Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:32])([F:31])[C:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][N:19]=[N:18]3)=[N:12][CH:13]=2)=C(F)C=1.BrC[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=1>>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C:15]([OH:22])([CH2:16][N:17]1[CH:21]=[N:20][N:19]=[N:18]1)[C:14]([F:31])([F:32])[C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:6][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=2)=[CH:13][N:12]=1
Reactant: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(OCc2ccc(Cl)cc2F)cn1
Reactant: Fc1cccc(CBr)c1
Product: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(OCc2cccc(F)c2)cn1

Procedure:
Compound 3 was prepared in a similar manner to compound 1 from 1-(bromomethyl)-3-fluorobenzene to afford a syrup (0.02 g, 0.04 mmol, 15.5%). 1H NMR (500 MHz, CDCl3): δ 8.73 (s, 1H), 8.25 (d, J=2.5 Hz, 1H), 7.52 (t, J=3.5 Hz, 2H), 7.40-7.26 (m, 3H), 7.17 (d, J=9.5 Hz, 1H), 7.12-7.04 (m, 2H), 6.77-7.6.75 (m, 1H), 6.66 (t, J=9.0 Hz, 1H), 5.56 (d, J=14.0 Hz, 1H), 5.12 (s, 2H), 5.06 (d, J=14.5 Hz, 1H). MS (ESI): m/z 478.2 [M++1]. HPLC: 99.49%.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:18]([O:20][CH3:21])=[O:19])=[CH:5][C:4]=2[N:3]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:17][S:16][C:13]1[N:14]=[CH:15][C:10]2[C:9]3[CH:8]=[CH:7][C:6]([C:18]([O:20][CH3:21])=[O:19])=[CH:5][C:4]=3[N:3]=[C:2]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11]=2[N:12]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc2c(c1)nc(Cl)c1nc(SC)ncc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2c(c1)nc(-c1ccccc1)c1nc(SC)ncc12
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
Methyl 5-chloro-3-(methylthio)pyrimido[4,5-c]quinoline-8-carboxylate (1.0 eq, 56 mg, 0.175 mmol) was mixed with benzeneboronic acid (2.0 eq, 43 mg, 0.35 mmol), PdCl2(dppf) (0.1 eq, 13 mg, 0.0178 mmol) and cesium carbonate (2.0 eq, 114 mg, 0.35 mmol) in dioxane (0.5 ml). The mixture was stirred for 10 minutes at 120° C. under microwave heating. Water was added and the resulting precipitate was filtered and dried. After trituration in ethylacetate and hexanes, methyl 3-(methylthio)-5-phenylpyrimido[4,5-c]quinoline-8-carboxylate was isolated by filtration (53 mg, 84% yield). LCMS (ES): >90% pure, m/z 362 [M+1]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[CH3:12][C:13]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]=[C:15]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=2)[C:14]=1[C:34](OC)=[O:35]>O1CCCC1>[OH:35][CH2:34][C:14]1[C:15]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=2)=[N:16][C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:18][C:13]=1[CH3:12]
Reactant: COC(=O)c1c(C)nc(-c2ccccc2)nc1-c1cccc([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1CO
Temperature: 0 °C
Yield: 72.5 %

Procedure:
To a suspension of lithium aluminum hydride (12.24 g) in a mixture of dry tetrahydrofuran (180 ml) and diethyl ether (360 ml) was dropwise added a solution of methyl 6-methyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylate (45 g) in dry tetrahydrofuran (180 ml) under cooling at -50°~-40° C. The excess lithium aluminum hydride was decomposed by a careful addition to ice water. The separated organic layer was washed with 15% sulfuric acid (400 ml) and extracted with ethyl acetate (1 l). The organic layer was washed with saturated aqueous sodium bicarbonate and aqueous sodium chloride successively and concentrated in vacuo. The residue was recrystallized from diethyl ether to give 5-hydroxymethyl-6-methyl-2-phenyl-4-(3-nitrophenyl)pyrimidine (30 g).
Reaction SMILES: [NH2:1][CH:2]1[C:28](=[O:29])[N:4]2[C:5]([C:25]([OH:27])=[O:26])=[C:6]([CH2:9][S:10][C:11]3[N:16]4[N:17]=[C:18]([CH2:20][OH:21])[N:19]=[C:15]4[N:14]=[C:13]([C:22]([OH:24])=[O:23])[CH:12]=3)[CH2:7][S:8][C@H:3]12.CO.[C:32]1([C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[N+]=[N-])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=NN)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl.CCOCC.CCCCCC>[NH2:1][CH:2]1[C:28](=[O:29])[N:4]2[C:5]([C:25]([O:27][CH:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:26])=[C:6]([CH2:9][S:10][C:11]3[N:16]4[N:17]=[C:18]([CH2:20][OH:21])[N:19]=[C:15]4[N:14]=[C:13]([C:22]([OH:24])=[O:23])[CH:12]=3)[CH2:7][S:8][C@H:3]12
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3cc(C(=O)O)nc4nc(CO)nn34)CS[C@H]12
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Agent: NN=C(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOCC
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3cc(C(=O)O)nc4nc(CO)nn34)CS[C@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 10 g of 7-amino-3-[(5-carboxy-2-hydroxymethyl-s-triazolo[1,5-a]pyrimidin-7yl)thiomethyl]-3-cephem-4-carboxylic acid, 100 ml of methanol and 300 ml of methylene chloride was added dropwise while stirring diphenyldiazomethane, which had been synthesized from 19.6 g of benzophenonehydrazone, 21.6 g of mercuric oxide (yellow) and 150 ml of n-hexane, in 30 ml of methylene chloride, and the mixture was stirred at room temperature overnight. After the reaction mixture was condensed and ether was added thereto to effect crystallization. The crystals were collected by filtration and dried to obtain 13.9 g of the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5]2[CH:8]=[C:9]([CH2:12][CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=3)[CH:10]=[CH:11][C:4]=2[O:3]1.[CH3:24][NH:25][CH3:26]>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5]2[CH:8]=[C:9]([CH2:12][CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22]([N:25]([CH3:26])[CH3:24])=[O:23])=[CH:19][CH:20]=3)[CH:10]=[CH:11][C:4]=2[O:3]1
Reactant: CNC
Reactant: CC1CCc2cc(CCOc3ccc(N=C=O)cc3)ccc2O1
Solvent: Cc1ccccc1
Product: CC1CCc2cc(CCOc3ccc(NC(=O)N(C)C)cc3)ccc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
3.1 g of 4-[(3,4-dihydro-2-methyl-2H-1-benzopyran-6-yl)ethyloxy]phenyl isocyanate was dissolved into 30 ml of toluene, and 0.9 g of dimethylamine dissolved in 5 ml of toluene was slowly added dropwise thereto at room temperature. After the mixture was stirred at room temperature for 2 hours, toluene was distilled off under a reduced pressure and the residue was recrystallized from ethyl acetate to obtain 2.7 g of Compound No. 67 shown in Table 4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:18](=[CH:19][CH:20]=1)[O:17][C:11]1([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)C[C:9]2=[O:21].COC(=O)/C=C/C1C=CC2OC3(CCN(C(OC(C)(C)C)=O)CC3)C(=O)C=2C=1>>[CH3:1][O:2][C:3](=[O:22])/[CH:4]=[CH:5]/[C:6]1[CH:20]=[CH:19][C:18]2[O:17][C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:9](=[O:21])[C:8]=2[CH:7]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Agent: COC(=O)/C=C/c1ccc2c(c1)C(=O)C1(CCN(C(=O)OC(C)(C)C)CC1)O2
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)C1(CCNCC1)O2

Procedure:
(E)-3-{3-Oxo-spiro[benzofuran-2(3H), 4′-piperidin]-5-yl}-acrylic acid methyl ester was synthesized according to the procedure for preparation of Intermediate 1, Step C, starting from (E)-3-{1′-tert-butoxycarbonyl-3-oxo-spiro[benzofuran-2(3H), 4′-piperidin]-5-yl}-acrylic acid methyl ester (750 mg, 1.93 mmol), giving its hydrochloride salt (380 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3Br)=[CH:4][CH:3]=1.[NH2:28][C:29]1[CH:43]=[CH:42][C:32]([O:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:31][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:28][C:29]2[CH:30]=[CH:31][C:32]([O:33][CH2:34][C:35]([O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:36])=[CH:42][CH:43]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(N)cc1
Reactant: Oc1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)COc1ccc(Nc2cc(=O)[nH]c3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-[bis(4-chlorophenyl)methyl]-4-bromoquinolin-2-ol (300 mg, 0.65 mmol, 1.00 equip), tert-butyl 2-(4-aminophenoxy)acetate (220.8 mg, 0.98 mmol, 1.50 equip, 99%), Pd2(dba)3 (60 mg, 0.06 mmol, 0.10 equip, 99%), dppf (126.7 mg, 0.23 mmol, 0.35 equip, 99%), Cs2CO3 (532.7 mg, 1.62 mmol, 2.50 equip, 99%), and 1,4-dioxane (9 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting solution was diluted with water (60 mL). The resulting solution was extracted with ethyl acetate (3×60 mL) and the organic layers combined. The resulting mixture was washed with water (1×60 mL) and brine (1×60 mL). The resulting mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (30:1). The resulting residue was recrystallized from EtOAc:n-hexane in the ratio of 1:20 to yield tert-butyl 2-(4-((6-(bis(4-chlorophenyl)methyl)-2-oxo-1,2-dihydroquinolin-4-yl)amino)phenoxy)acetate as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][N:4]=1.[Br:10]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:10][C:5]1[N:4]=[C:3]([O:2][CH3:1])[C:8]([NH2:9])=[CH:7][CH:6]=1
Reactant: COc1ncccc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(Br)ccc1N
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
A solution of 2-methoxypyridin-3-amine (39.4 g) in N,N-dimethylformamide (200 mL) was cooled to −30° C., and a solution of N-bromosuccinimide (62.1 g) in N,N-dimethylformamide (100 mL) was added dropwise. After stirring for 30 minutes, the reaction solution was poured into water and extracted with chloroform. The organic layer was sequentially washed with a saturated sodium sulfite solution, water and brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→4:1) to give 6-bromo-2-methoxypyridin-3-amine as a yellow powder (51.9 g, 80%).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[CH3:6][OH:7]>>[CH2:1]([NH:5][C:6]([C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CO
Reactant: CCCCN
Product: CCCCNC(=O)C(=O)NCCCC

Procedure:
The temperature is brought to 5° C. with an ice-bath and a solution of n-butyl-amine (25 ml, 0.253 mol) in anhydrous methyl alcohol (25 ml) is dripped in. The reaction is exothermic and dripping is adjusted to keep the temperature below 10°-12° C. When all the methyl alcohol solution of the amine has been added, the reaction mixture has a jelly appearance.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[C:35]([O:15][C@@H:13]([CH3:14])[C@@H:12]([NH:11][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=1[CH3:10])[C:16]1[O:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=2)=[N:19][N:20]=1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](C)OC(=O)c2ccccc2)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 91 %

Procedure:
To a 50 mL round bottomed flask was added 2-chloro-4-((1R,2S)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-methylbenzonitrile (200 mg, 0.508 mmol, pyridine (1 mL, 12.41 mmol) and methylene chloride (15 mL). Benzoyl chloride (0.295 mL, 2.54 mmol) was then added dropwise and the mixture was stirred at room temperature for 17 h. The reaction mixture was then quenched with 10% aq HCl (15 mL) and methylene chloride (30 mL) was added. The phases were partitioned and the aqueous phase extracted with methylene chloride (30 mL) (×2). The combined organics were washed with a saturated solution of sodium hydrogen carbonate, dried (Na2SO4) and concentrated to furnish a yellow oil (0.308 g, 91%). 1H NMR (Acetone d6, 400 MHz) δ 8.21-8.14 (m, 2H), 8.03 (d, J=9 Hz, 2H), 7.96 (d, J=9 Hz, 1H), 7.81 (t, J=8 Hz, 1H), 7.65-7.59 (m, 2H), 7.55-7.49 (m, 2H), 7.01 (d, J=9 Hz, 1H), 5.94-5.85 (m, 1H), 5.64 (dd, J=9 and 6 Hz, 1H), 5.48 (dd, J=5 and 8 Hz, 1H), 2.34 (s, 3H), 1.62 (d, J=6 Hz, 3H).
Reaction SMILES: [OH2:1].[C:2](#[N:9])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8]>>[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][C:2]([NH2:9])=[O:1])#[N:8]
Reactant: N#CCCCCC#N
Reactant: O
Product: N#CCCCCC(N)=O
Yield: 10 %

Procedure:
A process as claimed in claim 1, wherein at least 5 mol of water are employed per mole of adiponitrile and a yield of at least 10% of 5-cyanovaleramide is obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[S:21][C:20]2[CH:22]=[CH:23][C:24]([O:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])=[CH:25][C:19]=2[CH:18]=1)=[O:16])(C)(C)C.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[S:21][C:20]2[CH:22]=[CH:23][C:24]([O:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])=[CH:25][C:19]=2[CH:18]=1)=[O:16]
Reactant: CN(C)CCOc1ccc2sc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCOc1ccc2sc(C(=O)Nc3ccccc3N)cc2c1
Yield: 63.3 %

Procedure:
A solution of 72 mg (0.158 mmol) (2-{[5-(2-Dimethylamino-ethoxy)-benzo[b]thiophene-2-carbonyl]-amino}-phenyl)-carbamic acid tert-butyl ester (5) in 1.0 ml trifluoroacetic acid was stirred for 60 min at room temperature and then added to an aqueous solution of sodium bicarbonate. After extraction with ethyl acetate and removal of the solvent the residue was recrystallized from ethyl acetate/diethyl ether to yield 35 mg (0.10 mmol) 5-(2-Dimethylamino-ethoxy)-benzo[b]thiophene-2-carboxylic acid (2-amino-phenyl)-amide (1) as a yellow solid, mp. 191–193° C.
Reaction SMILES: COC1C=C(NC2C3C(=C(C)C=C(S(C4C=CC=C(C(=O)NC5C=CC(C6C=CC(CCCC=O)=CC=6)=CC=5)C=4)(=O)=O)C=3)N=CC=2C(N)=O)C=CC=1.[OH:53][CH2:54][CH2:55][CH2:56][C:57]1[CH:62]=[CH:61][C:60]([C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([S:69]([C:72]3[CH:73]=[C:74]4[C:79](=[C:80]([CH3:82])[CH:81]=3)[N:78]=[CH:77][C:76]([C:83]([NH2:85])=[O:84])=[C:75]4[NH:86][C:87]3[CH:92]=[CH:91][CH:90]=[C:89]([O:93][CH3:94])[CH:88]=3)(=[O:71])=[O:70])[CH:64]=2)=[CH:59][CH:58]=1>>[CH3:94][O:93][C:89]1[CH:88]=[C:87]([NH:86][C:75]2[C:74]3[C:79](=[C:80]([CH3:82])[CH:81]=[C:72]([S:69]([C:65]4[CH:64]=[C:63]([C:60]5[CH:61]=[CH:62][C:57]([CH2:56][CH2:55][CH:54]=[O:53])=[CH:58][CH:59]=5)[CH:68]=[CH:67][CH:66]=4)(=[O:70])=[O:71])[CH:73]=3)[N:78]=[CH:77][C:76]=2[C:83]([NH2:85])=[O:84])[CH:92]=[CH:91][CH:90]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(-c5ccc(CCCO)cc5)c4)cc23)c1
Agent: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(-c6ccc(CCCC=O)cc6)cc5)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(-c5ccc(CCC=O)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 124, using Intermediate 67 as substrate. ES/MS calcd. for C33H30N3O5S+ 580.2. Found m/z=580.3 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:43])[C@@H:7]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:42]=1[N:41]=[CH:40][CH:39]=[CH:38]2)(=[O:32])=[O:31])[CH2:8][NH:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]2[NH:22][CH2:23][CH2:24][CH2:25][N:26]=2)=[CH:13][CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:41]1[C:42]2[C:37](=[CH:36][CH:35]=[CH:34][C:33]=2[S:30]([NH:29][C@@H:7]([CH2:8][NH:9][C:10](=[O:28])[C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]3[NH:22][CH2:23][CH2:24][CH2:25][N:26]=3)=[CH:15][CH:16]=2)[C:6]([OH:43])=[O:5])(=[O:31])=[O:32])[CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1cccc2cccnc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2cccc3cccnc23)C(=O)O)cc1)NC1=NCCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
72 mg (0.11 mmol) of (2S)-2-(quinoline-8-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid tert-butyl ester was dissolved in 2 ml of dichloromethane and 2 ml of trifluoroacetic acid was added. The solution was stirred at room temperature for 3 hours. The solvent was removed in vacuo and toluene was added to the residue and then removed in vacuo. The residue was dissolved in acetonitrile/water (1/1) and lyophilized. Yield 54 mg. MS (ES+): m/e=553 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:4]=2[CH:3]=1.[CH2:22]1[O:24][CH2:23]1>CO>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[C:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][OH:24])[CH2:18][CH2:17]3)[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)C(=C1CCNCC1)c1ccccc1S2
Reactant: C1CO1
Solvent: CO
Product: OCCN1CCC(=C2c3ccccc3Sc3ccc(Cl)cc32)CC1
Reaction time: 8 h

Procedure:
To a solution of 13.2 g. (0.0318 m.) of 4-(2-chloro-9-thioxanthenylidene)-piperidine in 50 ml. of methanol at 50° C. is added a solution of 2.2 g. (0.0383 m.) of ethylene oxide in 30 ml. of methanol over ten minutes and the mixture is refluxed for one and one-half hours. After standing overnight at room temperature, the reaction mixture is filtered to yield 4-(2-chloro-9-thioxanthenylidene)-1-(β-hydroxyethyl)-piperidine, m.p. 178°-180° C.
Reaction SMILES: [C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5].[NH4+:9].[NH4+].[Cl-].[Mg+2].[Cl-]>>[NH2:9][C@H:2]([C:1]([OH:8])=[O:7])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: [NH4+]
Reactant: O=C([O-])/C=C/C(=O)[O-]
Agent: [Cl-]
Agent: [Mg+2]
Product: N[C@@H](CC(=O)O)C(=O)O
Temperature: 37 °C
Reaction time: 1 h

Procedure:
[Aspartase activity is indicated in terms of micromoles of L-aspartic acid which are produced by reaction with ammonium fumarate at 37° C. at pH 8.5. The reaction with ammonium fumarate is conducted by adding 2 g of the immobilized aspartase preparation to 30 ml of an aqueous 1 M ammonium fumarate solution (pH 8.5) containing 1 mM magnesium chloride, and then shaking the mixture at 37° C. for one hour. The amount of L-aspartic acid produced is bioassayed by using leuconostoc mesenterioides P-60(J. Biol. Chem., 172, 15(1948).]
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:21]([CH3:23])[CH3:22])[CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:11](O)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1.O.C(N(CC)CC)C.[CH:54]([O:57][C:58]1[C:59]([N:67]2[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]2)=[C:60]2[CH:66]=[CH:65][NH:64][C:61]2=[N:62][CH:63]=1)([CH3:56])[CH3:55]>C(Cl)Cl>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:10]([C:11]([N:70]2[CH2:71][CH2:72][N:67]([C:59]3[C:58]([O:57][CH:54]([CH3:56])[CH3:55])=[CH:63][N:62]=[C:61]4[NH:64][CH:65]=[CH:66][C:60]=34)[CH2:68][CH2:69]2)=[O:12])[CH2:9][N:8]([CH:21]([CH3:23])[CH3:22])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:15][CH:16]=1
Reactant: CC(C)Oc1cnc2[nH]ccc2c1N1CCNCC1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Oc1cnc2[nH]ccc2c1N1CCN(C(=O)[C@H](CN(C(=O)OC(C)(C)C)C(C)C)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.9 %

Procedure:
(S)-3-(tert-Butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (59 mg, 0.17 mmol, see Example H), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (44 mg, 0.23 mmol), HOBt-H2O (35 mg, 0.23 mmol) and triethylamine (12 mg, 0.12 mmol) were added to 5-isopropoxy-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine (30 mg, 0.12 mmol) in DCM (10 mL). The reaction was stirred at room temperature for 18 hours. The reaction was then diluted with DCM (50 mL) and washed with 1N HCL, 10% K2CO3 and brine. After drying over MgSO4, the residue was concentrated to dryness and purified by chromatography (SP4, 12+M, water/ACN 90/10→0/100, 20 CV) to yield (S)-tert-butyl 2-(4-chlorophenyl)-3-(4-(5-isopropoxy-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (42 mg, 62% yield) as a solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.Cl.[NH:24]1[CH2:29][CH2:28][CH:27]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH2:26][CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([C:8]1[C:7]([N:24]2[CH2:25][CH2:26][CH:27]([NH:30][S:31]([CH3:34])(=[O:32])=[O:33])[CH2:28][CH2:29]2)=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[N:15]2)=[C:10]([Cl:17])[CH:9]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Reactant: CS(=O)(=O)NC1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(NS(C)(=O)=O)CC1
Temperature: 65 °C
Yield: 37.2 %

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (0.16 g, 0.22 mmol, from Example 47, Step 2), N-piperidin-4-ylmethanesulfonamide hydrochloride (0.040 g, 0.19 mmol), palladium acetate (0.84 mg, 0.0037 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (3.5 mg, 0.0056 mmol), and cesium carbonate (0.23 g, 0.71 mmol) in tetrahydrofuran (4 mL) was heated at 65° C. overnight. The mixtures was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over MgSO4, evaporated and purified on silica gel (eluting with 0 to 5% methanol in dicholomethane) to give the desired product (27 mg, 38%). LCMS calculated for C17H21ClN3O3S (M+H)+: m/z=382.1; Found: 382.0.