Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[NH:13][C:14]2[C:15]([N:20]=1)=[N:16][CH:17]=[CH:18][CH:19]=2.[ClH:22].[H][H]>CO.[Pd]>[ClH:22].[ClH:22].[CH3:1][N:2]([CH3:21])[C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[C:12]1[NH:13][C:14]2[C:15]([N:20]=1)=[N:16][CH:17]=[CH:18][CH:19]=2
Reactant: [H][H]
Reactant: CN(C)c1cc([N+](=O)[O-])ccc1-c1nc2ncccc2[nH]1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)c1cc(N)ccc1-c1nc2ncccc2[nH]1

Procedure:
An amount of 2.83 gm of 2-(2'-dimethylamino-4'-nitrophenyl)-imidazo[4,5-b]pyridine was hydrogenated in a mixture of 100 ml of methanol, 10 ml of concentrated methanolic hydrochloric acid, and 1 gm of palladium/charcoal for 4.5 hours at ambient temperature with hydrogen gas at 5 bar. The catalyst was then removed by filtration, the filtrate was concentrated by evaporation, and the residue was triturated with acetone to form crystals, filtered, and then washed with a mixture of ether and acetone.
Reaction SMILES: [C:1]1([C:13]2[C:14](=[O:36])[NH:15][C:16](=[O:35])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[CH:25]=3)[NH:20][CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1>CO>[C:1]1([C@H:13]2[C@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]5[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=5)[CH:25]=4)[NH:20][CH:19]=3)[C:16](=[O:35])[NH:15][C:14]2=[O:36])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: COc1ccc(-c2ccc3[nH]cc(C4=C(c5cn6c7c(cccc57)CCC6)C(=O)NC4=O)c3c2)cc1
Solvent: CO
Product: COc1ccc(-c2ccc3[nH]cc([C@@H]4C(=O)NC(=O)[C@H]4c4cn5c6c(cccc46)CCC5)c3c2)cc1

Procedure:
3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(5-(4-methoxyphenyl)-1H-indol-3-yl)pyrrole-2,5-dione, prepared as in Example 33, was reduced with Mg in methanol as described in Example 2, Procedure C, to yield (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(5-(4-methoxyphenyl)-1H-indol-3-yl)pyrrolidine-2,5-dione. 1H NMR (CD3OD) δ: 2.03-2.22 (m, 2H), 2.98 (t, J=6.0 Hz, 2H), 3.80 (s, 3H), 3.97-4.06 (m, 1H), 4.06-4.14 (m, 1H), 4.38 (d, J=6.8 Hz, 1H), 4.67 (d, J=6.8 Hz, 1H), 6.86 (d, J=8.4 Hz, 2H), 6.91-7.00 (m, 2H), 7.08 (s, 2H), 7.17-7.27 (m, 4H), 7.31 (d, J=8.4 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H).
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)[CH2:8][C:9]2[C:10]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[N:11][C:12]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:13][C:14]=2[CH:15]([CH3:17])[CH3:16])C=CC=CC=1.[CH:38]([C@H:40]1[O:45][C:44]([CH3:47])([CH3:46])[O:43][C@@H:42]([CH2:48][C:49]([N:51]([O:53][CH3:54])[CH3:52])=[O:50])[CH2:41]1)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.CCCCCC>[CH3:23][N:18]([C:12]1[N:11]=[C:10]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:9](/[CH:8]=[CH:38]/[C@H:40]2[O:45][C:44]([CH3:47])([CH3:46])[O:43][C@@H:42]([CH2:48][C:49]([N:51]([O:53][CH3:54])[CH3:52])=[O:50])[CH2:41]2)=[C:14]([CH:15]([CH3:16])[CH3:17])[N:13]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CP(=O)(c1ccccc1)c1ccccc1
Reactant: CON(C)C(=O)C[C@H]1C[C@@H](C=O)OC(C)(C)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CON(C)C(=O)C[C@H]1C[C@@H](/C=C/c2c(-c3ccc(F)cc3)nc(N(C)S(C)(=O)=O)nc2C(C)C)OC(C)(C)O1
Yield: 75.3 %

Procedure:
Diphenyl[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-ylmethyl]phosphine oxide (10.9 g), 2-[(4R,6S)-6-formyl-2,2-dimethyl-[1,3]dioxan-4-yl]-N-methoxy-N-methyl-acetamide (4.5 g), and tetrahydrofuran (90.0 mL) were added to a reactor under nitrogen atmosphere. The reaction mixture was cooled to −40˜−30° C. A solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (1M, 20.0 mL) was slowly added to the reaction mixture, while maintaining the temperature of −40˜−30° C. The temperature of the reaction mixture was raised to 0˜5° C. for 30 minutes. The reaction mixture was stirred at the same temperature for 2˜3 hours. The reaction was monitored with thin layer chromatography (ethyl acetate/n-hexane=1:3). An ammonium chloride solution (50.0 mL) was added to the reaction mixture. The separated organic layer was washed with 8% sodium bicarbonate solution (50.0 mL) and then concentrated under reduced pressure. Isopropanol (45.0 mL) was added to the resulting residue. The reaction mixture was stirred at 0˜5° C. for 1˜2 hours and then filtered under reduced pressure. The resulting white solid was dried under vacuum to obtain E-(6-{2-[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-yl]vinyl}-[(4R,6S)-2,2-dimethyl-[1,3]dioxan-4-yl])-N-methoxy-N-methyl-acetamide (7.8 g, yield 75%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@:7]1([CH2:17][CH2:18][NH2:19])[CH2:16][C:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH3:27][O:28][C:29]1[CH:33]=[CH:32][S:31][C:30]=1[CH:34]=O.[BH4-].[Na+].[ClH:38]>CCOCC.CO.C(Cl)Cl>[ClH:38].[CH3:27][O:28][C:29]1[CH:33]=[CH:32][S:31][C:30]=1[CH2:34][NH:19][CH2:18][CH2:17][C@:7]1([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:16][C:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1
Reactant: COc1ccsc1C=O
Reactant: NCC[C@@]1(c2ccccn2)CCOC2(CCCC2)C1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: COc1ccsc1CNCC[C@@]1(c2ccccn2)CCOC2(CCCC2)C1
Reaction time: 8 h
Yield: 41 %

Procedure:
Into a vial were added 2-[(9R)-9-(Pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethan-1-amine (500 mg, 1.92 mmole), 18 mL CH2Cl2 and sodium sulfate (1.3 g, 9.6 mmole). The 3-methoxythiophene-2-carboxaldehyde (354 mg, 2.4 mmole) was then added, and the misture was stirred overnight. NaBH4 (94 mg, 2.4 mmole) was added to the reaction mixture, stirred for 10 minutes, and then MeOH (6.0 mL) was added, stirred 1 h, and finally quenched with water. The organics were separated off and evaporated. The crude residue was purified by a Gilson prep HPLC. The desired fractions collected and concentrated and lyophilized. After lyophilization, residue was partitioned between CH2Cl2 and 2N NaOH, and the organic layers were collected. After solvent was concentrated to half of the volume, 1.0 eq of 1N HCl in Et2O was added, and majority of solvent evaporated under reduced pressure. The solid obtained was washed several times with Et2O and dried to provide [(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine monohydrochloride (336 mg, 41% yield, m/z 387.0 [M+H]+ observed) as a white solid. The NMR for Compound 140 is described herein.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7])#[N:2].[NH2:12][C:13]1[CH:14]=[C:15]([CH:31]=[CH:32][CH:33]=1)[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[C:20]([OH:27])[C:19]=1[CH2:28][CH2:29][CH3:30].C(N(CC)CC)C>ClCCl>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][C:15]2[CH:14]=[C:13]([NH:12][C:6](=[O:7])[C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=3)[CH:33]=[CH:32][CH:31]=2)=[C:19]([CH2:28][CH2:29][CH3:30])[C:20]=1[OH:27])(=[O:26])[CH3:25]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: CCCc1c(OCc2cccc(N)c2)ccc(C(C)=O)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1c(OCc2cccc(NC(=O)c3cccc(C#N)c3)c2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
Add a solution of 3-cyanobenzoyl chloride (553 mg, 3.34 mmol) in dichloromethane (10 mL) to a solution of 1-[4-(3-amino-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (1.00 g, 3.34 mmol) in dichloromethane (10 mL), and triethyl amine (1.4 mL) at 0° C. Stir to room temperature for one hour. Partition the mixture between dichloromethane (20 mL) and 2N hydrochloric acid (30 mL). Wash the organic layer with 2N hydrochloric acid (20 mL), saturated sodium bicarbonate, brine, dry, filter, and concentrate to afford the title compound as a light yellow powder (1.33 g, 93%): 1H NMR (CDCl3) δ 0.96 (t, 3H), 1.59 (sextet, 2H), 2.55 (s, 3H), 2.72 (t, 2H), 5.19 (s, 2H), 6.47 (d, 1H), 7.26 (d, 1H), 7.42 (t, 1H), 7.54-7.59 (m, 2H), 7.65 (t, 1H), 7.77 (s, 1H), 7.84 (d, 1H), 7.88 (s, 1H), 8.11 (d, 1H), 8.17 (s, 1H), 12.75 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:5]=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[OH:9])[CH:7]=1.[C:24]([NH2:28])(=[O:27])[CH:25]=[CH2:26].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl.O>[C:24]([CH:25]=[CH:26][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:5]=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[OH:9])[CH:7]=1)(=[O:27])[NH2:28]
Reactant: CCOC(=O)C=Cc1cc(Br)cc(C(O)c2ccc(F)cc2)c1
Reactant: C=CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C=Cc1cc(C=CC(N)=O)cc(C(O)c2ccc(F)cc2)c1
Temperature: 100 °C
Yield: 59.4 %

Procedure:
A mixture of ethyl 3-[3-bromo-5-[(4-fluorophenyl)hydroxymethyl]phenyl]-2-propenoate (9.50 g), acrylamide (2.67 g), palladium(II) acetate (0.306 g), tri-o-tolylphosphine (0.763 g) and triethylamine (3.80 g) in acetonitrile (10 ml) was heated to 100° C. for 4 hours under an atmosphere of nitrogen and then cooled. Water (150 ml) and dichloromethane (150 ml) was added and the mixture was warmed with stirring to disperse the solid residue. The mixture was cooled and filtered, and the solid was dissolved in hot isopropanol (500 ml). The solution was filtered hot using a filter aid, and the filtrate was concentrated until crystallisation commenced. An equal volume of ether was added and the mixture was allowed to cool. The solid was filtered off and dried to give the title compound (5.50 g), m.p. 197°-199° C. Found: C,68.55; H,5.17; N,4.01. C21H20FNO4 requires C,68.28; H,5.46; N,3.79%.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH3:13])[CH:3]=1.[N:14]([O-])=O.[Na+].Cl[Sn]Cl>O.Cl>[CH3:13][O:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([NH:1][NH2:14])=[CH:3]2
Reactant: COc1cccc2cc(N)ccc12
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1cccc2cc(NN)ccc12
Temperature: -6 °C
Reaction time: 0.75 h
Yield: 93 %

Procedure:
To a suspension of 2-amino-5-methoxynaphthalene (3.5 g, 20 mmol) in water (65 ml) and HCl conc. (25 ml) cooled down to −6° C., sodium nitrite (1.55 g, 22 mmol) in water (15 ml) was added dropwise. It was kept at stirring, approximately at the same temperature, during 45 minutes and subsequently a solution of SnCl2 (9.3 g, 40 mmol) in HCl conc. (10 ml) was added. Once the addition was performed, it was allowed that the temperature would slowly increase until achieving room temperature, and it was filtered. The filtered solid was washed with water and ethylic ether and, subsequently, it was suspended in ethylic ether, with stirring, during a few minutes. It was filtered and dried resulting in 3.5 g of a crude brown solid, which was used directly in the following synthesis step.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:9]2[CH:10]=[C:11]([C:13](O)=[O:14])[O:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[CH3:29][N:30](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:31].F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CNC>CN(C=O)C.O>[CH3:29][N:30]([CH3:31])[C:13]([C:11]1[O:12][C:8]2[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[C:9]=2[CH:10]=1)=[O:14]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(C(=O)O)oc2c1
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(C(=O)N(C)C)oc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
To a solution of 6-(ethoxycarbonyl)-4-(4-(methylsulfonyl)phenoxy)benzofuran-2-carboxylic acid (450 mg, 1.11 mmol) in DMF (10 mL) was added HATU (846 mg, 2.23 mmol), DIEA (719 mg, 5.56 mmol) and the solution was stirred at 0° C. for 15 min. Dimethylamine hydrochloride (136 mg, 1.67 mmol) was added and the solution was warmed gradually to room temperature and stirred for 14 h. Water was added and the product was extracted with CHCl3. The combined organic layers were washed with water (2×), brine, dried over Na2SO4, and concentrated. The product was purified by gradient silica gel chromatography using CHCl3/MeOH (100/0 to 95/5) to give the title compound (460 mg, 96%) as a light yellow solid. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.40 (t, J=7.16 Hz, 3 H) 3.07 (s, 3 H) 3.13 (s, 3 H) 3.33 (s, 3 H) 4.40 (q, J=7.16 Hz, 2 H) 7.07-7.15 (m, 2 H) 7.16 (d, J=0.75 Hz, 1 H) 7.65 (d, J=0.94 Hz, 1 H) 7.87-7.94 (m, 2H) 8.10-8.15 (d, J=0.94 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](OB(O)O)=[CH:4][CH:3]=1.[C:12]1(=[O:17])[CH2:16][CH2:15][CH:14]=[CH:13]1>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>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:14]2[CH2:15][CH2:16][C:12](=[O:17])[CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C1C=CCC1
Reactant: OB(O)Oc1ccc(Br)cc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Product: O=C1CC[C@H](c2ccc(Br)cc2)C1
Yield: 91.3 %

Procedure:
4-Bromophenylboric acid (3.61 g, 18 mmol), cyclopentenone (0.50 mL, 6.0 mmol) and (S)-BINAP (224 mg, 0.36 mmol) were used and treated in a similar manner to (Step 1) of (Example 1) to give the title compound (1.31 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][O:16][NH2:17])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1.[H-].[Na+].[CH3:27]I>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][O:16][NH:17][CH3:27])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1
Reactant: CI
Reactant: NOCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNOCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 18 h

Procedure:
A stirred solution of 8-chloro-1-[(aminooxy)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine (0.02 mole) in dry dimethylformamide (50 ml.) is cooled in an ice bath under nitrogen and treated successively with a 57% mineral oil suspension of sodium hydride (0.84 g., 0.02 mole) and methyliodide (0.02 mole). The mixture is allowed to come slowly to ambient temperature and stand for 18 hours. It is then concentrated in vacuo. The residue is chromatographed on silica gel with methanol to give 8-chloro-1-[[(methylamino)oxy]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH2:2][CH3:3].[CH2:7]([NH2:10])[CH2:8][CH3:9]>>[CH2:1]([NH:4][C:5]([NH:10][CH2:7][CH2:8][CH3:9])=[O:6])[CH2:2][CH3:3]
Reactant: CCCN
Reactant: CCCN=C=O
Product: CCCNC(=O)NCCC
Yield: 98.4 %

Procedure:
1700 g. (98.4%) of product was prepared according to the method of Hayes et al., J. Agr. Food Chem. 17, 1077 (1969) from n-propylisocyanate (1020 g. 12 mole) and n-propylamine (708 g., 4.75 mole).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[C:29]([O:35][CH3:36])(=[O:34])[CH2:30][C:31]([CH3:33])=[O:32].Cl>CS(C)=O>[C:31]([CH:30]([C:29]([O:35][CH3:36])=[O:34])[C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])(=[O:32])[CH3:33]
Reactant: COC(=O)CC(C)=O
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc([N+](=O)[O-])c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C)(C(=O)OCC)c1ccc([N+](=O)[O-])c(C(C(C)=O)C(=O)OC)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 51.6 %

Procedure:
To a solution of diethyl 2-(3-chloro-4-nitrophenyl)-2-methylmalonate (1.0 g, 3.03 mmol.) in dimethyl sulfoxide (DMSO, 3mL) were added potassium carbonate (1.25 g, 9.09 mmol.) and methyl acetoacetate (0.99 mL, 9.0 mmol.). The resulting mixture was stirred at 70° C. for 6 hours. The reaction mixture was cooled to room temperature, neutralized with diluted hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate portion was washed with an aqueous saturated sodium chloride solution, and dried over magnesium sulfate. The dried portion was concentrated to leave a residue. The residue was purified by silica gel column chromatography (Wako Gel C-330, available from Wako Jyunyaku Industry Co., Ltd., toluene/ethyl acetate=100/4, v/v), to give 0.64 g (yield: 52%) of the desired compound as a yellow oil.
Reaction SMILES: C1[O:5][C:4]2([C:9]3(Br)[CH:10]4[CH:13]5[CH:6]2[CH:7]2C(=O)[C:12]5(Br)[CH:11]4[CH:8]23)[O:3]C1>[OH-].[K+]>[C:9]12([C:4]([OH:3])=[O:5])[CH:8]3[CH:7]4[CH:12]5[CH:11]3[CH:10]1[CH:13]5[CH:6]24
Reactant: O=C1C2C3C4C5C(C2C5(Br)C32OCCO2)C14Br
Agent: [K+]
Agent: [OH-]
Product: O=C(O)C12C3C4C5C3C1C5C42

Procedure:
Cubanecarboxylic acid (53578-15-7) (33) is obtained from (32) by the method of Eaton and Cole, by refluxing the ketal in 25% aqueous KOH overnight. Extraction with methylene chloride, drying over magnesium sulfate, stripping the solvent, and recrystallization from pentane yields (33), mp 154°-155° C.; λmax (CCl4) 5.91μ; proton NMR (CCl4, ppm τ): -2.2(1H, s) , and 5.6-6.2(7H, m).
Reaction SMILES: [N:1]([N:3]1[CH2:8][CH2:7][O:6][CH2:5][CH:4]1[C:9]([OH:11])=[O:10])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[N:1]1[O:11][C:9]([O-:10])=[C:4]2[N+:3]=1[CH2:8][CH2:7][O:6][CH2:5]2
Reactant: O=NN1CCOCC1C(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: [O-]c1on[n+]2c1COCC2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 38.9 %

Procedure:
The crude 4-nitrosomorpholine-3-carboxylic acid (11.0 g) from step 1 was dissolved in THF (250 ml) and cooled to 0° C. A solution of trifluoroacetic anhydride (7.4 ml, 52 mmol) in THF (20 ml) was added with stirring over 10 min. The resulting mixture was stirred at 0° C. for 5 hr, and warmed to room temperature for 16 hr. The solvent was evaporated and the residue was diluted with 250 ml of ethyl acetate and stirred with 30 g of anhydrous potassium carbonate. The mixture was filtered through a pad of silica gel and the filtrate evaporated. The residue was washed with a mixture of ethyl acetate-ether to give 3.80 g of a white solid; mp 132–133° C.; MS (ESI) m/z 143.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:9])[CH:3]=1.CCN(C(C)C)C(C)C.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>C(Cl)Cl.[Cl-].[Na+].O>[Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:4]([CH3:9])[CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc(Br)ncc1N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(Br)ncc1NC(=O)C(C)(C)C
Reaction time: 1 h

Procedure:
6-Bromo-4 methyl-3 pyridinamine (1.03 g, 5.51 mmol) was dissolved in DCM (20 ml) at 0° C. then added Hunig's Base (1.154 ml, 6.61 mmol) followed by pivaloyl chloride (0.745 ml, 6.06 mmol). After stirring for 1 hr, the reaction was not complete. Another equivalent of TEA and pivaloyl chloride were added then stirred for an hour. The reaction was poured into brine and extracted with DCM (2×). The organic layer was separated and dried over Na2SO4, filtered and concentrated. The residue was chromatographed thru a 200 g ISCO redisep column and eluted with 5% MeOH/DCM to yield title compound. LC-MS: M+2=273;
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([CH3:13])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[I-:14].[Na+].I>>[I:14][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([CH3:13])[CH3:12])=[N:9][N:10]=2)[N:7]=1
Reactant: CC(C)c1nnc2ccc(Cl)nn12
Reactant: [I-]
Agent: I
Agent: [Na+]
Product: CC(C)c1nnc2ccc(I)nn12
Temperature: 90 °C
Reaction time: 96 h
Yield: 157.6 %

Procedure:
Two reactions were set up side by side as follows. Each 250 mL round bottom flask was charged with 6-chloro-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (7.5 g, 38.1 mmol, Preparation #G.1), sodium iodide (8.58 g, 57.2 mmol) and hydriodic acid (57 wt % in water, stabilized with <1.5% hypophosphorous acid; 52.1 mL, 381 mmol). The mixture was heated in an oil bath to about 90° C. with stirring for about 4 days. The combined reactions were filtered then the filtrate was basified with 25 wt % aqueous NaOH. The solids from the filtration were then added to the filtrate (still basic) and extracted with DCM (750 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was crystallized from DMF (90 mL, about 90° C.) to give the title compound (17.3 g, 78%): LC/MS (Table 1, Method a) Rt=1.67 min; MS m/z: 289.0 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]#[N:14])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[C:15]1([CH:21]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)(=[O:29])=[O:28])[CH2:22][C:23](O)=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(Cl)CCl.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:13]([CH2:12][C:8]1[CH:7]=[C:6]2[C:11]([CH:2]([NH:1][C:23](=[O:24])[CH2:22][CH:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:26][S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:37])[F:38])[CH:31]=3)(=[O:29])=[O:28])[CH2:3][CH2:4][O:5]2)=[CH:10][CH:9]=1)#[N:14]
Reactant: N#CCc1ccc2c(c1)OCCC2N
Reactant: O=C(O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#CCc1ccc2c(c1)OCCC2NC(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (4-amino-chroman-7-yl)-acetonitrile (Step A, 400 mg, 2.15 mmol) in CH2Cl2 (15 mL) was added 3-phenyl-3-(3-trifluoromethyl-benzenesulfonylamino)-propionic acid (802 mg, 2.15 mmol), HATU (408 mg, 1.07 mmol), EDC (453 mg, 2.36 mmol), and DIEA (0.7 mL, 4.29 mmol). The resulting mixture was stirred at RT for 18 h. Solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel. Elution with CH2Cl2:MeOH mixture (95:5) gave final compound. MS m/z: 544.12 (M+H). Calc'd. for C27H24F3N3O4S-543.56.