3:23])=[O:21]
Reactant: C=C(C)C(=O)CC/C(C)=C/CC/C(C)=C\CO
Reactant: COC(=O)CS
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CSCC(C)C(=O)CC/C(C)=C/CC/C(C)=C\CO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4 g (0.0017 mol) of (6E,10Z)-12-hydroxy-2,6,10-trimethyl-1,6,10-dodecatrien-3-one in 13 ml of methanol is treated with 4.7 ml of methyl thioglycolate and 7.1 ml of triethylamine. The solution is stirred at room temperature for 18 hours under argon. After removing the solvent the residue is worked-up with water and methylene chloride. The organic phase is dried and freed from solvent. The residue is chromatographed on silica gel with ether. There is obtained methyl [[(6E,10Z)-12-hydroxy-2,6,10-trimethyl-3-oxo-6,10-dodecadienyl]thio]acetate which has the following bands in the IR spectrum: 1736 cm-1, 1711 cm-1, 1437 cm-1, 1408 cm-1, 1281 cm-1, 1137 cm-1, 1007 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([NH:21][C:22]3[CH:40]=[CH:39][C:25]([C:26]([N:28]4[CH2:33][CH2:32][CH2:31][C@@H:30]([C:34]([O:36]CC)=[O:35])[CH2:29]4)=[O:27])=[CH:24][CH:23]=3)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[C:10]([CH3:41])[CH:9]=2)=[N:6][CH:7]=1.C(O)C.[OH-].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([NH:21][C:22]3[CH:40]=[CH:39][C:25]([C:26]([N:28]4[CH2:33][CH2:32][CH2:31][C@@H:30]([C:34]([OH:36])=[O:35])[CH2:29]4)=[O:27])=[CH:24][CH:23]=3)[CH2:15][CH2:16][C:17]([F:19])([F:18])[F:20])=[C:10]([CH3:41])[CH:9]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)[C@@H]1CCCN(C(=O)c2ccc(NC(CCC(F)(F)F)c3ccc(-c4ncc(Cl)cn4)cc3C)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(-c2ncc(Cl)cn2)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)N2CCC[C@@H](C(=O)O)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
To a reaction mixture of ethyl (3R)-1-(4-((1-(4-(5-chloropyrimidin-2-yl)-2-methylphenyl)-4,4,4-trifluorobutyl)amino)benzoyl)piperidine-3-carboxylate (8.88 g), ethanol (30 mL) and tetrahydrofuran (30 mL) was added 1M aqueous sodium hydroxide solution (30.2 ml) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was neutralized with 1M hydrochloric acid at 0° C., and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was washed with ethyl acetate/diisopropyl ether to give the title compound (6.52 g) as a white solid.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][C:9]1[NH:14][C:13](=[O:15])[NH:12][C:11](=[O:16])[C:10]=1[Cl:17])SC)#[N:2].[CH3:18][NH2:19]>C(O)C>[C:1]([NH:3][C:4]([NH:19][CH3:18])=[N:7][CH2:8][C:9]1[NH:14][C:13](=[O:15])[NH:12][C:11](=[O:16])[C:10]=1[Cl:17])#[N:2]
Reactant: CSC(=NCc1[nH]c(=O)[nH]c(=O)c1Cl)NC#N
Reactant: CN
Solvent: CCO
Product: CNC(=NCc1[nH]c(=O)[nH]c(=O)c1Cl)NC#N
Temperature: 50 °C
Yield: 9 %

Procedure:
Next, 150 mg of the N-cyano-N′-(5-chlorouracil-6-ylmethyl)-S-methylisothiourea were suspended in ethanol (3 ml), followed by the addition of 2 ml of a 30% solution of methylamine in ethanol. The resulting mixture was heated at 50° C. for 3.5 hours under stirring. After an insoluble matter was filtered off, the filtrate was allowed to cool back to room temperature. A precipitate from the filtrate was collected by filtration, whereby 12 mg of the title compound were obtained (yield: 9%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5](Br)=[CH:4][N:3]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].CCN(C(C)C)C(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5](/[CH:12]=[CH:11]/[C:10]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]([CH3:8])[CH:7]=1
Reactant: C=CC(=O)OCC
Reactant: Cc1cc(N)ncc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C/c1cnc(N)cc1C
Temperature: 25 °C
Yield: 58.4 %

Procedure:
To a stirred solution of 2-amino-5-bromo-4-methylpyridine (10 g, 54 mmole) in propionitrile (50 mL) was added ethyl acrylate (17 mL, 157 mmole), DIEA (19 mL, 106 mmole), palladium(II) acetate (0.61 g, 2.7 mmole) and tri-o-tolylphosphine (1.64 g, 5.4 mmole). The reaction was purged with argon and heated at reflux for 6 hr, then was cooled to RT and concentrated to dryness under vacuum. The resulting residue was taken up in ethyl acetate and filtered through a pad of silica gel. The filtrate was concentrated and the remaining residue was triturated with 1:1 Et2O/petroleum ether (50 mL), filtered, and dried under vacuum to give the title compound (6.50 g, 59%) as a pale yellow solid: 1HNMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.66 (d, J=16.0 Hz, 1H), 6.40 (br s, 2H), 6.32 (d, J=16.0 Hz, 1H), 6.28 (s, 1H), 4.15 (q, 2H), 2.24 (s, 3H), 1.24 (t, 3H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][CH2:17][CH3:18])(=[O:15])[CH3:14].[Br:19][C:20]1[CH:37]=[CH:36][C:23]([O:24][C:25]2[CH:35]=[CH:34][C:28]([O:29][CH:30]([CH3:33])[CH:31]=[O:32])=[CH:27][CH:26]=2)=[C:22]([F:38])[CH:21]=1.[NH4+].[Cl-]>CCOCC.CCCCCC>[CH2:17]([O:16][C:13](=[O:15])[CH2:14][CH:31]([OH:32])[CH:30]([O:29][C:28]1[CH:34]=[CH:35][C:25]([O:24][C:23]2[CH:36]=[CH:37][C:20]([Br:19])=[CH:21][C:22]=2[F:38])=[CH:26][CH:27]=1)[CH3:33])[CH3:18]
Reactant: CCOC(C)=O
Reactant: CC(C=O)Oc1ccc(Oc2ccc(Br)cc2F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: CCOC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(Br)cc2F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
A solution of 1.54 ml (11 mmol) of diisopropylamine in 20 ml of ether was cooled under N2 to -78° C. and 6.9 ml (11 mmol) of 1.6M n-butyllithium in hexane was slowly added. After 15 min of -78° C. 0.97 g (11 mmol) of ethyl acetate in 3 ml of ether was added dropwise. The resulting mixture was stirred at -78° C. for 15 min when a solution of 3.39 g (10 mmol) of 2-(4-(4-bromo-2-fluorophenoxy)phenoxy)propanaldehyde in 5 ml of ether was slowly added. The mixture was allowed to warm to room temperature, poured into aqueous NH4Cl and the aqueous phase separated and extracted with ether. The combined organic layers were dried over MgSO4 and evaporated to dryness and the residue purified by prep LC, eluting with 85:15 hexane:acetone. The resulting colorless oil was thoroughly dried to leave 2.99 g of product. Structure was confirmed by IR and NMR analysis. Calc. for C17H20BrFO5 : C, 53.41, H, 4.72. Found: C, 53.10, H, 4.66.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:16][C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[OH:18])=[CH:9][CH:8]=1)(=O)=O.[F:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][C:41]=1[C:42]([O:44][CH3:45])=[O:43].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.O.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>[C:29]([O:28][C:26]([N:15]([CH2:16][C@@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[OH:18])[CH2:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:38]2[CH:39]=[CH:40][C:41]([C:42]([O:44][CH3:45])=[O:43])=[C:36]([F:35])[CH:37]=2)=[CH:8][CH:9]=1)=[O:27])([CH3:31])([CH3:32])[CH3:30]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(OS(=O)(=O)C(F)(F)F)cc1)C[C@H](O)c1cccc(Cl)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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)cc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
To a solution of 4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenyl trifluoromethanesulfonate (300 mg) in 1,2-dimethoxyethane (5 ml) was added [3-fluoro-4-(methoxycarbonyl)phenyl]boronic acid (125 mg), tetrakis(triphenylphosphine)palladium (53 mg) and aqueous solution of sodium carbonate (2M, 0.6 ml), and the mixture was stirred at 80° C. for 2 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=3/1) to give methyl 4′-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-3-fluoro-1,1′-biphenyl-4-carboxylate (230 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][CH3:23])[CH:15]=3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH2:24]([C@@H:28]1[O:30][C@H:29]1[CH2:31]O)[CH2:25][CH2:26][CH3:27]>[C@H]1(C(O)=O)O[C@@H]1C(O)=O>[CH2:24]([C@@H:28]1[O:30][C@H:29]1[CH2:31][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][CH3:23])[CH:15]=3)=[N:12][CH:13]=2)=[CH:6][CH:7]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCOc1cccc(-c2ncc(-c3ccc(O)cc3)cn2)c1
Reactant: CCCC[C@@H]1O[C@H]1CO
Agent: O=C(O)[C@H]1O[C@@H]1C(=O)O
Product: CCCC[C@@H]1O[C@H]1COc1ccc(-c2cnc(-c3cccc(OCCC)c3)nc2)cc1

Procedure:
5-(4-Hydroxyphenyl)-2-(3-propoxyphenyl)pyrimidine and (2S,3S)-3-butyloxiran-2-ylmethanol(preparation described in EP-0 046 033 and Journal of the American Chemical Society, Volume 109, 1987, page 5765) are reacted analogously to Example 1 to give 5-[4-((2S,3S)-3-butyloxiran-2-ylmethoxy)phenyl]-2-(3-propoxyphenyl)pyrimidine. ##STR43##
Reaction SMILES: CC1C=CC(S(O[C@H:12]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[C:26]4[C:22]([C:23](S(C)=O)=[CH:24][N:25]4[C:28]4[N:33]=[CH:32][C:31]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[F:40])=[CH:30][N:29]=4)=[CH:21][CH:20]=3)=[O:18])[CH2:13]2)(=O)=O)=CC=1.[CH3:44][S:45](C)(=[O:47])=[O:46].ClC1C=C(C=CC=1)C(OO)=O.[N-:60]=[N+]=[N-].[Na+]>>[NH2:60][C@@H:12]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:27]=[C:26]3[C:22]([C:23]([S:45]([CH3:44])(=[O:47])=[O:46])=[CH:24][N:25]3[C:28]3[N:29]=[CH:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[F:40])=[CH:32][N:33]=3)=[CH:21][CH:20]=2)=[O:18])[CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCN(C(=O)c3ccc4c(S(C)=O)cn(-c5ncc(-c6ccccc6F)cn5)c4c3)C2)cc1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(C)(=O)=O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Product: CS(=O)(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CC[C@@H](N)C3)ccc12

Procedure:
The target compound was obtained in three chemical steps from 68a). In the first step, compound 68a) was oxidized to the corresponding methylsulfone with use of m-chloroperoxybenzoic acid. The methylsulfone was then reacted with sodium azide and afterwards hydrogenated in analogy to the procedures 68b) and 68c), respectively. White solid. Yield: 75 mg. HPLC-MS (method 4): Rt=2.72 min; m/z [M+H]+=479.9
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]3[CH2:14][CH2:15][N:16]([CH3:19])[C:17](=[O:18])[CH:10]3[CH2:9]2)=[CH:6][C:5]([C:20]#[N:21])=[CH:4][C:3]=1[NH:22]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:22][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([N:8]2[CH2:13][CH2:12][N:11]3[CH2:14][CH2:15][N:16]([CH3:19])[C:17](=[O:18])[CH:10]3[CH2:9]2)[C:2]=1[Cl:1])[C:20]#[N:21]
Reactant: CN1CCN2CCN(c3cc(C#N)cc(NC(=O)OC(C)(C)C)c3Cl)CC2C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN2CCN(c3cc(C#N)cc(N)c3Cl)CC2C1=O
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a solution of racemic tert-butyl (2-chloro-5-cyano-3-(8-methyl-9-oxohexahydro-1H-pyrazino[1,2-a]pyrazin-2(6H)-yl)phenyl)carbamate (60 mg, 0.143 mmol) in DCM (1.5 mL) was added 1 mL of TFA. After stirring for 1 h, LC-MS indicated completion. It was concentrated and purification via flash chromatography (0-5% MeOH in DCM, 12 g) gave racemic 3-amino-4-chloro-5-(8-methyl-9-oxohexahydro-1H-pyrazino[1,2-a]pyrazin-2(6H)-yl)benzonitrile (35 mg, 0.109 mmol, 77% yield) as a yellow solid.