Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][OH:6])=[O:4].[F:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(C(C)C)C(C)C)C>ClCCl>[F:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][CH2:2][C:3]([NH:5][OH:6])=[O:4])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(OCCCCF)cc1
Reactant: NCC(=O)NO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNS(=O)(=O)c1ccc(OCCCCF)cc1)NO
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To the resin from stage 58.1 (350 mg, ˜0.3 mmol) are added successively 4-(4-fluorobutoxy)-benzenesulfonyl chloride (306 mg, 1.15 mmol) in dry dichloromethane (4 ml), and N-ethyldiisopropylamine (0.24 ml, 1.40 mmol) in dry dichloromethane (4 ml). After stirring for 15 h at r.t. the suspension is filtered and the resin washed with dichloromethane (2×), DMF (2×), alternating with H2O and DMF (3×), alternating with THF and 2-propanol (3×), dichloromethane (3×). The resin is dried under reduced pressure to provide polymer-bound 2-[4-(4-fluoro-butoxy)-benzenesulfonylamino]-N-hydroxy-acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:12].ClS([N:17]=[C:18]=[O:19])(=O)=O.O>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[N:8]2[C:18]([NH2:17])=[O:19])=[CH:4][C:3]=1[F:12]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C1Cc2cc(F)c(Cl)cc2N1
Solvent: O
Solvent: CC#N
Product: NC(=O)N1C(=O)Cc2cc(F)c(Cl)cc21
Reaction time: 0.75 h
Yield: 10.1 %

Procedure:
To a slurry of 6-chloro-5-fluoro-2-oxindole (0.04 mole) in acetonitrile (80 ml) was added chlorosulfonyl isocyanate (6.65 g, 0.047 mole) and the mixture was stirred for 45 minutes. Water (100 ml) was then added and the aqueous mixture was stirred for one hour. The precipitate which formed was filtered off and recrystallized from acetonitrile to give 0.92 g of the title product. Extraction of the filtrate from the aqueous reaction mixture with ethyl acetate (300 ml) followed by drying the extract over MgSO4 and then evaporating it under reduced pressure gave additional product. Recrystallization from acetonitrile gave an additional 2.2 g of product, m.p. 229°-231° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]([F:30])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[F:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[C:34]([CH3:39])[CH:33]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:36][C:35]3[CH:37]=[CH:38][C:32]([F:31])=[CH:33][C:34]=3[CH3:39])=[C:3]([C:16]([N:18]3[CH2:19][CH2:20][C:21]([F:30])([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:22][CH2:23]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Cc1cc(F)ccc1N
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(F)(c4ccccc4)CC3)cnc12
Product: CCOC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC(F)(c4ccccc4)CC3)cnc12
Yield: 72.7 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-fluoro-4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (250 mg, 0.58 mmol) obtained in step 2 and 4-fluoro-2-methylaniline (0.1 mL, 0.87 mmol), the title compound (219 mg, 73%) was obtained.
Reaction SMILES: [CH3:1][C@H:2]1[C:7](=O)[CH2:6][C@H:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH2:3]1.[CH3:12]COCC>>[CH3:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:9]([CH3:11])=[CH2:10])[CH2:6][C:7]1=[CH2:12]
Reactant: C=C(C)[C@@H]1CC[C@@H](C)C(=O)C1
Reactant: CCOCC
Product: C=C1CC(C(=C)C)CCC1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
BDAM (2.60 grams) was combined with ether (2 milliliters) and TMAL (1.0 milliliter) as described in Example 4, after which 1.50 grams of (+) dihydrocarvone were added. As in Example 4, a noticeable exotherm was observed. After 3 hours of stirring at room temperature, the reaction mixture was hydrolyzed as in Example 1. After the usual work up and column separation, 1.40 grams of 4-methyl-3-methylene-1-isopropenyl cyclohexane were isolated (95% yield).
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=[O:7])[CH:4]=[CH:3]1.[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>>[CH2:8]([O:1][CH:2]1[NH:6][C:5](=[O:7])[CH:4]=[CH:3]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=C1C=CC(O)N1
Reactant: CCCCCCO
Product: CCCCCCOC1C=CC(=O)N1
Temperature: 85 °C

Procedure:
A mixture of 2.5 g of 1,5-dihydro-5-hydroxy-2H-pyrrol-2-one in 75 cm3 of 1-hexanol and 1.3 g of Amberlite IR 120 H is heated to 85° C. for 2 hours. After allowing to cool to ambient temperature, the resin is filtered off and the solvent is evaporated under reduced pressure. The residue is distilled, and 3.4 g of the expected product is obtained. b.p. 120°-125° C. under 0.4 mbar.
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][CH2:12]Br)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([O:16][C:17]([NH:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:18])[CH3:15].C(=O)([O-])O.[Na+]>C(O)C>[C:1]([CH2:9][CH2:10][CH2:11][CH2:12][N:23]1[CH2:22][CH2:21][N:20]([NH:19][C:17]([O:16][CH2:14][CH3:15])=[O:18])[CH2:25][CH2:24]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)NN1CCNCC1
Reactant: O=C(CCCCBr)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)NN1CCN(CCCCC(=O)c2ccccc2)CC1
Yield: 91 %

Procedure:
17.0 g of 1-benzoyl-4-bromobutane, 13.4 g of 1-(ethoxycarbonylamino)piperazine and 17.8 g of sodium hydrogen carbonate were heated under reflux in ethanol for 6 hours with stirring. The insoluble materials were removed from the reaction mixture by filtration. The solvent was distilled off, and water was added to the residue. The mixture was extracted with benzene. The extract was recrystallized from benzene-hexane to give 21.4 g of 4-(4-benzoylbutyl)-1-(ethoxycarbonylamino)-piperazine having a melting point of 105° to 106° C.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:2]2[S:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:14][CH:13]=1
Reactant: Clc1nc2ccccc2s1
Reactant: Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Nc1ccc(Sc2nc3ccccc3s2)cc1
Yield: 88.4 %

Procedure:
2-Chlorobenzothiazole (0.06 moles, 10.1 g), 4-aminothiophenol (0.06 moles, 7.5 g) and potassium carbonate (0.06 moles, 8.3 g) were stirred for 3 days at room temperature in 250 ml ethanol, filtered, and concentrated. Ethyl acetate was added and the solution washed with water, dried over sodium sulfate and concentrated. The product was purified by HPLC over silica gel eluted with 40-60% ethyl acetate in hexane to yield 2-(4-aminophenylthio)benzothiazole 13.7 g, 88%. Mass spec (FD) 258. Calculated for C11H10N2S2:C, 60.44; H, 3.90; N, 10.84. Found: C, 60.63; H, 3.98; N, 11.01.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][CH2:4][CH3:5].CCN(CC)CC.CC(C)(C)C(Cl)=O.[CH3:22][C@H:23]1[C@@H:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:26][C:25](=[O:34])[NH:24]1.[Li+].[Cl-]>C1COCC1>[CH3:22][C@H:23]1[C@@H:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:26][C:25](=[O:34])[N:24]1[C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Reactant: CCCCC(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0° C. stirred solution of valeric acid (3.83 mL, 35.2 mmol) and Et3N (14.7 mL, 106 mmol) in dry THF (175 mL) was added trimethylacetyl chloride (5.29 mL, 42.3 mmol) dropwise. The mixture was stirred at 0° C. for 1 hour and (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone (7.50 g, 42.3 mmol) was added followed by LiCl (1.79 g, 42.3 mmol). The reaction was warmed to room temperature overnight with good stirring. The mixture was filtered and the filtrate was concentrated under reduced pressure. Et2O (75 mL) was added to the residue, which was washed with sat. NaHCO3 (3×40 mL), 1N HCl (3×40 mL), and brine (2×40 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give a quantitative yield of crude product.
Reaction SMILES: ClC1C=C(C(OO)=[O:9])C=CC=1.[CH2:12]([N:15]1[C:39](=[O:40])[C:18]2=[N:19][N:20]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([N:34]4[CH:38]=[CH:37][CH:36]=[N:35]4)=[CH:30][CH:29]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:17]2=[N:16]1)[CH:13]=[CH2:14].C(=O)(O)[O-].[Na+]>ClCCl.[Cl-].[Na+].O>[O:9]1[CH2:14][CH:13]1[CH2:12][N:15]1[C:39](=[O:40])[C:18]2=[N:19][N:20]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([N:34]4[CH:38]=[CH:37][CH:36]=[N:35]4)=[CH:30][CH:29]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:17]2=[N:16]1
Reactant: C=CCn1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)nc-2c1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=c1c2nn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1CC1CO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3-chlorobenzenecarboperoxoic acid (29 mg, 0.17 mmol, 1.3 equiv) in dichloromethane (3 mL) was cooled to 0° C. and treated with a dichloromethane (1 mL) solution of 2-allyl-5-[4-(1H-pyrazol-1-yl)benzyl]-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one [(Example 10), 50 mg, 0.13 mmol]. After stirring for 1 hour at 0° C., the mixture was warmed to ambient temperature and stirred for an additional 14 hours. The mixture was treated with additional 3-chlorobenzenecarboperoxoic acid (50.0 mg, 0.29 mmol, 2.2 equiv) and after three hours, the mixture was cooled to 0° C., treated with sodium bicarbonate (3 mL, saturated aqueous), diluted with brine (10 mL) and extracted with dichloromethane (3×30 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel gradient chromatography (0:100 to 100:0; hexanes:ethyl acetate), providing the titled compound as a dark red solid: 1H-NMR (400 MHz, CDCl3) δ 8.31-8.28 (1H, m), 7.89 (1H, d, J=2.5 Hz), 7.71 (1H, d, J=1.4 Hz), 7.68 (2H, d, J=8.7 Hz), 7.57-7.51 (3H, m), 7.38 (2H, d, J=8.7 Hz), 6.46 (1H, dd, J=2.4, 1.8 Hz), 5.85 (2H, s), 4.32 (1H, dd, J=14.5, 4.5 Hz), 4.22 (1H, dd, J=14.5, 5.5 Hz), 3.43-3.38 (1H, m), 2.88 (1H, dd, J=4.7, 4.1 Hz), 2.79 (1H, dd, J=4.8, 2.6 Hz) ppm. high resolution mass spectrometry (ES+) m/z 399.1563 [(M+H)+; calculated for C22H18N6O2: 399.1564].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[CH:8][CH:7]=[CH:6]2.[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([Br:24])=[C:20]([CH:23]=1)[CH2:21]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:24][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:23][C:20]=1[CH2:21][O:13][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(Br)c(CO)c1
Reactant: COc1ccc2c(O)cccc2c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(Br)c(COc2cccc3cc(OC)ccc23)c1
Reaction time: 8 h
Yield: 59.2 %

Procedure:
To a solution of 6-methoxynaphthol (12.9 g, 74.1 mmol), 5-methoxy-2-bromobenzyl alcohol (17.7 g, 81.6 mmol), and triphenylphosphine (31.1 g, 119 mmol) in THF (400 mL) was slowly added a solution of DEAD (20.6 g, 119 mmol) in THF (50 mL). The solution was stirred overnight, concentrated onto silica, and purified by silica column (10% ethyl acetate—hexanes) to yield 16.38 g (59%) of the title compound as a white solid: mp 83-84° C.; 1H NMR (CDCl3): δ 3.78 (3H, s), 3.92 (3H, s), 5.25 (2H, s), 6.75-6.77 (2H, m), 7.12 (1H, d, J=2.44 Hz), 7.15 (1H, dd, J=2.44 Hz, J=9.28 Hz), 7.24 (1H, d, J=2.93 Hz), 7.32-7.36 (2H, m), 7.48 (1H, d, J=8.79 Hz), 8.27 (1H, d, J=9.23 Hz); MS (ESI) m/z373/375 ([M+H]+);
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH3:24])[CH:17]=3)=[CH:12][CH:11]=2)[N:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[N:6]=1)=[O:4].[OH-].[K+].CO>O>[CH2:23]([O:22][C:18]1[CH:17]=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([CH:8]3[N:7]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH2:9]3)=[CH:11][CH:12]=2)[CH:21]=[CH:20][CH:19]=1)[CH3:24]
Reactant: CCOc1cccc(-c2ccc(C3CC(C(=O)OC)=NN3c3ccccc3F)cc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOc1cccc(-c2ccc(C3CC(C(=O)O)=NN3c3ccccc3F)cc2)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
5-(3′-Ethoxy-biphenyl-4-yl)-1-(2-fluoro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid methyl ester (250.0 mg, 0.60 mmol) prepared in Step 1 and a solution of potassium hydroxide (67.0 mg, 1.19 mmol) in distilled water (4.0 mL) were added to methanol (4.0 mL). The reaction mixture was stirred at 70° C. for 2 hours and then concentrated under reduced pressure to discard methanol. The resulting residue was washed with diethyl ether, acidified by a 1N hydrochloric acid solution, and then extracted with ethyl acetate. The extract was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 200.0 mg of the titled compound as a pale yellow solid.
Reaction SMILES: [CH:1]([C:3]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:23]=[N:24][N:25]([CH3:27])[CH:26]=3)=[CH:18][CH:17]=2)=[CH:9][C:4]=1[C:5](OC)=[O:6])=[O:2].[O:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[CH2:33][NH2:34].S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1.C(OCC)(=O)C>[OH:2][CH:1]1[C:3]2[C:4](=[CH:9][C:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[N:23]=[N:24][N:25]([CH3:27])[CH:26]=4)=[CH:18][CH:17]=3)=[C:11]([CH3:14])[C:12]=2[CH3:13])[C:5](=[O:6])[N:34]1[CH2:33][C@@H:29]1[CH2:30][CH2:31][CH2:32][O:28]1
Reactant: COC(=O)c1cc(Cc2ccc(-c3cn(C)nn3)cc2)c(C)c(C)c1C=O
Reactant: NC[C@@H]1CCCO1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(Cc2ccc(-c3cn(C)nn3)cc2)cc2c(c1C)C(O)N(C[C@@H]1CCCO1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-formyl-3,4-dimethyl-5-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)benzoate (0.13 g) in THF (3.00 mL) were added 1-((2S)-tetrahydrofuran-2-yl)methanamine (0.04 mL) and anhydrous magnesium sulfate (0.04 g), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.11 g).
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[B-](F)(F)(F)[F:10].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[F:10][C:2]1([CH3:1])[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8]
Reactant: F[B-](F)(F)F
Reactant: CC1C(=O)CCC1=O
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CC1(F)C(=O)CCC1=O
Temperature: 25 °C
Yield: 86.2 %

Procedure:
A mixture of 2-methylcyclopentane-1,3-dione (4.50 g, 40.1 mmol) and Selectfluor (17.06 g, 48.2 mmol) in acetonitrile (80 mL) was heated to reflux for 2 h, cooled to room temperature and concentrated in vacuo. The residue was diluted with ethyl acetate (200 mL), washed with saturated sodium bicarbonate, water, brine, dried (MgSO4) and concentrated. Purification by silica gel chromatography, eluting with 20 to 50% ethyl acetate in hexanes, gave 2-fluoro-2-methylcyclopentane-1,3-dione (4.50 g, 82% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 2.65-3.19 (4H, m), 1.38-1.77 (3H, m).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](=O)CCCC)CCC.C[Si]([N:30]=[N+:31]=[N-:32])(C)C>C1(C)C=CC=CC=1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([C:12]2[NH:32][N:31]=[N:30][N:13]=2)=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(Oc2ccccc2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: c1ccc(Oc2ccc(-c3nnn[nH]3)cc2)cc1

Procedure:
A solution of 4-phenoxybenzonitrile (9.87 g), dibutyltin oxide (3.88 g), and trimethylsilyl azide (33.5 ml) in anhydrous toluene (200 ml) was heated to reflux for 6 hours. The reaction mixture was washed with 1.6M sodium hydroxide (2×250 ml). The combined aqueous layer was washed with diethyl ether (4×120 ml) then acidified to pH 6 with concentrated hydrochloric acid. The acidic solution was washed with ethyl acetate (3×200 ml) and the combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give 5-(4-phenoxyphenyl)-1H-tetrazole as a white powder.
Reaction SMILES: [P:1]([Cl:4])(Cl)Cl.[CH2:5]([NH:7][CH2:8][CH3:9])[CH3:6]>C(OCC)C>[Cl:4][P:1]([N:7]([CH2:8][CH3:9])[CH2:5][CH3:6])[N:7]([CH2:8][CH3:9])[CH2:5][CH3:6]
Reactant: ClP(Cl)Cl
Reactant: CCNCC
Solvent: CCOCC
Product: CCN(CC)P(Cl)N(CC)CC
Yield: 52.6 %

Procedure:
In a 300 ml three-necked flask equipped with a dropping funnel and a magnetic stirrer, 10.0 g (0.0728 mol) of phosphorus trichloride and 100 ml of anhydrous diethyl ether were charged at room temperature in a nitrogen gas atmosphere, and the mixture was cooled to 5° C. or less in an ice bath. While the resulting reaction mixture was stirred, 30.0 ml (0.291 mol) of diethylamine were slowly added dropwise to the reaction mixture over 3 hours. The resulting crystals were filtered off under pressure in a nitrogen gas atmosphere. After the crystals were washed with anhydrous diethyl ether three times, they were purified by vacuum-distillation (0.4 kPa, 77.8-78.2° C.), and 8.07 g of chlorobis(diethylamino)phosphine were obtained in the form of a transparent liquid; the yield was 53%.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[C:13](C(OCC)=O)[C:12]2=[O:28])=[CH:2]1>CN(C)C=O.C(Cl)(Cl)Cl>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[C:12](=[O:28])[CH:13]=[C:14]([NH:16][CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[O:15]2)=[CH:2]1
Reactant: CCOC(=O)C1=C(NCc2cccs2)OC(=Cc2c[nH]c3ncccc23)C1=O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C1C=C(NCc2cccs2)OC1=Cc1c[nH]c2ncccc12
Temperature: 25 °C
Yield: 22.6 %

Procedure:
A solution of the compound (0.10 g, 0.26 mmol) of Example 60 in N,N-dimethylformamide (0.80 mL) was refluxed for 16 h. Cooled to ambient temperature, the reaction mixture was diluted with chloroform and the precipitate was collected by filtration. The solid was washed with chloroform/methanol (10/1) and hexane then dried to afford the titled compound as solid (0.019 g, y. 22%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([OH:20])[CH:11]=2)[CH:5]=[C:4]([C:21]2[C:26]([O:27]CC3C=CC(OC)=CC=3)=[CH:25][CH:24]=[CH:23][C:22]=2[O:37][CH2:38][CH:39]2[CH2:41][CH2:40]2)[N:3]=1.Cl>O1CCOCC1.C(OCC)C>[NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([OH:20])[CH:11]=2)[CH:5]=[C:4]([C:21]2[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][C:22]=2[O:37][CH2:38][CH:39]2[CH2:41][CH2:40]2)[N:3]=1
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(-c3ccc(NC(C)=O)c(O)c3)c(CO)c(N)n2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(-c2cc(-c3c(O)cccc3OCC3CC3)nc(N)c2CO)cc1O
Reaction time: 8 h

Procedure:
To a solution of N-{4-[2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-3-(hydroxymethyl)-4-pyridinyl]-2-hydroxyphenyl}acetamide (0.013 g, 0.023 mmol) in 1,4-dioxane (0.5 mL) was added a solution of HCl in 1,4-dioxane (4N, 1.0 mL). After being stirred overnight, the mixture was diluted with diethyl ether. The resulting precipitate was collected by filtration under argon atmosphere, washed with Et2O, and dried under reduced pressure to give of N-{4-[2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-3-(hydroxymethyl)-4-pyridinyl]-2-hydroxyphenyl}acetamide. (0.025 g, 80%); LC-MS (m/z=436, M+1)
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:15]([NH2:17])=[O:16])=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:6]=1.C1(C)C=CC=CC=1.CO[CH:27](OC)[N:28]([CH3:30])[CH3:29]>>[Br:1][C:2]1[S:3][C:4]([C:15](/[N:17]=[CH:27]\[N:28]([CH3:30])[CH3:29])=[O:16])=[C:5]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)[N:6]=1
Reactant: NC(=O)c1sc(Br)nc1Cc1ccc(Cl)cc1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)/C=N\C(=O)c1sc(Br)nc1Cc1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
In a 250 mL round bottomed flask were placed 2-bromo-4-(4-chlorobenzyl)-1,3-thiazole-5-carboxamide (0.66 g, 2.0 mmol) and toluene (30 mL, 300 mmol). The mixture was turned into a suspension by ultrasonication. To the suspension was added 1,1-dimethoxy-N,N-dimethylmethanamine (80 uL, 6.0 mmol) and the mixture was stirred for 2 h at 50° C. The mixture was allowed to cool to rt then was concentrated under reduced pressure. The residue was used in the next step without further purification. LC/MS (FA) ES+ 388.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[C:14](=[O:21])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[NH2:15]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:17]([O:16][C:14](=[O:21])[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: Brc1ccccc1C1CCCCC1
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccccc1C1CCCCC1
Temperature: 80 °C

Procedure:
To a solution of 1-bromo-2-cyclohexyl-benzene (5 mmol) in dioxane (20 mL) was added solid Pd(OAc)2 (0.1 g) and solid CsCO3 (10 mmol). tert-Butyl carbamate (7 mmol) was added to the reaction mixture, and the contents were heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature and filtered through Celite. The solvent was removed in vacuo and the residue obtained was purified by flash column chromatography using DCM as eluant to yield (2-cyclohexylphenyl)-carbamic acid tert-butyl ester.
Reaction SMILES: C[O-].[Na+].[C:4]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[N:19]([CH2:31][C:32]#[C:33][CH3:34])[C:20]3[C:25](=[O:26])[N:24]([CH2:27][C:28]#[N:29])[N:23]=[CH:22][C:21]=3[N:30]=2)[CH2:13]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].C(O)(=O)C.[C:39]([OH:48])(=O)[C:40]1[C:41](=[CH:43][CH:44]=[CH:45][CH:46]=1)[NH2:42]>CO>[C:4]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[N:19]([CH2:31][C:32]#[C:33][CH3:34])[C:20]3[C:25](=[O:26])[N:24]([CH2:27][C:28]4[NH:29][C:39](=[O:48])[C:40]5[C:41](=[CH:43][CH:44]=[CH:45][CH:46]=5)[N:42]=4)[N:23]=[CH:22][C:21]=3[N:30]=2)[CH2:13]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC#CCn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2cnn(CC#N)c(=O)c21
Reactant: Nc1ccccc1C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC#CCn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2cnn(Cc3nc4ccccc4c(=O)[nH]3)c(=O)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
40 mg sodium methoxide (95%) are added to a solution of 605 mg 2-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-3-(2-butyn-1-yl)-5-cyanomethyl-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one in 9 ml of methanol. The mixture is stirred for one hour at ambient temperature and then neutralised with 41 μL glacial acetic acid. Then a solution of 195 mg anthranilic acid in 2 ml of methanol is added and the reaction mixture is heated to 70° C. After about two hours a white, voluminous precipitate is formed and the reaction mixture is cooled to ambient temperature. The precipitate formed is suction filtered, washed with cold methanol and dried.