Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18](O)=[O:19])[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18](=[O:19])[N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[O:8][N:9]=2
Reactant: C1CCNC1
Reactant: O=C(O)Cc1cc(Cl)cc2c(-c3ccccc3)onc12
Product: O=C(Cc1cc(Cl)cc2c(-c3ccccc3)onc12)N1CCCC1

Procedure:
The title compound is prepared by reacting the acid chloride of 5-chloro-3-phenyl-2,1-benzisoxazole-7-acetic acid with pyrrolidine in an aprotic solvent and washing the reaction mixture with sodium bicarbonate and isolating the product by crystallization.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][NH2:8])=[CH:5][N:4]=[CH:3]1.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([C:23]2[S:24][C:25]([C:29](O)=[O:30])=[C:26]([CH3:28])[N:27]=2)[C:19](=[O:32])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([C:23]2[S:24][C:25]([C:29]([NH:8][CH2:7][C:6]3[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=3)=[O:30])=[C:26]([CH3:28])[N:27]=2)[C:19](=[O:32])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cn1cncc1CN
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1cncn1C
Yield: 52 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use (1-methyl-1H-imidazol-5-yl)methanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 52% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.65-8.58 (m, 2H), 7.51 (s, 1H), 7.44-7.30 (m, 5H), 6.78 (s, 1H), 6.38 (dd, J=8.1, 2.6 Hz, 1H), 6.22 (d, J=2.6 Hz, 1H), 5.15 (s, 2H), 4.36 (d, J=5.3 Hz, 2H), 3.58 (s, 3H), 2.52 (s, 3H); MS (ES+) m/z 436.2 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].Cl.C[CH:10](C(Cl)=O)[C:11](Cl)=[O:12].[C:17](=O)([O-])[OH:18].[Na+]>C(Cl)Cl>[CH3:17][O:18][C@@H:7]1[CH2:6][N:3]2[C@H:4]([CH2:10][C:11](=[O:12])[CH2:2][CH2:1]2)[CH2:5]1
Reactant: O=C([O-])O
Reactant: CC(C(=O)Cl)C(=O)Cl
Reactant: CCN(CC)CC
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CO[C@H]1C[C@H]2CC(=O)CCN2C1
Reaction time: 0.25 h

Procedure:
7.52 ml (54 mmol) of triethylamine were added dropwise with ice-cooling and stirring to a suspension of 4.40 g (22.5 mmol) of (2S,4S)-4-methoxyhomoproline hydrochloride in 100 ml of methylene chloride, followed by the further dropwise addition with ice-cooling of 2.66 ml (24.8 mmol) of methyl malonyl chloride, and the resulting mixture was then stirred for 15 minutes at the same temperature. After the reaction mixture was stirred for a further 2 hours at room temperature, a saturated aqueous solution of sodium hydrogencarbonate was added, the pH value of the separated aqueous layer was adjusted to 2 by the addition of concentrated hydrochloric acid, and then the mixture was extracted with a 4:1 by volume mixture of methylene chloride and isopropanol. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure to afford 5.83 g (yield: quantitative) of the title compound as a brown oil.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]2[C:12](=[O:15])[NH:13][N:14]=[C:4]2[C:3]1=[O:16].[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(O)(=O)C>[C:17]([N:13]1[C:12](=[O:15])[N:5]2[C:6]3[CH:11]=[CH:10][CH:9]=[N:8][C:7]=3[N:2]([CH3:1])[C:3](=[O:16])[C:4]2=[N:14]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(=O)c2n[nH]c(=O)n2c2cccnc21
Solvent: CC(=O)O
Product: CC(=O)n1nc2c(=O)n(C)c3ncccc3n2c1=O

Procedure:
A mixture of 1.8 g. of 5-methyl-pyrido(2,3-e)(1,2.4)triazolo(4,3-a)pyrazine-1,4-(2H,5H)dione in 25 ml. of acetic anhydride and 50 ml. of acetic acid was stirred and refluxed for 5 hours.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.[I:10][CH2:11][CH2:12][CH2:13][CH2:14]I>C(#N)C.CCOC(C)=O>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([CH2:14][CH2:13][CH2:12][CH2:11][I:10])[C:4](=[O:9])[N:3]=1
Reactant: ICCCCI
Reactant: Nc1nc(O)ncc1F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Nc1nc(=O)n(CCCCI)cc1F
Temperature: 70 °C
Reaction time: 16 h
Yield: 43.2 %

Procedure:
To a suspension of 4-amino-5-fluoropyrimidin-2-ol (0.50 g, 3.87 mmol) in acetonitrile (CH3CN; 20 mL) was added BSA (1.58 g, 7.75 mmol), and the mixture was heated to 70° C. for 1 h resulting in a clear solution. After cooling to room temperature, 1,4-diiodobutane (1.2 g, 3.87 mmol) was added, and the mixture was stirred for 16 h at room temperature and then at 70° C. for 3 h. The solvent was evaporated and the residue was purified by normal phase chromatography (24 g SiO2; gradient, 0 to 15% MeOH/CH2Cl2) to give an orange oil. The oil was dissolved in EtOAc and the solution was slowly cooled. The resulting solid was collected by filtration, washed with additional EtOAc, and dried to give 4-amino-5-fluoro-1-(4-iodobutyl)-1H-pyrimidin-2-one (0.52 g, 43%) as a tan solid: mp 181-184° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 2H), 8.25 (d, J=6.7 Hz, 1H), 3.70 (t, J=6.7 Hz, 2H), 3.29 (t, J=6.7 Hz, 2H), 1.73 (m, 4H); ESIMS m/z 312 ([M+H]+).
Reaction SMILES: COC1C=C(OC)C=C(OC)C=1C[NH:6][C:7]1[CH:12]=[C:11](Cl)[N:10]=[CH:9][N:8]=1.[F:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[OH:32].COCCOCCOC>O>[F:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[O:32][C:11]1[N:10]=[CH:9][N:8]=[C:7]([NH2:6])[CH:12]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: COc1cc(OC)c(CNc2cc(Cl)ncn2)c(OC)c1
Solvent: COCCOCCOC
Solvent: O
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Temperature: 160 °C
Reaction time: 4 h
Yield: 25.1 %

Procedure:
A mixture of N-(2,4,6-trimethoxybenzyl)-6-chloropyrimidin-4-amine (2.2 g, 7.11 mmol), 2-fluoro-4-nitrophenol (1.1 g, 7.0 mmol), and 2-methoxyethyl ether (50 mL) was heated at 160° C. for 60 h. The reaction mixture was cooled to RT and poured into H2O (200 mL). The solid was collected, washed with 2 M aqueous Na2CO3 and H2O, and then vacuum dried on a Büchner funnel. The crude product was treated with TFA (20 mL) in dioxane (40 mL) and stirred at RT for 4 h. The reaction mixture was concentrated, the residue partitioned between EtOAc and saturated NaHCO3 solution. The EtOAc phase was separated, dried (MgSO4), concentrated and the crude product purified by flash chromatography using 1-2% MeOH in CH2Cl2 as the eluent to give 6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-amine (440 mg, 31%). 1H NMR (DMSO-d6) δ 8.31 (dd, 1H, J=10.4, 2.5 Hz), 8.14 (dd, 1H, J=9.8, 2.0 Hz), 8.04 (s, 1H), 7.61 (dd, 1H, J=8.3, 8.3 Hz), 7.07 (s, 2H), 6.02 (s, 1H); MS(ESI+) m/z 251.15 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH:9]=[C:8]([O:18][CH3:19])[CH:7]=2)[CH2:3][CH2:2]1.C([N:22](CC)CC)C.[C:27]([O:31][C:32]([N:34]1[CH2:41][CH:40]2[CH2:42][CH:36](C(=O)[O:38][C:39]2=O)[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.[Si](CCO)(C)(C)C>C1COCC1.C1(C)C=CC=CC=1>[C:27]([O:31][C:32]([N:34]1[CH2:41][C@H:40]([C:39](=[O:38])[N:4]([CH:1]2[CH2:2][CH2:3]2)[CH2:5][C:6]2[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH:9]=[C:8]([O:18][CH3:19])[CH:7]=2)[CH2:42][C@H:36]([NH2:22])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CC2CC(C1)C(=O)OC2=O
Reactant: COCCCOc1cc(CNC2CC2)cc(OC)c1
Agent: C[Si](C)(C)CCO
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COCCCOc1cc(CN(C(=O)[C@@H]2C[C@H](N)CN(C(=O)OC(C)(C)C)C2)C2CC2)cc(OC)c1
Reaction time: 2 h
Yield: 12.5 %

Procedure:
To a solution of Cyclopropyl-[3-methoxy-5-(3-methoxy-propoxy)-benzyl]-amine (1.18 g, 4.45 mmol) and triethylamine (0.68 mL, 4.90 mmol) in THF (20 mL) at room temperature is added 2,4-Dioxo-3-oxa-7-aza-bicyclo[3.3.1]nonane-7-carboxylic acid tert-butyl ester (1.07 g, 4.19 mmol). After stirred for 2 h, bulk of the solvent is concentrated. The residue is diluted with EtOAc, and washed with aq. KHSO4, water, and brine, dried over Na2SO4, filtered, and concentrated. To a solution of a part of the residue (673 mg, 1.29 mmol) in toluene (5 mL) at room temperature are added triethylamine (0.2 mL, 1.44 mmol) and DPPA (0.31 mL, 1.43 mmol). After stirred for 40 min, TMSCH2CH2OH (0.9 mL, 6.31 mmol) is added. The reaction mixture is refluxed for 2 h. After dilution with EtOAc, the mixture is washed with aq. KHSO4, water, aq. sat. NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated. The residue is purified by silica gel column chromatography to afford the desired carbamate (332 mg, 0.522 mmol), which is treated with TBAF (410 mg, 1.57 mmol) in THF (5 mL) at 50° C. for 2.5 h. After dilution with EtOAc, the mixture is washed with water (×2) and brine, dried over Na2SO4, filtered, and concentrated to afford the title compound as a pale yellow oil. MS: 491 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 2 min then 100% CH3CN+0.1% TFA for 1 min, flow 0.5 ml/min): 1.67 min.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:13](O)[CH2:14][OH:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:15]1[C:2]2([CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)[O:1][CH2:13][CH2:14]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCC2(CC1)OCCO2
Temperature: 150 °C
Reaction time: 18 h
Yield: 97.6 %

Procedure:
To a solution of ethyl 4-oxocyclohexanecarboxylate (10.0 g, 58.8 mmol) in toluene (196 mL), ethylene glycol (3.6 mL, 64.6 mmol) and p-toluenesulfonic acid monohydrate (1.12 g, 5.88 mmol) were added, and the obtained solution was heated to reflux at 150° C. The resulting solution was stirred for 18 hours. The reaction was quenched by adding a saturated sodium bicarbonate solution to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (12.3 g, 57.4 mmol, 98%) as a colorless oily compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:46]([C:50]1[CH:67]=[CH:66][C:53]([CH2:54][NH:55][CH2:56][CH:57]([C:59]2[CH:64]=[CH:63][C:62]([F:65])=[CH:61][CH:60]=2)[OH:58])=[CH:52][CH:51]=1)([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([C:50]1[CH:67]=[CH:66][C:53]([CH2:54][N:55]([CH2:56][CH:57]([C:59]2[CH:60]=[CH:61][C:62]([F:65])=[CH:63][CH:64]=2)[OH:58])[C:12]([C:9]2[C:10]([F:11])=[C:2]([F:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:52][CH:51]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: O=C(O)c1c(F)c(F)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCC(O)c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(CN(CC(O)c2ccc(F)cc2)C(=O)c2c(F)c(F)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47 %

Procedure:
To a solution of 43 mg (0.22 mmol) of 5,6-difluoro-1H-indole-7-carboxylic acid and 68 mg of TBTU (0.22 mmol) in 2 ml DMF, were added 0.19 ml (1.09 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 66 mg (0.22 mmol) of [rac]-(4-tert-butyl-benzyl)-[2-(4-fluoro-phenyl)-2-hydroxy-ethyl]-amine were added. After stirring for 17 h at rt, the reaction mixture was diluted with 20 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:2) to give 56 mg light yellow foam (47%). MS(ISP): 481.4 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:15][CH2:14][CH2:13][CH2:12][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCCCCl)cc1
Yield: 93.7 %

Procedure:
A mixture of 7.0 g (0.05 mole) of 4-nitrophenol, 15.7 g (0.1 mole) of 1-bromo-3-chloropropane and 20.7 g (0.15 mole) of anhydrous potassium carbonate in 350 ml of acetone was heated at reflux for 17 hr. The mixture was cooled, filtered, and the filtrate was concentrated to give an oil which crystallized. The solid was collected by filtration, washed with petroleum ether, and dried to yield 10.1 g (94%) of the title compound. An analytical sample was prepared from ethyl ether-petroleum ether, m.p. 37°-39° C.
Reaction SMILES: [N:1]([CH:4]([CH3:26])[CH:5]([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[CH2:6][C:7]1[O:11][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)C>O1CCCC1.O>[NH2:1][CH:4]([CH3:26])[CH:5]([C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1)[CH2:6][C:7]1[O:11][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1ccc(CC(c2ccc([N+](=O)[O-])cc2)C(C)N=[N+]=[N-])o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)c1ccc(CC(c2ccc([N+](=O)[O-])cc2)C(C)N)o1
Temperature: 25 °C
Yield: 96.2 %

Procedure:
3.24 g of ethyl 5-{(2RS,3RS)-3-azido-2-(4-nitrophenyl)butyl}-2-furancarboxylate was dissolved in a mixed solution of 50 ml of tetrahydrofuran and 5 ml of water, and 2.37 g of triphenylphosphine was added thereto, followed by heating and refluxing for 6 hours. The reaction solution was left to cool to room temperature, and then ethyl ether and water were added thereto for extraction. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1→20/1) to obtain 2.89 g of the above-identified compound.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[C@H:27]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:34][CH:33]=2)[CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15]C(OCC2C=CC=CC=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:46].[Li+].[CH2:48]([CH2:51][O:52][CH3:53])OC>O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:53]([O:52][CH2:51][C:48]2[CH:26]=[CH:25][CH:9]=[CH:10][CH:11]=2)=[CH:13][CH:12]=1)[C@@H:25]([OH:46])[CH2:26][C@@H:27]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[CH:34][CH:33]=1)[C:28]([OH:29])=[O:30])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H]1C[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)O1
Reactant: COCCOC
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H](O)C[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O

Procedure:
Analogously to Example 1i), 2.7 g (4.43 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)-ethyl]-3(R)-(p-benzyloxyphenylmethyl)dihydrofuran-2-(3H)-one in 59 ml of dimethoxyethane and 31.8 ml of water are hydrolysed with 14.8 ml of 1M lithium hydroxide solution. The reaction mixture, partially concentrated by evaporation, is poured onto a mixture of ice, 181 ml of sat. NH4Cl solution, 16.2 ml of 10% citric acid solution and 400 ml of ethyl acetate, and THF is added until the precipitated solid has dissolved. The aqueous phase is extracted with 2 portions of ethyl acetate, and the organic phases are washed with brine, dried with Na2SO4, concentrated by evaporation and digested in hexane: TLC Rf (A)=0.07.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:47][O:48][C:49](=[O:63])[C@H:50]([NH:53][CH2:54][C:55]1[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=1)[CH2:51][CH3:52]>CN(C=O)C.O>[CH3:47][O:48][C:49](=[O:63])[C@H:50]([N:53]([C:11](=[O:13])[C@@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:10])[CH2:54][C:55]1[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=1)[CH2:51][CH3:52]
Reactant: CC[C@@H](NCc1ccc(OC)cc1)C(=O)OC
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C(=O)OC)N(Cc1ccc(OC)cc1)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a solution of 3.99 g of Boc-L-alanine in 50 ml of DMF were added 12.02 g of HATU, 4.3 ml of Hünig's base and 5.00 g (R)-2-(4-Methoxy-benzylamino)-butyric acid methyl ester. The reation was stirred overnight, and 6.01 g of HATU and 2.1 ml of Hünig's base were added, and the reaction was stirred for 24 h at r.t. and then for 4 h at 50° C. The reaction was poured unto water, the layers were separated and the aqueous phase was extracted with EtOAc twice. The combined organic layers wer washed with 10% aqueous citric acid twice, dried over Na2SO4, fitrered and concentrated in vacuo. The residue was purified by flash chromatography (silica, heptane/EtOAc) to obtain 7.60 g (88%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[CH2:17])[CH2:9][CH:10](O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[NH2:41][C:42]([NH2:44])=[S:43]>C(#N)C>[NH2:44][C:42]1[S:43][CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)([CH3:17])[N:41]=1
Reactant: NC(N)=S
Reactant: C=C(CC(O)C(=O)OCC)c1cccc(Br)c1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: CCOC(=O)C1CC(C)(c2cccc(Br)c2)N=C(N)S1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of ethyl 4-(3-bromophenyl)-2-hydroxypent-4-enoate (5.1 g, 17 mmoles) in acetonitrile (68 mL) is added 2,6-lutidine (2.19 g, 20.4 mmol, 1.2 equiv). The reaction is cooled to 0° C. and trifluoromethanesulfonic anhydride (3.30 mL, 19.6 mmol, 1.15 equiv) is added dropwise over approximately 5 minutes. The mixture is stirred at 0° C. for 20 minutes. Thiourea (2.59 g, 34.0 mmol, 2 equiv) is added and the reaction is warmed to room temperature. After 45 minutes, the mixture is concentrated under reduced pressure. The resulting viscous orange oil is then added via large pipette to stirring sulfuric acid (17.8 M, 8 mL) at room temperature. After 20 minutes, the mixture is added dropwise to a vigorously stirring, 0° C. solution of K2CO3 (ca. 50 g) in 50 mL H2O). Additional water is added to enable stirring upon solid formation during the quench. The tan/orange solid is collected by filtration. The solid is allowed to dry on the filter paper by a stream of air for 1 h to give the title compound as a mixture of diastereomers which is used without further purification: MS (m/z): 357, 359 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[NH4+:17].[NH4+].O.C(OCC)(=O)C>CN(C)C=O>[NH2:17][C:11]1[C:2]([Cl:1])=[N:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=1
Reactant: [NH4+]
Reactant: Clc1nc2ccccc2nc1Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc2ccccc2nc1Cl
Temperature: 60 °C
Reaction time: 72 h
Yield: 26.8 %

Procedure:
2,3-Dichloroquinoxaline (9.90 g, 50.0 mmol) and ammonium carbonate (24.3 g, 300 mmol) were suspended in N,N-dimethylformamide (50 mL) in a stainless steel sealed tube and the mixture was stirred at 60° C. for 72 hours. After water was added to the reaction mixture, extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3). Further, slurry purification was performed using diisopropyl ether, to give 2-amino-3-chloroquinoxaline (2.41 g, yield: 27%).
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([O:19]CC)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]1.C([Li])CCC>CCCCCC.O1CCCC1>[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:17]([C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:16]=1)=[O:19]
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Reactant: CC1CCCCN1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1CCCCN1C(=O)c1nc(-c2ccccc2)nc2ccccc12

Procedure:
The procedure of Example 24 is followed using ethyl 2-phenylquinazoline-4-carboxylate (3 g), 2-methylpiperidine (3 ml), a 1.6M solution of butyllithium in hexane (15 ml) and tetrahydrofuran (20 ml) as the starting materials. After recrystallisation from ethanol, 2-methyl-1-[(2-phenylquinazolin-4yl)-carbonyl]-piperidine (1.7 g), melting at 150° C., is obtained.
Reaction SMILES: [CH2:1]([C:8]1([O:12][C:13]([NH:15][C@@H:16]([CH2:21][CH2:22][CH2:23][CH3:24])[C:17]([O:19]C)=O)=[O:14])[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].[C:28]1([P:34](=[CH:47][C:48]#[N:49])([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>O1CCCC1.O.CN(C)C1C=CN=CC=1>[C:48]([C:47](=[P:34]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:17]([C@@H:16]([NH:15][C:13](=[O:14])[O:12][C:8]1([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10][CH2:11]1)[CH2:21][CH2:22][CH2:23][CH3:24])=[O:19])#[N:49]
Reactant: CCCC[C@H](NC(=O)OC1(Cc2ccccc2)CCC1)C(=O)OC
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCC[C@H](NC(=O)OC1(Cc2ccccc2)CCC1)C(=O)C(C#N)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.7 %

Procedure:
To 2.44 g (7.32 mmol) of methyl(2S)-2-({[(1-benzylcyclobutyl)oxy]carbonyl}amino)hexanoate in 24 mL of tetrahydrofuran:water (1:1) was added 429.9 mg (10.24 mmol) of lithium hydroxide monohydrate and the mixture was stirred at room temperature for 4 h. The solution was concentrated and extracted with diethyl ether. The aqueous layer was acidified with 1 N hydrochloric acid and extracted with diethyl ether. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was dissolver in 36 mL of dichloromethane, then 44.7 mg (365.9 μmol) of 4-dimethylaminopyridine was added. To this solution was added 2.31 g (7.68 mmol) of (triphenylphosphoranylidene)acetonitrile, followed by 1.55 g (8.05 mmol) of 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide, and the mixture was stirred at room temperature for 17 h. Water was added to the solution and it was extracted with ethyl acetate. The organic layer was washed with 10% citric acid, followed by saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with an ethyl acetate:hexanes solution (1:1) to give 3.25 g (74%) of 1-benzylcyclobutyl(1S)-1-[cyano(triphenylphosphoranylidene)acetyl]pentylcarbamate. Rf=0.25 (1:1 ethyl acetate:hexanes); 1H NMR (300 MHz, DMSO-d6) δ 7.75-7.66 (m, 3H), 7.64-7.54 (m, 12H), 7.20-7.14 (m, 5H), 7.03 (d, J=8 Hz, 1H), 4.55-4.50 (m, 1H), 3.21 (m, 2H), 2.24-2.16 (m, 2H), 2.14-2.06 (m, 2H), 1.80-1.70 (m, 2H), 1.70-1.60 (m, 1H), 1.60-1.46 (m, 1H), 1.42-1.24 (m, 4H), 0.89 (t, J=7 Hz, 3H); ES-LCMS m/z 603 (M+H).