Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([CH2:27][NH:28][C:29](=[O:33])[CH:30](Cl)[CH3:31])[CH2:10]1)(C(C)(C)C)(C)C.[O-:34][C:35]#[N:36].[K+].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[OH:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])[C@H:11]([CH2:27][N:28]2[C:29](=[O:33])[CH:30]([CH3:31])[NH:36][C:35]2=[O:34])[CH2:10]1
Reactant: N#C[O-]
Reactant: CC(Cl)C(=O)NC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1NC(=O)N(C[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
A solution of (2S,4R)-4-(t-butyldimethylsilyloxy)-2-(2-chloropropionyl)aminomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (18.4 g), potassium cyanate (14.9 g) and tetrabutylammonium iodide (13.6 g) in N,N-dimethylformamide (180 ml) was stirred at 100°-110° C. for 3 hours. The reaction mixture was poured into water (300 ml) and extracted twice with ethyl acetate (200 ml). The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was dissolved in a mixture of methanol (150 ml) and conc. hydrochloric acid (6.1 ml). The solution was stirred at ambient temperature for 2 hours and evaporated in vacuo. The resulting residue was chromatographed on silica gel (250 g) eluting with a mixture of chloroform and methanol (19:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-4-hydroxy-2-(4-methyl-2,5-dioxoimidazolidin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (8.16 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:14]=[C:13]([CH2:15][CH2:16][CH:17]=O)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=1[CH2:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][N:27]3[CH2:26][CH2:25][N:24]([CH2:23][C:22]4[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=4[C:20]([F:34])([F:35])[F:19])[CH2:29][CH2:28]3)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=CCCc1cc(-c2cccc([N+](=O)[O-])c2)no1
Reactant: FC(F)(F)c1ccccc1CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(-c2cc(CCCN3CCN(Cc4ccccc4C(F)(F)F)CC3)on2)c1
Yield: 81.1 %

Procedure:
About 2 min after dissolving 3-[3-(3-nitrophenyl)isoxazol-5-yl]propanal (10 mg, 0.04 mmol) and 1-[2-(trifluoromethyl)benyl]piperazine (8.4, 0.04 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (26 mg, 0.12 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 4.8 hr and followed the same processes as in Example 1 to obtain 15.4 mg (79.9%) of the target compound.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][C:6]1([CH2:23][CH2:24][CH3:25])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH:8]([CH3:22])[O:7]1)=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][C:14]=3[F:21])C.[OH-].[Na+]>C1COCC1.CO>[C:19]([C:17]1[CH:16]=[CH:15][C:14]([F:21])=[C:13]2[C:18]=1[C:10]1[CH2:9][CH:8]([CH3:22])[O:7][C:6]([CH2:5][C:4]([OH:26])=[O:3])([CH2:23][CH2:24][CH3:25])[C:11]=1[NH:12]2)#[N:20]
Reactant: CCCC1(CC(=O)OCC)OC(C)Cc2c1[nH]c1c(F)ccc(C#N)c21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCC1(CC(=O)O)OC(C)Cc2c1[nH]c1c(F)ccc(C#N)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of (5-cyano-8-fluoro-3-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic Acid Ethyl Ester (156 mg, 0.435 mmol) in THF/MeOH (1.5 mL/1.5 mL) was added 1 N NaOH (0.871 mL, 0.871 mmol). The reaction mixture was stirred at ambient temperature overnight. The most of THF/MeOH was removed under reduced pressure and the resulting mixture was acidified with 1 N HCl. The mixture was extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (20 mL), dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC to give 125 mg (87%) of title compound as a white solid. LCMS retention time: 2.775 minutes, [M+H]+ calculated for C18H20FN2O3 331.36, found 331.10, [M−1]+ calculated for C18H18FN2O 329.36, found 329.10.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)[CH2:11][C:12]#[CH:13].C(N(CC)CC)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:20]1([N:17]2[CH2:16][CH2:15][N:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]3[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=3)[CH2:19][CH2:18]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C#CCCN1CCN(c2ccccc2)CC1
Reactant: O=Cc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=Cc1ccc(C#CCCN2CCN(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.3 %

Procedure:
A mixture of 4-bromobenzaldehyde (4.05 g), 1-but-3-ynyl-4-phenylpiperazine (Step A) (4.69 g), triethylamine (9.2 mL), bis (triphenylphosphine)palladium dichloride (0.31 g) and copper (I) iodide (0.08 g) in acetonitrile (100 mL) is degassed with nitrogen and stirred at room temperature for 16 hours. The solvent is evaporated and the residue is dissolved in dichloromethane (200 mL), washed with 2N sodium carbonate (150 mL), dried over MgSO4, filtered and evaporated to leave a brown oil. This oil is purified by MPLC on silica gel eluting with 15% then 30% ethyl acetate (EtOAc)/hexanes to give 4.2 g of the title compound as a yellow waxy solid.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CC#N>[CH2:19]([O:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1ccccc1OCc1ccccc1
Yield: 94.71 %

Procedure:
To a solution of 68 (5.8 g, 34.9 mmol) in CH3CN (150 ml) was added K2CO3 (10.6 g, 76.8 mmol). The mixture was added benzyl bromide (6.57 g, 38.39 mmol) and refluxed for 8 h under N2 atmosphere. The reaction mixture was cooled to 25° and poured into H2O (500 ml), and then extracted with CH2Cl2. The organic layer was washed with H2O, dried over MgSO4 and evaporated. The crude products were purified by distillation to give 73 as colorless liquid. (8.5 g, 33.2 mmol). Yield: 94.71%; MS (EI, 70 eV): m/z 256.3 (M+); 1H-NMR (CDCl3, 200 MHz): δ 1.33=(t, J=7.2 Hz, 3H), 4.35 (q, =7.2, 7.0 Hz, 2H), 5.15 (s, 2H), 7.00 (d, =8.0 Hz, 2H), 7.32-7.45 (m, 5H), 7.49 (d, J=8.2 Hz, 1H), 7.82 (dd, J=8.2, 1.8 Hz, 1H); 13C-NMR (CDCl3, 50 MHz) δ: 166.60, 158.01, 136.77, 133.25, 131.69, 128.49, 127.80, 126.99, 121.20, 120.56, 113.75, 70.57, 60.93, 14.29; Anal. Calcd for C16H16O3: C, 74.98; H, 6.29.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:26])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:13]([CH2:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:16])[C@@H:12]([OH:24])[CH2:11][C@H:10]1[OH:25].[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:26])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:13]([CH2:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:16])[C:12](=[O:24])[CH2:11][C@H:10]1[OH:25].[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](CC(=O)CCCCC(=O)O)[C@@H](O)C[C@H]1O
Agent: O=[Cr](=O)=O
Agent: C1CCC(OC2CCCCO2)OC1
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CC(=O)CCCCC(=O)O
Reaction time: 1.5 h

Procedure:
The reaction product from part A, containing 6-keto-PGF1α, bis(tetrahydropyranyl)ether, methyl ester corresponding to formula IV, is oxidized to compound V. A composite from several lots, weighing 0.93 g., in 20 ml. of acetone is treated at -10° C. with 2.0 ml. of Jones reagent. After stirring for 1.5 hr. the reaction mixture is quenched with isopropanol and extracted with diethyl ether. The extract is washed with brine, dried, and concentrated. The residue is subjected to silica gel chromatography, eluting with ethyl acetate (20-50%)-Skellysolve B to yield the formula-V 6-keto-PGE1, bis(tetrahydropyranyl)ether, methyl ester, 0.52 g., having Rf 0.52 (TLC on silica gel in ethyl acetate-Skellysolve B (1:1)); and infrared peaks at 1745 and 1725 cm-1 (free of OH at 3000-3500).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[C:15]1([CH:21]([NH2:29])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:29][CH:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: NC(Cc1ccccc1)c1ccccc1
Solvent: CO
Product: N#CNC(=NC(Cc1ccccc1)c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 56.3 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.60 g, 3.2 mmol) was dissolved in methanol (10 ml), and 1,2-diphenylethylamine (0.69 g, 3.5 mmol) was added. The mixture was stirred at room temperature for 45 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 50 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure to give N-cyano-N'-(1,2-diphenylethyl)-3-pyridinecarboximidamide (0.60 g, 1.8 mmol, yield: 58%) as colorless syrup. Next, to this syrup was added a 5% hydrogen chloride solution in methanol (2.5 ml). The solution was crystallized from a methanol-diethyl ether to give N-cyano-N'-(1,2-diphenylethyl)-3-pyridinecarboximidamide hydrochloride as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH3:20].CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH:20]=[CH:23][N:24]([CH3:26])[CH3:25]
Reactant: Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Temperature: 140 °C
Yield: 90.4 %

Procedure:
A mixture of 3-(2-chloro-phenyl)-6-fluoro-2-methyl-3,4-dihydro-quinazolin-4-one (1.0 g, 3.46 mmol) and dimethylformamide dimethyl acetal (0.92 mL, 6.92 mmol) in dimethylformamide (4 mL) was heated to 140° C. for 24 hours. The reaction was cooled to ambient temperature and concentrated at reduced pressure. The dark residue was triturated with methanol and the bright yellow crystalline solid which formed was collected and dried to give 1.075 g (90%) of 3-(2-chloro-phenyl)-6-fluoro-2-(2-dimethylamino-vinyl)-3,4-dihydro-quinazolin-4-one which had: mp 210-211° C.; 1H NMR δ 7.86 (d, J=12.3 Hz, 1 H), 7.79 (dd, J=3, 8.5 Hz, 1 H), 7.61-7.54 (m, 1 H), 7.51-7.29 (m, 5 H), 4.06 (d, J=12.3 Hz, 1 H), 2.80 (br s, 6 H). Analysis calculated for C18H15ClFN3O: C, 62.89; H, 4.40; N, 12.22. Found: C, 62.75; H, 4.28; N, 12.29.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[CH:16][N:17]4[CH2:22][C:23]([NH2:25])=[O:24])[N:9]=2)=[CH:4][C:3]=1[CH3:26].[F:27][C:28]([F:33])([F:32])[C@H:29]([OH:31])[CH3:30].[H-].[Na+].O>CN(C=O)C>[CH3:26][C:3]1[CH:4]=[C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[CH:16][N:17]4[CH2:22][C:23]([NH2:25])=[O:24])[N:9]=2)[CH:6]=[CH:7][C:2]=1[O:31][C@H:29]([CH3:30])[C:28]([F:33])([F:32])[F:27]
Reactant: Cc1cc(-c2nc(-c3cccc4c3ccn4CC(N)=O)no2)ccc1F
Reactant: C[C@@H](O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2nc(-c3cccc4c3ccn4CC(N)=O)no2)ccc1O[C@H](C)C(F)(F)F
Temperature: 80 °C
Reaction time: 4 h
Yield: 55.2 %

Procedure:
To a solution of 2-{4-[5-(4-fluoro-3-methylphenyl)-1,2,4-oxadiazol-3-yl]-1H-indol-1-yl}acetamide (100 mg) and (2R)-1,1,1-trifluoropropane-2-ol (109 mg) in DMF (3 ml) was added 60% NaH (17 mg) at 0° C., followed by stirring at 80° C. for 4 hours. The reaction solution was added with water (15 ml) to complete the reaction, filtered, and then dried. The obtained powder was purified by silica gel column chromatography (chloroform:CH3OH=100:0 to 95:5), and crystallized with diisopropyl ether to obtain 2-[4-(5-{3-methyl-4-[(1R)-2,2,2-trifluoro-1-methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]acetamide (70 mg) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].ClC1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23]
Reactant: CSc1ccc(NC(C)=O)cc1F
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(Sc2ccc(C)cc2[N+](=O)[O-])c(F)c1
Temperature: 25 °C
Yield: 64.9 %

Procedure:
The product from Example 39c (1.00 g, 5.0 mmol) and t-BuSNa (1.88 g, 15.1 mmol) in anhydrous DMF (10 mL) was heated at 160° C. for 4 hours under N2 flow, and then cooled to room temperature. To the reaction mixture was added 1-chloro-4-methyl-2-nitrobenzene (2.36 mL, 17.6 mmol) at room temperature and then the mixture was heated at 80° C. for 4 hours under N2 flow. The mixture was diluted with H2O and then extracted with EtOAc. The extract washed with H2O and brine, dried over MgSO4, and evaporated. The residue was purified by silica gel column chromatography eluting with 2:1 EtOAc/hexane to give the title compound as yellow crystals (1.04 g, 65%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])([O-])=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[NH2:14])(=[O:25])=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccccc2N)CC1
Yield: 82 %

Procedure:
The title compound (2 g, 82%) was obtained as a white solid from piperazine-1-carboxylic acid tert-butyl ester and 2-nitrobenzenesulfonyl chloride following the same procedure as described in Preparation 2.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.[CH3:19][O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH2:23].CN(C)CCCN=C=NCC.[CH2:37]([C:40]1([C:55](O)=[O:56])[CH2:44][CH2:43][CH2:42][N:41]1[C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[CH:38]=[CH2:39]>CN(C=O)C>[CH3:19][O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH:23][C:55](=[O:56])[C:40]1([CH2:37][CH:38]=[CH2:39])[CH2:44][CH2:43][CH2:42][N:41]1[C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46]
Reactant: C=CCC1(C(=O)O)CCCN1C(=O)OCc1ccccc1
Reactant: COC(=O)[C@H](C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C=CCC1(C(=O)N[C@@H](C)C(=O)OC)CCCN1C(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 83.2 %

Procedure:
HOBT (7.7 g), N-methylmorpholine (6.6 g), L-alanine methyl ester hydrochloride (4.5 g) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (5.7 g) was added to (RS)-2-allyl-N-(benzyloxycarbonyl)proline (6.5 g) in DMF (30 ml) and the mixture was stirred for 18 hours and then evaporated. The residue was partitioned between ether and water, filtered to remove HOBt and the organic layer separated. The organic layer was evaporated and the residue was purified by chromatography on silica using a gradient of 20% ethyl acetate in hexane increasing to 50% ethyl acetate in hexane. The appropriate fractions were combined and evaporated to dryness to give [(RS)-2-allyl-N-(benzyloxycarbonyl)prolyl]-(S)-alanine methyl ester (7 g); NMR (d6-DMSO (373K)): some doubling of peaks due to the mixture of diastereoisomers, 1.25 and 1.3 (2d, 3H), 1.75 (m, 2H), 2.2 (m,2H), 2.65 (m, 1H), 2.9 (m, 1H), 3.4 (m, 1H), 3.65 (2s, 3H), 3.7 (m, 1H), 4.3 (2q, 1H), 5.0 (m, 4H), 5.7 (m,1H), 7.3 (m, 5H), 7.4 and 7.5 (bs, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=2)[NH:19][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]([C:29]([CH3:31])=[O:30])=[CH2:28]>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH:28]=[CH:27][C:29](=[O:30])[CH3:31])[CH:24]=2)[NH:19][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(C)=O
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Solvent: CO
Product: CC(=O)C=Cc1ccc2[nH]cc(C[C@H]3CCCN3C(=O)OCc3ccccc3)c2c1

Procedure:
Obtained by a procedure similar to that described in Example 1, from 3-(N-benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5-bromo-1H-indole (Preparation 1) and methyl vinyl ketone, as a foam. Rf 0.60 (SS 7). [α]D25 -51° (c=0.1, CH3OH). Found: C,74.16; H,6.39; N,6.92. C25H26N2O3 requires C,74.60; H,6.51; N,6.96%.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:11]2[C:12](=[O:24])[O:13][C:14]3[C:19]([C:20]=2[CH3:21])=[CH:18][CH:17]=[C:16]([O:22][CH3:23])[CH:15]=3)=[CH:5][N:4]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1C(=O)N([Br:42])C(=O)C1>C1COCC1>[Br:42][CH2:21][C:20]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][CH:18]=2)[O:13][C:12](=[O:24])[C:11]=1[C:6]1[C:7]([O:9][CH3:10])=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=1
Reactant: COc1ccc2c(C)c(-c3cnc(OC)nc3OC)c(=O)oc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(CBr)c(-c3cnc(OC)nc3OC)c(=O)oc2c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-(2,4-dimethoxy-pyrimidin-5-yl)-7-methoxy-4-methyl-chromen-2-one (210 mg, 0.64 mmoL) in anhydrous THF (5 mL) at −78° C. was added LiHMDS (1.0 M, 1.28 mmoL, 1.28 mL) dropwise. The resulting reddish solution was stirred at −78° C. for 20 min. To this solution was added NBS (114 mg, 0.64 mmoL) in THF (2 mL) slowly. The reaction was stirred for 2 hours at −78° C. and then quenched with sat. NaHCO3, warmed to room temperature. THF was removed in vacuo and the residue was partitioned between CH2Cl2 and water. The aqueous phase was extracted 3× with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to afford a yellow solid, which was then purified by silica gel column chromatography using hexanes:ethyl acetate (4:1 to 2:1) to afford the title product as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][CH2:8][CH2:9][CH2:10][S:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][CH:13]=1.O>O1CCCC1>[Cl:7][CH2:8][CH2:9][CH2:10][S:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][OH:17])=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(SCCCCl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(SCCCCl)cc1
Reaction time: 0.75 h
Yield: 85.3 %

Procedure:
5 g of lithium aluminum hydride are suspended in 200 ml of tetrahydrofuran, and a solution of 31.9 g of methyl 4-(3-chloro-propylthio)benzoate in 200 ml of tetrahydrofuran is added thereto at 5° to 15° C. The mixture is stirred at the same temperature for 45 minutes. Water is added to the mixture at a temperature of below 20° C., and insoluble materials are filtered off. The filtrate is concentrated under reduced pressure to remove solvent, and the residue is distilled under reduced pressure. 24.1 g of 4-(3-chloropropylthio)benzylalcohol are obtained as an oil. Yild: 85%.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12](Cl)=[N:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH2:24].[Na]>>[CH2:1]([NH:8][C:9]([C:11]1[C:12]([SH:24])=[N:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccccc1)c1cnc(-c2ccccc2)nc1Cl
Reactant: S
Agent: [Na]
Product: O=C(NCc1ccccc1)c1cnc(-c2ccccc2)nc1S
Yield: 16.2 %

Procedure:
Using the procedure from Preparation 34, 5.8 g (17.9 mol) of 4-chloro-2-phenyl-pyrimidine-5-carboxylic acid benzylamide was reacted with 5.1 g (72 mmol) of sodium hydrogen sulfide to give 3.75 g of the title compound, mp 189°-193° C.
Reaction SMILES: N[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].C([O-])(=O)/C=C/C([O-])=O.[NH4+].[NH4+].[Ca:20]>>[C:7]([O-:9])(=[O:8])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5].[Ca+2:20]
Reactant: [Ca]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: O=C([O-])/C=C/C(=O)[O-]
Agent: [NH4+]
Product: [Ca+2]

Procedure:
A process for the preparation of aspartic acid via a fermentation process for the preparation of ammonium fumarate, wherein the pH of the fermentation broth is controlled by the addition of a calcium base to produce a calcium fumarate precipitate, characterised in that ammonium fumarate is produced by separating said precipitated calcium fumarate from said fermentation broth, and reacting said precipitate with a reagent selected from ammonia, ammonium carbonate, ammonia in combination with CO2 and mixtures thereof, to form ammonium fumarate solution and a co-product selected from calcium carbonate and calcium hydroxide, wherein the energy of indirect neutralisation of fumaric acid by ammonia serves as the driving force for the conversion of calcium fumarate to the desired ammonium fumarate product with a conversion yield of at least 90% and for the regeneration of a calcium base reagent, and wherein said ammonium fumarate product is enzymatically converted to ammonium aspartate and acidulated to form aspartic acid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([CH:26]=O)=[CH:23][CH:24]=2)[N:19]=[C:18]([CH3:28])[CH:17]=1.[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1.C(O)(=O)C>ClCCCl>[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][NH:29][C:30]3[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=3)=[CH:23][CH:24]=2)[N:19]=[C:18]([CH3:28])[CH:17]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(Cl)c2ccc(C=O)cc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1cc(Cl)c2ccc(CNc3ccc(C#N)cc3)cc2n1
Yield: 65 %

Procedure:
Sodium triacetoxyborohydride (74 mg, 0.34 mmol) was added to a solution of 4-chloro-2-methyl-quinoline-7-carbaldehyde (example 13a, 50 mg, 0.24 mmol), 4-aminobenzonitrile (29 mg, 0.24 mmol), and acetic acid (88 mg, 1.5 mmol) in 1,2-dichloroethane (0.5 mL), then after 16 h the reaction mixture was partitioned between ethyl acetate and 2 M aq. sodium hydroxide solution. The organic layer was washed with brine, dried (MgSO4), and evaporated. Flash chromatography (SiO2, hexane/ethyl acetate 1:1) afforded the title compound (48 mg, 64%); White solid, ISP-MS: m/e=308.2 ([M+H]+).