Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]12[C@@:11]([OH:16])([C:12]([CH2:14][OH:15])=[O:13])[CH2:10][CH2:9][C@H:8]1[C@@H:7]1[CH2:17][CH2:18][C:19]3[C@@:25]([CH3:26])([C@H:6]1[C:4](=[O:5])[CH2:3]2)[CH:24]=[CH:23][C:21](=[O:22])[CH:20]=3.[CH3:27]C(OCC([C@]1(O)[C@@]2(C)CC([C@@H]3[C@]4(C)C(=CC(C=C4)=O)CC[C@H]3[C@@H]2CC1)=O)=O)=O>>[CH3:27][C@@H:18]1[C:19]2=[CH:20][C:21]([CH:23]=[CH:24][C@:25]2([CH3:26])[C@@H:6]2[C@H:7]([C@H:8]3[C@:2]([CH3:1])([CH2:3][C@@H:4]2[OH:5])[C@@:11]([OH:16])([C:12]([CH2:14][OH:15])=[O:13])[CH2:10][CH2:9]3)[CH2:17]1)=[O:22]
Reactant: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3C(=O)C[C@@]21C
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2C(=O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Product: C[C@H]1C[C@@H]2[C@H]([C@@H](O)C[C@@]3(C)[C@H]2CC[C@]3(O)C(=O)CO)[C@@]2(C)C=CC(=O)C=C12

Procedure:
BRAND_NAMES Ancortone, Colisone, Cortancyl, Dacortin, Decortancyl, Decortin, Delcortin, Deltacortone, Deltasone, Deltison, Di-Adreson, Encorton, Meticorten, Nurison, Orasone, Paracort, Prednilonga, Pronison, Rectodelt, Sone, Ultracorten CHEMICAL_NAME 17,21-dihydroxypregna-1,4-diene-3,11,20,trione CHEMICAL_FORMULA C21H26O5 CAS_NUMBER 53-03-2 Formulation
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[CH2:4][O:5][C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1N.N([O-])=O.[Na+].[OH-].[K+].[SH:21][C:22]1[N:26]=[CH:25][NH:24][N:23]=1>O>[F:2][C:3]([F:14])([F:13])[CH2:4][O:5][C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[S:21][C:22]1[N:26]=[CH:25][NH:24][N:23]=1
Reactant: Nc1ccccc1OCC(F)(F)F
Reactant: Sc1nc[nH]n1
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: FC(F)(F)COc1ccccc1Sc1nc[nH]n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 200-ml round-bottom flask is charged with conc. HCl (4 ml) and water (40 ml), and 2-(2,2,2trifluoroethoxy)aniline (3.82 g) is added. The resulting solution is cooled at a temperature of not more than 5° C. and an aqueous solution consisting of sodium nitrite (1.7 g) dissolved in water (10 ml) is added dropwise with tile temperature held at 4° C. or below, followed by stirring For one hour. In a separate step, 3-mercapto-1,2,4-triazole (4.5 g) and potassium hydroxide (2.2 g) is dissolved in water (40 ml) to give an aqueous solution which is cooled at 0° C. A preliminarily prepared diazonium salt solution is added dropwise to this aqueous solution. Thereafter, the resulting mixture is stirred at room temperature for about one hour. The organic layer is extracted with ethyl acetate, washed with water and dried. The solvent is distilled off and the resulting crude crystal is recrystallized with a mixed solvent of n-hexane and ethyl acetate; yield 4.4 g (71 %); m.p. 100°-101° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][C:12](=[O:14])[CH:11]=[CH:10][NH:9]2)=[CH:4][CH:3]=1.[Li]CCCC.[Br:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][C:22]=1[N:31]=[C:32]=[O:33]>C1COCC1>[Br:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][C:22]=1[NH:31][C:32]([N:9]1[CH:10]=[CH:11][C:12](=[O:14])[CH2:13][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:33]
Reactant: O=C1C=CN[C@H](c2ccc(F)cc2)C1
Reactant: COc1cc(Br)c(N=C=O)cc1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(Br)c(NC(=O)N2C=CC(=O)C[C@H]2c2ccc(F)cc2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
(S)-2-(4-Fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one (57 mg, 0.30 mmol) from Preparation 3 was dissolved in 10 ml of THF and cooled to −40° C. n-BuLi (1.1 eq, 0.12 ml of a 2.5 M soln) was added dropwise, forming a purple suspension. This mixture was allowed to stir for 30 minutes until the purple color changed to white. 1-Bromo-2-isocyanato-4,5-dimethoxy-benzene (1 eq, 77 mg) was added. The mixture was allowed to stir for 15 minutes at −40° C. then allowed to warm to room temperature and stir for 2 hours. The reaction was then quenched with saturated ammonium chloride solution. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/ethyl acetate 7:3) to obtain (S)-2-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid (2-bromo-4,5-dimethoxy-phenyl)-amide (82 mg, 61%) as a brown oil. MS (ES+) m/z 449 (M+H).
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5]1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([CH2:3][CH:4]1[CH2:9][CH2:8][NH:7][CH:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5]1)#[N:2]
Reactant: CCOC(=O)C1CC(CC#N)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CC(CC#N)CCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
To a solution of 19.9 g (67.2 mmol) of ethyl 4-cyanomethyl-N-t-butoxycarbonyl-2-piperidinecarboxylate (prepared in Example 3F) in 100 ml of dichloromethane was added 50 ml of trifluoroacetic acid (CO2 evolution). The mixture was stirred for 3 hr at room temperature and then was concentrated under vacuum. To the residue was added 100 ml of dichloromethane, and the solution was again concentrated under vacuum. The residue was dissolved in 200 ml of dichloromethane, 200 ml of saturated aqueous sodium bicarbonate was added, and the mixture was stirred for 15 minutes at room temperature. The organic layer was separated and washed with 100 ml of saturated aqueous sodium bicarbonate, and the combined aqueous washes were extracted twice with 100 ml each of dichloromethane and once with 50 ml of diethyl ether. The combined organic extracts were dried over Na2SO4, filtered and concentrated to afford 12.7 g (96%) of ethyl 4-cyanomethyl-2-piperidinecarboxylate. GC analysis showed an 85:15 mixture of cis:trans isomers. To a solution of 11.6 g (59.1 mmol) of the product in 60 ml of dimethylsulfoxide was added 9.9 g (118.2 mmol) of sodium bicarbonate and 5.7 ml (7.9 g, 65.0 mmol) of allyl bromide. After 1 hr at room temperature, another 1.1 ml portion of allyl bromide was added, and after another 2 hours at room temperature, the mixture was poured into 100 ml of water and 100 ml of brine and was extracted 5 times with 50 ml each of dichloromethane and once with 50 ml of diethyl ether. The combined organics were washed with 100 ml of water, then dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC to afford 8.6 g (62%) of ethyl cis-(±)-4-cyanomethyl-N-allyl-2-piperidinecarboxylate and 1.2 g (9%) of ethyl trans-(±)-4-cyanomethyl-N-allyl-2-piperidinecarboxylate, both of which were >99.9% one isomer by GC.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[C:14]1([CH:21]=[CH:20][C:18]([OH:19])=[CH:17][CH:16]=1)[OH:15]>O1CCCC1>[OH:15][C:14]1[CH:21]=[CH:20][C:18]([O:19][C:9](=[O:10])[C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[CH:13][CH:12]=2)=[CH:17][CH:16]=1
Reactant: C=CCOc1ccc(C(=O)Cl)cc1
Reactant: Oc1ccc(O)cc1
Solvent: C1CCOC1
Product: C=CCOc1ccc(C(=O)Oc2ccc(O)cc2)cc1
Reaction time: 4 h

Procedure:
A solution containing 78.8 g of 4-(prop-2-en-1-oxy)benzoyl chloride (obtainable according to DE-A 2,944,591) and 220.0 g of hydroquinone in 400 ml of dry tetrahydrofuran was boiled for 4 hours under reflux. After being concentrated the product was recrystallized from toluene and ethanol (1:1 parts by volume). Melting point: 146° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[Cl:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[S:29])[CH:23]=[CH:24][C:25]=1[Cl:26]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28](=[S:29])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1ccc(Cl)c(Cl)c1
Yield: 78.4 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.972 g, 4.00 mmol) and 3,4-dichlorophenyl isothiocyanate (0.82 g, 4.02 mmol) to afford the product (1.40 g) in two crops; m.p. 174-175° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[SH:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[S:18][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:12])[CH2:7][CH2:8][O:9][C:10]=2[CH:11]=1
Reactant: O=C1CCOc2cc(Br)ccc21
Reactant: Sc1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CCOc2cc(Sc3cccs3)ccc21
Temperature: 78 °C
Yield: 92.4 %

Procedure:
7-Bromochroman-4-one (1.5 g, 6.6 mmol), thiophene-2-thiol (0.68 mL, 7.3 mmol), and potassium carbonate (1.37 g, 9.9 mmol) were combined in ACN (50 mL) in a sealed vessel, and the reaction was heated at 78° C. overnight. The reaction was cooled, filtered, and concentrated. Purification by silica gel chromatography (10-60% EtOAc/hexanes) gave 1.6 g (93%) of the title compound as a yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 2.75 (2H, t, J=6.4 Hz), 4.48 (2H, t, J=6.4 Hz), 6.59 (1H, d, J=1.8 Hz), 6.75 (1H, dd, J=8.4, 1.8 Hz), 7.13-7.17 (1H, m), 7.34 (1H, dd, J=3.6, 1.2 Hz), 8.58 (1H, dd, J=5.4, 1.2 Hz), 7.75 (1H, d, J=8.4 Hz). [M+H] calc'd for C13H10O2S2, 263. found 263.
Reaction SMILES: [OH:1][C:2]1([C:12]2[S:13][CH:14]=[C:15]([C:17]([OH:19])=O)[N:16]=2)[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1.CN.C[CH2:23][N:24](CC)CC.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CCOC(C)=O>[OH:1][C:2]1([C:12]2[S:13][CH:14]=[C:15]([C:17]([NH:24][CH3:23])=[O:19])[N:16]=2)[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1csc(C2(O)CCC3(CC2)OCCO3)n1
Agent: CN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC(=O)c1csc(C2(O)CCC3(CC2)OCCO3)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
To a stirred solution of 2-(8-hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)-1,3-thiazole-4-carboxylic acid (0.30 g, 1.05 mmol) and methylamine (2M in THF, 2 mL, 4 mmol)in CH2Cl2 (10 mL) was added Et3N (0.5 mL, 3.6 mmol) followed by EDC (0.242 g, 1.262 mmol) and HOBt (0.193 g, 1.26 mmol). The mixture was stirred at room temperature overnight. Then the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3 and brine. The organic layer was dried (MgSO4), concentrated and flash chromatographed (50% EtOAc/hexanes) to give 0.16 g of the title compound in 50% yield. MS (EI) (M+H)+=299.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[N:2]=1.[F:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:26][CH:27]=2)[CH:20]=[CH:21][CH:22]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]([CH:28]3[CH2:33][CH2:32][N:31]([C:8]([NH:7][C:3]4[N:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:30][CH2:29]3)[S:26][CH:27]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Nc1cccnn1)OCC(Cl)(Cl)Cl
Reactant: Fc1cccc(-c2csc(C3CCNCC3)n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1cccnn1)N1CCC(c2nc(-c3cccc(F)c3)cs2)CC1
Temperature: 70 °C
Reaction time: 6 h
Yield: 43.8 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridazin-3-ylcarbamate (250 mg, 0.922 mmol), 4-[4-(3-fluorophenyl)-1,3-thiazol-2-yl]piperidine (220 mg, 0.839 mmol) and diisopropylethylamine (0.292 ml, 1.68 mmol) in dimethylsulfoxide (2.8 ml) was stirred at 70° C. for 6 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and ethyl acetate to give the desired product (141 mg, 43.7%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]([OH:23])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([S:31]([NH:34][C:35]2([CH2:40][OH:41])[CH2:39][CH2:38][CH2:37][CH2:36]2)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>>[OH:41][CH2:40][C:35]1([NH:34][S:31]([C:27]2[CH:26]=[C:25]([NH:24][C:21]([C:20]3[CH:19]=[N:18][N:11]4[C:12]([C:14]([F:17])([F:15])[F:16])=[CH:13][C:8]([C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)=[N:9][C:10]=34)=[O:23])[CH:30]=[CH:29][CH:28]=2)(=[O:33])=[O:32])[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: Nc1cccc(S(=O)(=O)NC2(CO)CCCC2)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)NC2(CO)CCCC2)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.4) and 3-amino-N-(1-hydroxymethyl-cyclopentyl)-benzenesulfonamide (example B.13) according to general procedure II. Yellow solid. MS (ISP) 594.0 [(M+H)+]; mp 253-255° C.
Reaction SMILES: [Br-].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[S:34]1[CH:38]=[CH:37][C:36]2[C:39](=[O:43])[CH2:40][CH2:41][CH2:42][C:35]1=2>O1CCCC1>[S:34]1[CH:38]=[CH:37][C:36]2[C:39]([OH:43])=[CH:40][CH:41]=[CH:42][C:35]1=2
Reactant: O=C1CCCc2sccc21
Agent: C[N+](C)(C)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Oc1cccc2sccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
Phenyltrimethylammonium tribromide (11.4 g) was added in portions under nitrogen at ambient temperature over 35 minutes to a stirred solution of 6,7-dihydrobenzo[b]thiophen-4(5H)-one (4.6 g) in tetrahydrofuran (45 ml), the mixture was stirred for 1 hour and allowed to stand at ambient temperature overnight, then it was filtered and the solvent was removed in vacuo. The residue was dissolved in dimethylformamide (20 ml), the solution was added under nitrogen to a suspension of lithium carbonate (8.2 g) in dimethylformamide (50 ml), the mixture was heated under reflux for 4 hours, then it was cooled to ambient temperature and added to 10% aqueous acetic acid solution (500 ml). The product was extracted into dichloromethane (3×100 ml) and the combined extracts were washed with water (3×100 ml), dried (MgSO4), and the solvent was removed in vacuo. The residue was purified by flash chromatography over silica using dichloromethane as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give benzo[b]thiophen-4-ol (4 g) as a white solid which was used without further purification.
Reaction SMILES: [O:1]=[C:2]1[NH:21][C:5]2=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][C:12]=3[CH:13]=[C:4]2[NH:3]1.[CH:22]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([NH:29][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][O:14][C:10]2[CH:9]=[CH:8][C:7]3[N:6]=[C:5]4[NH:21][C:2](=[O:1])[NH:3][C:4]4=[CH:13][C:12]=3[CH:11]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Reactant: NC1CCCCCC1
Product: O=C(CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1)NC1CCCCCC1

Procedure:
This compound, m.p. 314°-316°, was prepared analogous to Example 15 from 4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butyric acid and N-cycloheptylamine.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:13]([O:15]CC)=[O:14])[CH2:9][CH:8]([CH2:10][CH2:11][CH3:12])[CH2:7]1)=[O:5])C.[OH-].[Na+].O.Cl>C1C=CC=CC=1>[CH2:10]([CH:8]1[CH2:9][C:6]([C:13]([OH:15])=[O:14])([C:4]([OH:5])=[O:3])[CH2:7]1)[CH2:11][CH3:12]
Reactant: CCCC1CC(C(=O)OCC)(C(=O)OCC)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CCCC1CC(C(=O)O)(C(=O)O)C1

Procedure:
A solution of 3-n-propylcyclobutane-1,1-dicarboxylic acid diethyl ester (100 g., 0.413 mol, prepared as described in Reference Example 2) in benzene (200 ml.) was treated with sodium hydroxide (320 g., 8.00 mol) in water (400 mol.) for 20 hours at room temperature. The reaction mixture was acidified with 6 N hydrochloric acid and extracted with diethyl ether (3×400 ml.). After concentration of the extracts under reduced pressure, the resulting crude solid was recrystallized from chloroform to give the title compound in quantitative yield, having the following physical characteristics:
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:10]=[C:11]([N+:13]([O-])=O)[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([O-])=O.[NH4+]>CCO.[Pd]>[N:1]1([C:7]2[CH:12]=[C:11]([CH:10]=[C:9]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[CH:8]=2)[NH2:13])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1cc(N2CCOCC2)cc(N2CCOCC2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1cc(N2CCOCC2)cc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
4-[3-(morpholin-4-yl)-5-nitrophenyl]morpholine (123 mg, 0.42 mmol) was hydrogenated using ammonium formate (0.26 g, 10 eq) and Pd/C (10% Pd, 45 mg, 0.1 eq) in 4 mL of EtOH. The mixture was stirred overnight at room temperature and then filtered through a celite pad. The filtrate was evaporated and the residue was dissolved in DCM and washed with a saturated aqueous solution of Na2CO3. The aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and evaporated to yield expected compound as a brown powder (63 mg, 57% yield).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1.Cl[C:16]1[C:17]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[C:30]([CH3:35])=[N:31][N:32]([CH3:34])[CH:33]=3)[CH2:24][CH2:23]2)=[N:18][CH:19]=[CH:20][N:21]=1.CN(C)C(=O)C.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:34][N:32]1[CH:33]=[C:29]([CH2:28][N:25]2[CH2:24][CH2:23][N:22]([C:17]3[C:16]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:14])([F:13])[F:1])[CH:5]=4)=[N:21][CH:20]=[CH:19][N:18]=3)[CH2:27][CH2:26]2)[C:30]([CH3:35])=[N:31]1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: Cc1nn(C)cc1CN1CCN(c2nccnc2Cl)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1nn(C)cc1CN1CCN(c2nccnc2-c2cccc(OC(F)(F)F)c2)CC1
Temperature: 110 °C
Yield: 35.9 %

Procedure:
Charge a carousel tube with 3-(trifluoromethoxy)benzeneboronic acid (140 mg, 0.68 mmol), 3′-chloro-4-(1,3-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (173 mg, 0.56 mmol) and N,N-dimethylacetamide (1 mL). Add N,N-dimethylacetamide (3 mL) and potassium carbonate (190 mg, 1.35 mmol) and purge with nitrogen for about 45 min. Add water (2 mL, purged with nitrogen for 1 hr.), then tetrakis(triphenylphosphine)palladium(0) (0.004 g, 0.0034 mmol), purge the reaction for about 30 min., and then heat overnight at 110° C. Cool to room temperature, add water and extract with DCM (3×30 mL). Concentrate the combined DCM extracts and purify using silica gel chromatography followed by reverse phase HPLC to give the title compound (0.087 g, 30%). MS (ES): m/z=433.1 [M+H]+.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:37])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[C:19]([O:21][CH3:22])[CH:20]=3)[N:14]=1)[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:10](=[O:30])[C:9]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:8]2)=[O:4].[NH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42].C[O-].[Na+]>>[CH2:23]([N:11]1[C:12]2[C:7](=[C:6]([OH:37])[C:5]([C:3]([NH:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[C:19]([O:21][CH3:22])[CH:20]=2)[CH:8]=[C:9]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:10]1=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1nc(-c2cncc(OC)c2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: COc1cncc(-c2nc(C(=O)NCCC(=O)O)c(O)c3cc(-c4ccccc4)c(=O)n(Cc4ccccc4)c23)c1
Temperature: 25 °C
Yield: 69.9 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-8-(5-methoxy-pyridin-3-yl)-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (45 mg, 0.091 mmol), β-alanine (651 mg, 7.30 mmol) and NaOMe solution (11 mL, 5.48 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The organic layer was dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 35 mg of the title compound as a light tan solid. MS: (+) m/z 551.32 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][C:26]1[S:27][C:28]([S:32](Cl)(=[O:34])=[O:33])=[C:29]([CH3:31])[N:30]=1.O>N1C=CC=CC=1>[CH3:25][C:26]1[S:27][C:28]([S:32]([NH:1][C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=2[CH3:24])[O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[N:11]=2)(=[O:34])=[O:33])=[C:29]([CH3:31])[N:30]=1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Solvent: c1ccncc1
Solvent: O
Product: Cc1nc(C)c(S(=O)(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.4 %

Procedure:
To a solution of N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol) in pyridine (4.0 mL) was added 2,4-dimethyl-1,3-thiazole-5-sulfonyl chloride (157 mg, 0.74 mmol), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=3/1→ethyl acetate alone) and washed with hexane/ethyl acetate to give the title compound (196 mg, 64%) as a white powder.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH:8]([C:29]([O:31]C(C)(C)C)=[O:30])[CH:9]([CH3:28])[C@@H:10]([C:21]([O:23]C(C)(C)C)=[O:22])[NH:11][C:12](=[O:20])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][CH2:6][Cl:7].FC(F)(F)C(O)=O>ClCCl>[Cl:1][CH2:2][CH2:3][N:4]([CH:8]([C:29]([OH:31])=[O:30])[CH:9]([CH3:28])[C@@H:10]([C:21]([OH:23])=[O:22])[NH:11][C:12](=[O:20])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][CH2:6][Cl:7]
Reactant: CC(C(C(=O)OC(C)(C)C)N(CCCl)CCCl)[C@H](NC(=O)Nc1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C(C(=O)O)N(CCCl)CCCl)[C@H](NC(=O)Nc1ccccc1)C(=O)O
Reaction time: 72 h

Procedure:
A solution of di-t-butyl 4-[N,N-bis(2-chloroethyl)amino]-3-methylphenylcarbamoyl-L-glutamate (0.6 g) in dichloromethane (6 ml) was cooled to 0° C., trifluoroacetic acid (15 ml) was added. This solution was then left at 0° C. for 3 days. The solution was then evaporated to dryness to yield (4-[N,N-bis(2-chloroethyl)amino]-3-methylphenylcarbamoyl-L-glutamic acid as an oil. Yield 0.49 g.