Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][NH:21][CH2:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][N:21]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNCC3)cc1
Reactant: CCOC(=O)Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)OCC)CC3)cc1

Procedure:
Method as example 34 using (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)phenyl)urea (example 12) and ethyl chloroformate as starting materials.
Reaction SMILES: [CH:1]([C:4]1[N:5]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[N:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:3])[CH3:2].C(C1N=CN(CCC2C=CC=CC=2)C=1C1C=CC=CC=1)(C)C.[Li+].CC([N-]C(C)C)C.CN([CH:56]=[O:57])C>C1COCC1>[CH:1]([C:4]1[N:5]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6]([CH:56]=[O:57])=[N:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)c1c(-c2ccccc2)ncn1CCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: CC(C)c1ncn(CCc2ccccc2)c1-c1ccccc1
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1c(-c2ccccc2)nc(C=O)n1CCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of the mixture of 4-isopropyl-3-phenethyl-5-phenylimidazole and 5-isopropyl-3-phenethyl-4-phenylimidazole (example 243C) (1.2 g, 4.14 mmoles) in THF (15 mL) under argon is cooled to −78° C. A 2.0M LDA solution (2.2 mL, 4.4 mmoles) is added dropwise. After 30 minutes at −78° C., DMF (1.83 g, 25 mmoles) is added dropwise. The reaction mixture is allowed to reach 0° C., then it is quenched by adding a half-saturated NaHCO3 solution. The aqueous phase is extracted three times with AcOEt. The organic phase is washed with water, brine, dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (heptane:AcOEt) as eluent with a gradient from (1:0) to (8:1) to give 5-isopropyl-1-phenethyl-4-phenylimidazole-2-carbaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[CH2:14][S:15][CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[O:10])=[C:4]([C:28](=[O:43])[NH:29][C:30]2[CH:34]=[CH:33][N:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([CH3:42])[CH:36]=3)[N:31]=2)[CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[CH2:14][S:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:10])=[C:4]([C:28](=[O:43])[NH:29][C:30]2[CH:34]=[CH:33][N:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([CH3:42])[CH:36]=3)[N:31]=2)[CH:3]=1
Reactant: Cc1ccc(-n2ccc(NC(=O)c3cc(Cl)ccc3NC(=O)c3cccc(CSCCC(=O)OC(C)(C)C)c3)n2)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-n2ccc(NC(=O)c3cc(Cl)ccc3NC(=O)c3cccc(CSCCC(=O)O)c3)n2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.9 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-(4-chloro-2-(1-(3,4-dimethylphenyl)-1H-pyrazol-3-ylcarbamoyl)phenylcarbamoyl)benzylthio)propanoate (150 mg, 0.24 mmol, 1.00 equiv) in dichloromethane (4 mL), and 2,2,2-trifluoroacetic acid (2 mL). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 36.3 mg (27%) of a white solid. 1H-NMR (300 MHz, DMSO, ppm): δ 11.82 (s, 1H), 11.48 (s, 1H), 8.52 (d, J=8.70 Hz, 1H), 8.41 (s, 1H), 8.11 (s, 1H), 7.92 (s, 1H), 7.79 (m, 1H), 7.67 (m, 1H), 7.57 (m, 4H), 7.26 (m, 1H), 6.92 (d, J=1.8 Hz, 1H), 3.86 (s, 2H), 2.60 (m, 2H), 2.29 (m, 6H). MS (ES, m/z): 563 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[CH:7][CH:8]=2)[N:3]=1.[CH3:14][O-:15].[Na+].[H-].[Na+]>CO>[Cl:13][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([CH3:12])=[CH:11][C:2]([O:15][CH3:14])=[N:3]2)=[CH:8][CH:7]=1
Reactant: Cc1cc(Cl)nc2cc(Cl)ccc12
Reactant: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)c2ccc(Cl)cc2n1

Procedure:
2-Chloroquinoline 14 (7.0 g; 32.8 mmol) was added to a solution of sodium methoxide in methanol generated from 1.08 g (36.1 mmol) of 80% sodium hydride in 80 ml of methanol. The resulting mixture was refluxed overnight. It was filtered while still hot to remove undissolved matter. The product crystallized from the methanol upon cooling to deliver 6.1 g (70%) of 15 as a white solid. 1H NMR (CDCl3);: δ2.62 (s, 3H); 4.10 (s, 3H); 6.78 (s, 1H); 7.38 (d, 1H); 7.81 (d, 1H); 7.93 (d, 1H).
Reaction SMILES: C1([Li])C=CC=CC=1.[C:8]1([S:14][CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)=O.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]I)=[CH:23][CH:22]=1>O.O1CCCC1>[C:8]1([S:14][CH2:15][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:24]2[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1ccc(CCCCCCI)cc1
Reactant: CSc1ccccc1
Agent: O=C=O
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CCCCCCCSc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Phenyllithium (378 ml., 0.755 mole) was added over a period of 2-5 minutes to a solution of 94.5 g. of thioanisole in 600 ml. of tetrahydrofuran, stirred under nitrogen. The mixture was stirred at room temperature for about 16 hours, then cooled to -70° C. (solid CO2), and 141 g. of 6-(4-methoxyphenyl)hexyl iodide in 210 ml. of tetrahydrofuran was added slowly. The reaction mixture was stirred at -65° C. for 2 hours and then allowed to warm to room temperature. Water was added and the mixture extracted with pentane. The pentane extracts were washed with water, dried and concentrated to remove the solvent. The residue was distilled in vacuo, b.p. 171°-174° C. (0.15 mm.). The distillate crystallized and was recrystallized from pentane, to give 7-(4-methoxyphenyl)heptyl phenyl sulfide, m.p. 58°-59° C.
Reaction SMILES: C([N-:3][CH:4]=O)=O.[Na+].C(#N)C.CN(C)C=O.ClC/[C:17](=[CH:27]/[F:28])/[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1>O>[NH2:3][CH2:4]/[C:17](=[CH:27]/[F:28])/[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1
Reactant: F/C=C(/CCl)CCc1ccc(F)cc1
Reactant: O=C[N-]C=O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: NC/C(=C/F)CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Combine sodium diformylamide (28.8 g, 0.31 mol), acetonitrile (360 g), and N,N-dimethylformamide (48 g). Add (E)-1-chloro-2-(fluoromethylene)-4-(p-fluorophenyl)butane (50.6 g, 0.23 mol). Heat to reflux. After 5 hours, cool to ambient temperature. Add water (466 g) and stir for 15 minutes. After 30 minutes, the aqueous layer is removed. Evaporate the organic layer in vacuo to give the title compound. 1H NMR (CDCl3, 300 MHz) δ2.28 (m, 2H), 2.72 (m, 2H), 4.07 (d , J=3Hz, 2H), 6.74 (d, J=81Hz, 1H), 6.94 (m, 2H), 7.13 (m, 2H), 8.73 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][C:12]([OH:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].[CH3:21][C:22](C)=O>>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:11][C:12]([O:14][CH2:21][CH3:22])=[O:13])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C(O)CBr
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)COc1ccc(C=O)cc1

Procedure:
p-Hydroxybenzaldehyde (4.88 g), bromoacetic acid (6.68 g) and potassium carbonate (5.53 g) were suspended in 100 ml of acetone, and refluxed for 15 hours. After the solvent was distilled off under reduced pressure, water was added followed by extraction with methylene chloride. The organic phase was washed in saturated aqueous sodium chloride, and dried over magnesium sulfate. After distillation of the solvent under reduced pressure, 8.32 g of ethyl 4-formylphenoxyacetate was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:19]2[N:20]=[CH:21][N:22]([CH3:34])[C:23]=2[C:24]2[S:33][C:27]3[N:28]=[CH:29][N:30]=[C:31]([NH2:32])[C:26]=3[CH:25]=2)[CH:16]=[CH:17][CH:18]=1.N1C=CC=CC=1>C1COCC1>[NH2:32][C:31]1[C:26]2[CH:25]=[C:24]([C:23]3[N:22]([CH3:34])[CH:21]=[N:20][C:19]=3[C:15]3[CH:14]=[C:13]([NH:12][C:9](=[O:10])[O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:18]=[CH:17][CH:16]=3)[S:33][C:27]=2[N:28]=[CH:29][N:30]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cn1cnc(-c2cccc(N)c2)c1-c1cc2c(N)ncnc2s1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cn1cnc(-c2cccc(NC(=O)OCc3ccccc3)c2)c1-c1cc2c(N)ncnc2s1
Reaction time: 1 h
Yield: 28 %

Procedure:
Benzylchloroformate (0.027 mL) was added to a solution of 6-[4-(3-aminophenyl)-1-methyl-1H-imidazol-5-yl]thieno[2,3-d]pyrimidin-4-amine (Intermediate 110) (40 mg) and pyridine (0.02 mL) in THF (7 mL). The mixture was stirred under an inert atmosphere for 1 hour, then quenched with H2O (10 mL) and extracted EtOAc (3×10 mL). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with CH2Cl2:MeOH (0-10%) gave the title compound as a gum (16 mg, 28%);
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][OH:18])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].CC(=O)OCC>C(Cl)Cl>[CH3:26][S:27]([O:18][CH2:17][CH2:16][CH2:15][NH:14][C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=1)=[O:13])(=[O:29])=[O:28]
Reactant: CC(C)(C)c1ccc(NC(=O)NCCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)NCCCOS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 108.3 %

Procedure:
A solution of 1-(4-tert-butylphenyl)-3-(3-hydroxypropyl)urea (563 mg, 2.25 mmol) in methylene chloride (14 mL) was cooled at 0° C. and treated dropwise with triethylamine (0.376 mL, 2.70 mmol) followed by methanesulfonyl chloride (0.191 mL, 2.47 mmol) and the mixture was stirred at 0° C. until complete by TLC. After 30 minutes, the reaction was complete by TLC (100% EA). The reaction mixture was diluted with 15 mL CH2Cl2 and the organic phase was washed with 15 mL portions of 1N HCl, sat NaHCO3 and H2O and dried over MgSO4. The solution was filtered and concentrated to a viscous oil that was placed under high vacuum to yield the title compound (800 mg) as a colorless viscous oil that was stored in the freezer: MS (ESI+) for C15H24N2O4S m/z 329.1 (M+H)+; HPLC purity 93% (ret. time, 3.95 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][C:6]1[N:7]=[C:8]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[S:9][C:10]=1[C:11](O)=[O:12].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[O:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH:47]1[O:52][NH2:53]>CN(C)C=O.CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][C:6]1[N:7]=[C:8]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[S:9][C:10]=1[C:11]([NH:53][O:52][CH:47]1[CH2:48][CH2:49][CH2:50][CH2:51][O:46]1)=[O:12]
Reactant: O=C(O)c1sc(N2CCOCC2)nc1Cc1ccc(Cl)c(Cl)c1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NOC1CCCCO1)c1sc(N2CCOCC2)nc1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of 4-(3,4-dichlorobenzyl)-2-morpholin-4-yl-1,3-thiazole-5-carboxylic acid.Na (125 mg, 0.316 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (72.8 mg, 0.380 mmol), and 1-hydroxybenzotriazole (51.3 mg, 0.380 mmol) in N,N-dimethylformamide (1.50 mL) was added O-(tetrahydropyran-2-yl)hydroxylamine (55.6 mg, 0.474 mmol). The reaction was stirred at rt for 15 hrs. The mixture was distributed between water and EtOAc, and the aqueous layer was extracted with EtOAc (×2). The combined organic layer was washed with NaHCO3(aq) saturated solution and 10% LiCl (aq) soln (×2), dried over Na2SO4, and concentrated to provide 4-(3,4-dichlorobenzyl)-2-(morpholin-4-yl)-N-(tetrahydro-2H-pyran-2-yloxy)-1,3-thiazole-5-carboxamide as a white solid (153 mg, quantitative). LCMS: (AA) ES+ 472, 474, 476; 1H NMR (400 MHz, CDCl3) δ 7.49-7.43 (d, J=1.9 Hz, 1H), 7.30-7.26 (m, 1H), 7.26-7.17 (m, 1H), 5.01-4.89 (d, J=2.8 Hz, 1H), 4.31-4.21 (m, 2H), 3.96-3.86 (td, J=10.4, 9.1, 2.8 Hz, 1H), 3.80-3.70 (t, J=4.9 Hz, 4H), 3.66-3.56 (m, 1H), 3.51-3.42 (t, J=4.9 Hz, 4H), 1.90-1.73 (m, 3H), 1.69-1.49 (m, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[CH3:7][N:8]1[C:21]2[CH:20]=[CH:19][C:18]([CH:22]=O)=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.C(OP([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45]P(OCC)(OCC)=O)=[CH:41][CH:40]=2)=[CH:35][CH:34]=1)(=O)OCC)C>CN1CCCC1=O>[CH3:7][N:8]1[C:21]2[CH:20]=[CH:3][C:2]([CH:5]=[CH:45][C:42]3[CH:41]=[CH:40][C:39]([C:36]4[CH:35]=[CH:34][C:33]([CH:32]=[CH:22][C:18]5[CH:19]=[CH:20][C:21]6[N:8]([CH3:7])[C:9]7[C:14]([S:15][C:16]=6[CH:17]=5)=[CH:13][CH:12]=[CH:11][CH:10]=7)=[CH:38][CH:37]=4)=[CH:44][CH:43]=3)=[CH:1][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: CC(C)(C)[O-]
Reactant: CCOP(=O)(Cc1ccc(-c2ccc(CP(=O)(OCC)OCC)cc2)cc1)OCC
Reactant: CN1c2ccccc2Sc2cc(C=O)ccc21
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN1c2ccccc2Sc2cc(C=Cc3ccc(-c4ccc(C=Cc5ccc6c(c5)Sc5ccccc5N6C)cc4)cc3)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.80 g (7.1 mmol) of potassium tert-butoxide and then 1.82 g (3.3 mmol) of 10-methylphenothiazine-3-carbaldehyde were added under nitrogen at room temperature with stirring to a solution of 1.42 g (3.14 mmol) of diethyl[4′-(diethoxyphosphoryl-methyl)biphenyl-4-ylmethyl]phosphonate (U.S. Pat. No. 3,984,399, Example 2, column 29, line 58-66) in 32 ml of dimethyl sulfoxide dried over molecular sieve. After stirring at room temperature for four hours, the reaction solution was diluted with 70 ml of methanol and stirred for a further 15 min. The precipitate was filtered off, washed with 172 ml of methanol and dried at 35° C. under reduced pressure. The crude product (1.70 g) was recrystallized in 255 ml of N-methylpyrrolidone. After the solvent residues had been removed at 225° C. under high vacuum, 0.98 g (50% of theory) of analytically pure yellow solid having a melting point of 380° C. was obtained, whose solution in N-methylpyrrolidone fluoresced at λ=576 nm.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:3]1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][O:57][C:58]1[N:63]=[CH:62][C:61]([C:64](O)=[O:65])=[CH:60][CH:59]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C@H:2]1[CH2:3][N:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)(=[O:9])=[O:10])[CH2:5][CH2:6][N:7]1[C:64]([C:61]1[CH:62]=[N:63][C:58]([O:57][CH3:56])=[CH:59][CH:60]=1)=[O:65]
Reactant: COc1ccc(C(=O)O)cn1
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]2C)cn1
Yield: 59.2 %

Procedure:
To a solution of (3S)-3-methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 2) (100 mg, 0.324 mmol) in DMF (5 ml) was added HOBT.H2O (49.7 mg, 0.324 mmol), HBTU (123 mg, 0.324 mmol), 6-(methyloxy)-3-pyridinecarboxylic acid (49.7 mg, 0.324 mmol) and DIPEA (0.170 ml, 0.973 mmol) and the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was evaporated in vacuo. The residue was dissolved in DCM (50 ml), transferred to a separating funnel and the solution was washed with NaHCO3 (5 ml), twice. The organic layer was dried with magnesium sulphate which was removed by filtration and the filtrate evaporated to dryness in vacuo. The residual oil was dissolved in 1:1 MeCN/DMSO (1.8 ml) and purified by MDAP in two batches. The fractions containing the desired product were combined and evaporated to dryness in vacuo to yield the title compound (85 mg).
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[N+:24]([O-])=O)[CH2:4][CH3:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCC(CC)Nc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Yield: 109.4 %

Procedure:
A mixture of N4-(1-ethyl-propyl)-6-methyl-3-nitro-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,4-diamine (40 mg, 0.112 mmol) and 8 mg of 10% palladium/carbon (Pd/C) in 20 ml of ethanol was hydrogenated at 50 psi overnight. The mixture was filtered through celite and the filtrate was concentrated to dryness to give adark residue (40 mg). 1H NMR (CDCl3) δ 6.88 (s, 2H), 5.97 (s, 1H), 4.32 (d, 1H), 3.28 (m, 1H), 2.27 (s, 3H), 2.26 (s, 3H), 2.18 (s, 6H), 1.45–1.75 (m, 4H), 0.93 (t, 6H) ppm. The corresponding di-HCl salt was prepared as a tan solid, mp 213–216° C., 1H NMR(DMSO-d6) δ 11.1 (s, 1H), 8.48 (s, 1H), 6.98 (s, 2H), 6.73 (brs, 1H), 6.38 (s, 1H), 3.36 (m, 1H), 2.28 (s, 3H), 2.19 (s, 3H), 2.08 (s, 6H), 1.54 (m, 4H), 0.88 (t, 6H) ppm.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]([CH2:31][CH:32]1[CH2:36][O:35]C(C)(C)[O:33]1)[C:9]1[C:10]([I:30])=[C:11]([C:17]([I:29])=[C:18]([NH:21][C:22](=[O:28])[CH2:23][O:24]C(=O)C)[C:19]=1[I:20])CCC([O-])=O)=[O:7])(=O)C.[OH-:39].[Na+].Cl.[CH3:42]O>O>[OH:4][CH2:5][C:6]([N:8]([CH2:31][CH:32]([OH:33])[CH2:36][OH:35])[C:9]1[C:10]([I:30])=[C:11]([C:17]([I:29])=[C:18]([NH:21][C:22](=[O:28])[CH2:23][OH:24])[C:19]=1[I:20])[CH2:42][OH:39])=[O:7]
Reactant: [OH-]
Reactant: CO
Reactant: CC(=O)OCC(=O)Nc1c(I)c(CCC(=O)[O-])c(I)c(N(CC2COC(C)(C)O2)C(=O)COC(C)=O)c1I
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(CO)Nc1c(I)c(CO)c(I)c(N(CC(O)CO)C(=O)CO)c1I
Reaction time: 2 h
Yield: 81 %

Procedure:
N,N′-Bis(acetoxyacetyl)-N-[(2,2-dimethyl-1,3-dioxolane-4-yl)-methyl]-3,5-diamino-2,4,6-triiodobenzylacetate (36 mg, 0.042 mmol) was dissolved in a mixture of methanol (3 ml) and water (4 ml) and the pH was adjusted to 12 using a 1 M aqueous solution of NaOH. After stirring for 2 h, pH was adjusted to 1 using 1 M aqueous HCl and stirring was continued for 16 h. The solution was neutralized with an aqueous NaH2PO4 buffer, the solvents were removed by evaporation and the residue was purified by preparative HPLC to give 24 mg (81%) of the pure product.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:11][CH:10]([C:12]#[N:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([N:22]=[C:23]([NH2:25])[NH2:24])#[N:21].[OH-].[K+]>COCCO.O>[C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:11][CH:10]([C:12]3[N:24]=[C:23]([NH2:25])[N:22]=[C:20]([NH2:21])[N:13]=3)[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CN=C(N)N
Reactant: N#CC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCO
Product: Nc1nc(N)nc(C2CN(C(c3ccccc3)c3ccccc3)C2)n1
Temperature: 25 °C

Procedure:
A solution of 1-(diphenylmethyl)-3-azetidinecarbonitrile (500 mg, 2.01 mmol), dicyandiamide (220 mg, 2.62 mmol) and KOH (34 mg, 0.604 mmol) in 2-methoxyethanol (10 mL) was heated at reflux for 4 hours, diluted with water, and cooled to room temperature. The precipitate was rinsed with water and dried under vacuum to provide the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][N:3]=1.[CH3:13][CH:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:15]>>[CH:14]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[C:6]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][N:3]=2)[CH2:18][CH2:17]1)([CH3:15])[CH3:13]
Reactant: CC(C)N1CCNCC1
Reactant: CC(=O)N(C)c1ccnc(Cl)c1
Product: CC(=O)N(C)c1ccnc(N2CCN(C(C)C)CC2)c1
Temperature: 120 °C

Procedure:
A mixture of 4 g (22 mmol) N-(2-chloro-pyridin-4-yl)-N-methyl-acetamide and 2.8 g (22 mmol) 1-(2-propyl)-piperazine was heated to 120° C. for 24 h. The crude product was purified by flash column chromatography on silica elutingwith a gradient formed from heptane and ethyl acetate (0.1% NEt3) to yield after evaporation of the product fractions 2.5 g (41%) of the title compound as light brow oil. MS: (m/e): 277.2 (MH+).
Reaction SMILES: [CH2:1]([C@H:6]1[C@H:14]([CH3:15])[O:13][C:12](=[O:16])[C@@H:11]([NH:17]C(=O)OC(C)(C)C)[CH2:10][CH2:9][CH2:8][C@@H:7]1[O:25][CH2:26][CH2:27][CH3:28])[CH2:2][CH:3]([CH3:5])[CH3:4].[ClH:29].O1CCOCC1>C(Cl)Cl>[Cl-:29].[CH2:1]([C@H:6]1[C@H:14]([CH3:15])[O:13][C:12](=[O:16])[C@@H:11]([NH3+:17])[CH2:10][CH2:9][CH2:8][C@@H:7]1[O:25][CH2:26][CH2:27][CH3:28])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CCCO[C@H]1CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@@H](C)[C@@H]1CCC(C)C
Reactant: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCO[C@H]1CCC[C@H]([NH3+])C(=O)O[C@@H](C)[C@@H]1CCC(C)C
Product: [Cl-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl ((3S,7S,8S,9S)-8-isopentyl-9-methyl-2-oxo-7-propoxyoxonan-3-yl)carbamate (330 mg, 0.826 mmol) in DCM (3 mL) was added a solution of HCl in dioxane (2.07 mL, 8.26 mmol, 4M) under N2 and the resulting solution was stirred at room temperature for 2 h. The solvent was removed under a stream of N2, which afforded a white solid. This solid was triturated with Et2O (3×3 mL) and the resulting powder was dried under high vacuum for 1 h to give (3S,7S,8S,9S)-8-isopentyl-9-methyl-2-oxo-7-propoxyoxonan-3-aminium chloride (59): ESIMS m/z 300 ([M+H]+).
Reaction SMILES: [CH:1]1[CH:10]=[C:9]([OH:11])[C:8]2[N:7]=[CH:6][C:5]([OH:12])=[CH:4][C:3]=2[CH:2]=1>C(OC(=O)C)(=O)C.N1C=CC=CC=1.C(OCC)(=O)C>[C:9]([O:12][C:5]1[CH:6]=[N:7][C:8]2[C:3]([CH:4]=1)=[CH:2][CH:1]=[CH:10][C:9]=2[O:11][C:5](=[O:12])[CH3:4])(=[O:11])[CH3:8]
Reactant: Oc1cnc2c(O)cccc2c1
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cnc2c(OC(C)=O)cccc2c1
Yield: 78 %

Procedure:
Jineol of 5.0 mg was dissolved in 0.5 ml of acetic acid anhydride and 0.5 ml of pyridine, and then the solution was agitated at room temperature for 9 hours. After the solution was diluted with ethyl acetate, it was washed with sodium dicarbonate solution and brine. The solution was dried with anhydrous magnesium sulfate anhydride. After the residue was removed, the solution was purified by silicagel chromatography to give 5.9 mg of 3,8-diacetoxy quinoline with 78% yield.
Reaction SMILES: [NH2:1][C:2]1[C:6]2=[N:7][N:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:9](=[O:11])[CH:10]=[C:5]2[NH:4][N:3]=1.Cl[C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1>CN1CCCC1=O.CO>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[C:9](=[O:11])[CH:10]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][C:21]4[N:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:6]3=[N:7]2)=[CH:13][CH:14]=1
Reactant: COc1ccc(-n2nc3c(N)n[nH]c3cc2=O)cc1
Reactant: Clc1ncccn1
Solvent: CN1CCCC1=O
Solvent: CO
Product: COc1ccc(-n2nc3c(Nc4ncccn4)n[nH]c3cc2=O)cc1
Temperature: 130 °C
Reaction time: 5 h
Yield: 56.6 %

Procedure:
To 3-amino-5-(4-methoxy-phenyl)-1,5-dihydro-pyrazolo[4,3-c]pyridazin-6-one (purchased from Bionet, 67.6 mg, 0.2628 mmoles) in N-methylpyrrolidinone (263 uL) was added 2-chloro-pyrimidine (15.1 mg, 0.5 eq). The reaction was stirred for 5 hours at 130° C. to give crude desired product as evidenced by mass spectrometry. The reaction was diluted with methanol (2 ml) and purified by reverse phase chromatography to give 25 mg (28%) of pure 5-(4-methoxy-phenyl)-3-(pyrimidin-2-ylamino)-1,5-dihydro-pyrazolo[4,3-c]pyridazin-6-one (I-17) as a solid. LC/MS: tret=2.13 min, M+H+=336.1.