Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].Cl.[C:4]([NH2:12])(=[NH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:13]([O:15][C:16]([CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([S:29](Cl)(=[O:31])=[O:30])=[C:24]([CH3:33])[C:23]=1[CH3:34])=[O:17])[CH3:14]>CC(C)=O>[CH2:13]([O:15][C:16]([CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([S:29]([NH:11][C:4](=[NH:12])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)(=[O:31])=[O:30])=[C:24]([CH3:33])[C:23]=1[CH3:34])=[O:17])[CH3:14]
Reactant: CCOC(=O)CCCOc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Reactant: N=C(N)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1cc(C)c(S(=O)(=O)NC(=N)c2ccccc2)c(C)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.3 %

Procedure:
1N NaOH (6.43 ml) was added into a mixture of benzamidine hydrochloride (1.00 g) and acetone (25 ml) under ice-water cooling, and then a mixture of 4-(3-ethoxycarbonylpropoxy)-2,3,6-trimethylbenzenesulfonyl chloride (3.36 g) and acetone (5 ml) was added dropwise thereto over 10 minutes. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated by N2 flow to remove the excess of solvents, and was poured into a mixture of water and AcOEt. The separated organic phase was washed with sat. NaHCO3aq., water, and brine, and was dried over MgSO4. After evaporation, the resulting residue was purified by chromatography over silica gel (CHCl3-methanol (MeOH) as eluent) to give N-[4-(3-ethoxycarbonylpropoxy)-2,3,6-trimethylbenzenesulfonyl]benzamidine (1.39 g) as an oil compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[C@@H:11]([C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1)[CH3:12].[H-].[Na+].[CH3:30]I>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:30])=[CH:4][C:3]=1[C@@H:11]([C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1)[CH3:12]
Reactant: CI
Reactant: C[C@@H](c1cc2cn[nH]c2cc1F)c1cnc2ccc(-c3cnn(C)c3)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](c1cc2cnn(C)c2cc1F)c1cnc2ccc(-c3cnn(C)c3)nn12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-[(S)-1-(6-Fluoro-1H-indazol-5-yl)-ethyl]-6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Example 165, 23 mg, 0.065 mmol) was dissolved in DMF (0.374 mL) and cooled down to 0° C. under nitrogen conditions. NaH (3.82 mg, 0.095 mmol) was added and the RM was stirred at 0° C. for 30 min. Then methyliodide (10.84 mg, 0.076 mmol) was introduced. The RM was allowed to warm up to rt and stirred for 2.5 h, then it was quenched with water. It was extracted twice with EtOAc. The organics were joined and washed with brine, dried over Na2SO4. The solvent was removed and the residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The acetonitrile was removed and the aqueous solution was basified with 5% NaHCO3. It was extracted twice with EtOAc and then the organics were joined and washed with brine. It was dried over Na2SO4 and the solvent was removed. The residue was triturated with pentane and the precipitate was filtered off to afford the title compound as a white solid (tR 1.0 min (conditions 2), MH+=376, 1H-NMR in DMSO-d6: 8.30 (s, 1H); 8.06 (d, 1H); 7.94 (s, 2H); 7.67 (s, 1H); 7.59 (d, 1H); 7.54 (d, 1H); 7.46 (d, 1H); 4.95 (q, 1H); 3.95 (s, 3H); 3.88 (s, 3H); 1.77 (d, 3H)).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH:6]=[CH:5]2.[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27](B(O)O)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.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>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:27]4[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=4[CH3:31])[C:24]([O:23][CH3:22])=[O:35])[CH:3]=3)[C:8]2=[O:12])=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(C)c(B(O)O)c1
Reactant: COc1ccc(Cn2ccc3cc(Br)ccc3c2=O)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: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-c2ccc3c(=O)n(Cc4ccc(OC)cc4)ccc3c2)c1
Temperature: 95 °C

Procedure:
A mixture of 6-bromo-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (product of step iv)) (1.2 g), intermediate 2 (0.7 g), potassium carbonate (1.0 g) and tetrakis(triphenylphosphine)palladium(0) (0.4 g) in N,N-dimethylformamide (20 mL) was heated to 95° C. for 17 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried, filtered and evaporated. The residue was purified (SiO2, 1:2 ethyl acetate:iso-hexane as eluent) to yield the sub-titled compound (1.03 g).
Reaction SMILES: [NH2:1][C:2]1([CH2:15][OH:16])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[C:17](#[N:20])[CH:18]=[CH2:19]>C(O)C>[OH:16][CH2:15][C:2]1([NH:1][CH2:19][CH2:18][C:17]#[N:20])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: NC1(CO)CCN(Cc2ccccc2)CC1
Reactant: C=CC#N
Solvent: CCO
Product: N#CCCNC1(CO)CCN(Cc2ccccc2)CC1

Procedure:
A mixture of 4-amino-1-(phenylmethyl)-4-piperidinemethanol (0.0182 mol) and 2-propenenitrile (0.0304 mol) in ethanol (80 ml) was stirred and refluxed for two days. 2-Propenenitrile (2 ml) was added. The mixture was stirred and refluxed for 5 hours. 2-Propenenitrile (2 ml) was added again. The mixture was stirred and refluxed overnight. The solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/(CH3OH/NH3) 95/5). The desired fractions were collected and the solvent was evaporated, yielding 3-[[4-(hydroxymethyl)-1-(phenylmethyl)4-piperidinyl]amino]-propanenitrile (intermediate 14).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11](=[O:17])[NH:12][C:13](=[O:16])[NH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:18]([N:24]=[C:25]=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CN(C1C=CN=CC=1)C>[Si:1]([O:8][CH2:9][C:10]1[C:11](=[O:17])[NH:12][C:13](=[O:16])[N:14]([C:25]([NH:24][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:26])[CH:15]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1c[nH]c(=O)[nH]c1=O
Reactant: CCCCCCN=C=O
Agent: CN(C)c1ccncc1
Product: CCCCCCNC(=O)n1cc(CO[Si](C)(C)C(C)(C)C)c(=O)[nH]c1=O
Reaction time: 66 h
Yield: 73 %

Procedure:
The title compound: was obtained according to the procedure described for the synthesis of Example 1, starting from 5-[[tert-butyl(dimethyl)silyl]oxymethyl]-1H-pyrimidine-2,4-dione (0.28 g, 1.08 mmol); 2.2 equiv of DMAP and 2.2 equiv of hexyl isocyanate were used herein. The reaction was here stirred for 66 hrs, and the crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 75:25) to afford the title compound (0.30 g, 73%) as a white solid. 1H NMR (400 MHz, CDCl3); δ 0.12 (s, 6H), 0.89 (t, J=6.9 Hz, 3H), 0.94 (s, 9H), 1.29-1.39 (m, 6H), 1.58-1.63 (m, 2H), 3.39 (td, J=7.1, 5.7 Hz, 2H), 4.52 (d, J=1.7 Hz, 2H), 828 (s, 1H), 8.47 (t, J=1.7 Hz, 1H), 9.06 (t, J=4.8 Hz, 1H). MS (ESI) m/z: 384 [M-H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([O:31]COC)[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([I:11])[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.O1CCCC1.Cl>CO>[Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([I:11])[N:8]([S:12]([C:15]3[CH:16]=[CH:17][C:18]([CH3:19])=[CH:20][CH:21]=3)(=[O:13])=[O:14])[C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(I)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1
Temperature: 65 °C

Procedure:
To a solution of 5-(5-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(1-(methoxymethoxy)cyclobutyl)thiazole (Example 1F) (1.5 g, 2.381 mmol) in a solvent mixture of tetrahydrofuran (24 mL) and methanol (10 mL) was added 10% aqueous HCl solution (7.24 ml, 23.81 mmol). The reaction was heated to 65° C. for 8 hours and was then cooled to room temperature. The reaction was partitioned between ethyl acetate (50 mL) and water (50 mL), and the layers were separated. The aqueous layer was extracted with additional ethyl acetate (2×50 mL). The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used without further purification. MS ESI(+) m/z 586.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[Cl:11][CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N)C1C=CC=CC=1.C(O)(=O)C>C(O)(C)C>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1/[CH:4]=[C:14](/[C:13](=[O:20])[CH2:12][Cl:11])\[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: O=Cc1ccc(Cl)cc1Cl
Solvent: CC(C)O
Solvent: NCc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)/C(=C\c1ccc(Cl)cc1Cl)C(=O)CCl

Procedure:
A solution 2,4-dichlorobenzaldehyde (4.6 g, 26.1 mmol), ethyl 4-chloro-3-oxobutanoate (4.5 g, 27.4 mmol), benzylamine (165 mg, 1.5 mmol), and acetic acid (118 mg, 2.0 mmol) in isopropyl alcohol (30 mL) stirred at ambient temperature for 96 h. The mixture was diluted with isopropyl alcohol to give a total volume of 50 mL and was saved as a stock solution (0.52 mmol/mL).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH:11]([CH2:16][CH:17]2[O:19][CH2:18]2)[C:12]([O:14]C)=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:26]1(C2C=CC=CC=2)[CH:31]=[CH:30][C:29]([S:32](NC(CC=C)C(OC)=O)(=O)=O)=[CH:28][CH:27]=1.O.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH:11]([CH2:16][CH:17]([OH:19])[CH2:18][S:32][C:29]2[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=2)[C:12]([OH:14])=[O:13])(=[O:8])=[O:9])=[CH:3][CH:2]=1
Reactant: C=CCC(NS(=O)(=O)c1ccc(-c2ccccc2)cc1)C(=O)OC
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(O)C(CC(O)CSc1ccccc1)NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 8 h

Procedure:
Methyl 2-[[(1,1′-biphenyl)-4-yl]sulfonyl]amino-4,5-epoxypentanoate: To a solution of methyl 2-[[(1,1′-biphenyl)-4-yl]sulfonyl]amino-4-pentenoate 16a (2.0 g, 5.8 mmol) in CH2Cl2 (15 mL), NaHCO3 (0.58 g, 7 mmol) and water (10 mL) at 0° C., is added slowly m-chloroperbenzoic acid (3.3 g, 11.6 mmol, 57-86%). The reaction mixture is stirred overnight. The resulting mixture is diluted with aqueous NaHCO3, and the mixture is extracted three times with CH2Cl2. The combined CH2Cl2 layers are washed with NaHCO3, brine, dried over MgSO4 and concentrated to an oil which is purified by column chromatography eluting with EtOAc/hexane (4:6) to give the desired product as a mixture of two isomers (ratio 2:3).
Reaction SMILES: [CH2:1]([C:3]1([CH2:20][CH3:21])[CH:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:18])[CH2:15][O:16][CH3:17])=[CH:10][CH:9]=2)[NH:5][C:4]1=[O:19])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:28]([C@@H:31]([N:39]=[C:40]=[O:41])[C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)[CH:29]=[CH2:30].O>CN(C=O)C>[CH2:20]([C:3]1([CH2:1][CH3:2])[C@H:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:18])[CH2:15][O:16][CH3:17])=[CH:10][CH:9]=2)[N:5]([C:40]([NH:39][C@H:31]([CH2:28][CH:29]=[CH2:30])[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[O:41])[C:4]1=[O:19])[CH3:21]
Reactant: C=CC[C@@H](N=C=O)c1ccc(C)cc1
Reactant: CCC1(CC)C(=O)NC1Oc1ccc(C(=O)COC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CC[C@@H](NC(=O)N1C(=O)C(CC)(CC)[C@@H]1Oc1ccc(C(=O)COC)cc1)c1ccc(C)cc1

Procedure:
To a solution of 1.64 gm (5.6 mmol) of 3,3-diethyl-4-(RS)-[4-(1-oxo-2-methoxyethyl) phenoxy]azetidin-2-one in 23 mL of dry DMF was added 78 mg (0.56 mmol) of powdered potassium carbonate and then 1.27 gm (6.8 mmol) of (R)-α-allyl-4-methyl-benzyl isocyanate, and the mixture was stirred for one hour. The solution was treated with 50 mL of water and was extracted with 100 mL of 50:50 hexanes: ethyl acetate, 80 mL of ethyl acetate and then 100 mL of hexanes: ethyl acetate. Each extract was washed with 10 mL of water and 10 mL of brine. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on 240 gm of silica with 4 L of 70:30 hexanes: ethyl acetate to give a small amount of higher Rf material (3,3-diethyl-1-[(R)-α-(allyl)-4-(methyl)benzylaminocarbonyl]-4-(S)-[4-(1-(oxo)-2-(methoxy) ethyl)phenoxy]azetidin-2-one) and a substantial amount of mixed fractions. The mixed fractions were purified by flash chromatography on 173 gm of silica eluting with 4 L of 75:25 hexanes:ethyl acetate, and the mixed cuts from that chromatography were fractionated again under the same conditions. The pooled fractions containing mostly desired product were subjected to a final purification by flash chromatography on 143 gm of silica eluting with 3 L of 98:2 methylene chloride: ethyl acetate to give 1.40 gm of product as an oil.
Reaction SMILES: CC1C=CC2C(=C(O)C=CC=2)N=1.[CH3:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[C:17]([OH:36])[C:18]([CH:24]=[CH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:19][CH:20]=2)[N:15]=1>>[CH3:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[C:17]([OH:36])[C:18]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:19][CH:20]=2)[N:15]=1
Reactant: CCCCCCCCCCC=Cc1ccc2ccc(C)nc2c1O
Agent: Cc1ccc2cccc(O)c2n1
Product: CCCCCCCCCCCCc1ccc2ccc(C)nc2c1O

Procedure:
Example N was essentially repeated using 2-methyl-8-hydroxyquinoline in place of 5-chloro-8-hydroxyquinoline. The resulatant 2-methyl-7-dodecenyl-8-hydroxyquinoline was hydrogenated by the procedure of Example O, Part B to give 2-methyl-7-dodecyl-8-hydroxyquinoline.
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[C:13](F)[CH:12]=1.O>CS(C)=O>[Br:10][C:11]1[CH:18]=[CH:17][C:14]2[CH:15]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[S:3][C:13]=2[CH:12]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: CCOC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cc2ccc(Br)cc2s1
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.73 g, 18.3 mmol) was suspended in DMSO (10 mL) and ethyl mercaptoacetate (1.1 mL, 10.1 mmol) was added potionwise using a water bath to moderate the exotherm. On complete addition, the water bath was removed and stirring continued for 15 minutes. A solution of 4-bromo-2-fluorobenzaldehyde (1.86 g, 9.16 mmol) in DMSO (2 mL) was added in one portion. The dark solution was stirred for 15 minutes before pouring into cold water (300 mL). The products were extracted into Et2O (2×200 mL). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by MPLC gave the desired product (pale yellow solid). 1H NMR (DMSO-d6) δ 8.37 (d, J=1.8 Hz, 1H), 8.17 (s, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.60 (dd, J=8.4, 1.8 Hz, 1H), 4.32 (q, J=7.2 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(OCC)(=O)C.[CH3:7][N:8]1[CH:16]=[C:15]2[C:10]([C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14]2)=[N:9]1>[Pd].C1COCC1>[CH3:7][N:8]1[CH:16]=[C:15]2[C:10]([C:11]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:12][C:13]([NH2:17])=[CH:14]2)=[N:9]1
Reactant: Cn1cc2cc([N+](=O)[O-])cc(-c3ccccc3)c2n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cc2cc(N)cc(-c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl acetate (5 mL) and THF (2 mL) were added to 2-methyl-5-nitro-7-phenyl-2H-indazole obtained in the above-described Step 2 (260 mg). Thereafter, 10% palladium on carbon (300 mg) was added under nitrogen atmosphere, and the reaction solution was stirred under hydrogen atmosphere at room temperature overnight. The insolubles were filtrated, and then the solvent was evaporated under vacuum. Subsequently, the resultant residue was purified by column chromatography on basic silica gel (developing solvent:hexane/ethyl acetate) to obtain 2-methyl-7-phenyl-2H-indazol-5-amine as brown amorphous.
Reaction SMILES: C1OC2C(=CSC=2)[O:3]C1CO.[CH:12]1([N:18]=[C:19]=[N:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.BrC1C=CC(C2C=CC(OC(CCC)C(O)=O)=CC=2)=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:21]1([NH:20][C:19]([NH:18][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)=[O:3])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: OCC1COc2cscc2O1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCC(Oc1ccc(-c2ccc(Br)cc2)cc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3.26 g of a mixture of 80% of EDT-methanol and 20% of hydroxy-PDT (corresponding to 18.9 mmol; 15.1 mmol based on the main component EDT-methanol), 3.14 g (15.2 mmol) of N,N′-dicyclohexylcarbodiimide and 0.3 g (2.45 mmol) of 4-(dimethylamino)pyridine are dissolved in 100 ml of CH2Cl2 and cooled in an ice bath. 5.25 g (15.0 mmol) of [(4′-bromo-1,1′-biphenyl-4-yl)oxy]-valeric acid are added a spatula at a time to the ice-cooled solution while stirring. After 1 hour, the reaction is continued at room temperature. After a further 65 hours, the colourless precipitate formed (N,N′-dicyclohexylurea) is filtered off. The clear, colourless solution is washed in succession with 3×250 ml of 1 N HCl, 3×150 ml of saturated NaHCO3 solution and 1×150 ml and 2×100 ml of saturated NaCl solution. The organic phase is dried over MgSO4, the desiccant is filtered off and the solvent is removed on a rotary evaporator. This gives 7.98 g of crude product.
Reaction SMILES: [CH:1]1([N:7]2[C:12]3=[N:13][O:14][CH:15]=[C:11]3[C:10](=[O:16])[NH:9][C:8]2=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH:1]1([N:7]2[C:12]3=[N:13][O:14][CH:15]=[C:11]3[C:10](=[O:16])[N:9]([CH3:18])[C:8]2=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c(=O)n(C2CCCCC2)c2nocc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(=O)c2conc2n(C2CCCCC2)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.5 %

Procedure:
In 50 ml of dimethylformamide is dissolved 1 g of the 7-cyclohexyl-5H,7H-isoxazolo[3,4-d]pyrimidine-4,6-dione obtained in Example 18, followed by addition of 800 mg of potassium carbonate and 1 ml of methyl iodide. The mixture is stirred at room temperature for 20 hours, after which the insolubles are filtered off. The filtrate is concentrated to dryness and the concentrate is dissolved in chloroform. After the insolubles are filtered off, the chloroform is removed by distillation and the residue is recrystallized from water-ethanol. By the above procedure is obtained 0.8 g of the captioned compound as pale-white platelets. melting point: 194°-197° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2.CCN(CC)CC.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[C:35]([N:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:7]3[NH:6][C:5](=[O:27])[C:4]4[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=4[O:2][CH3:1])[N:8]=3)=[CH:16][CH:17]=2)[CH2:26][CH2:25]1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(=O)c5ccccc5)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
To a solution of 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.150 g, 0.40 mmol) in CH2Cl2 (10 mL) was added Et3N (0.08 mL, 0.60 mmol) and benzoyl chloride (0.04 mL, 0.36 mmol). The resulting solution was stirred at room temperature for 3 hours. The solution was concentrated in vacuo. The material was purified by flash chromatography on silica gel eluting with 0% to 10% of MeOH/EtOAc to afford the title compound (0.110 g, 64%). 1H NMR (300 MHz, DMSO-d6): δ 11.79 (s, 1H), 8.11 (d, J=8.7 Hz, 2H), 7.37-7.54 (m, 5H), 7.04 (d, J=8.9 Hz, 2H), 6.68 (s, 1H), 6.47 (s, 1H), 3.61-4.03 (m, 8H), 3.23-3.62 (m, 6H); ESI MS m/z 471 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1(/[CH:9]=[CH:10]/[CH2:11]S(C)(=O)=O)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[Na+].[I-:17]>CC(C)=O>[CH3:1][O:2][C:3]1(/[CH:9]=[CH:10]/[CH2:11][I:17])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: [I-]
Reactant: COC1(/C=C/CS(C)(=O)=O)CCOCC1
Agent: [Na+]
Solvent: CC(C)=O
Product: COC1(/C=C/CI)CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To a 0° C. solution in acetone of 4-methoxy-4-(3-methanesulfonyl-trans-prop-1-enyl)tetrahydropyran (730 mg, 2.92 mmol), prepared as in step 5, was added NaI (5.84 mmol, 875 mg). The cold bath was removed and the reaction mixture was stirred for 2 hours at ambient temperature. The reaction mixture was then concentrated and the residue partitioned between ether and H2O. The organic phase was washed twice with brine, dried over MgSO4, decolorized with activatedcarbon, filtered, through a pad of celite and concentrated in vacuo. The 4-methoxy-4-(3-iodo-trans -prop-1-enyl)tetrahydropyran (800 mg) so obtained was used without further purification.
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[O:21][CH2:22][C:23](O)=[O:24].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[O:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:23](=[O:24])[CH2:22][O:21][C:12]3[CH:13]=[CH:14][C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:11]=3)[CH2:6][C:5]=2[CH:4]=[CH:3]1
Reactant: O=C(O)COc1ccc2ccccc2c1
Reactant: c1cc2c(o1)CCNC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(COc1ccc2ccccc2c1)N1CCc2occc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.24 g (1.2 mmol) of 2-naphthoxyacetic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1). The resulting product was washed with diethyl ether to yield the desired product.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[CH3:2].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13])[CH3:2]
Reactant: CCc1ccc(C(=O)O)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
To a suspension of 4-ethyl benzoic acid (4.53 g, 30.16 mmol) in concentrated sulfuric acid (24 mL) at 0° C. was added nitric acid (12 mL). The mixture was stirred for 1.5 h at 0° C. Poured into ice water, filtered and dried the solid to give 5.79 g of the title compound (98%). 1H NMR (400 MHz, DMSO-d6): δ 1.23 (3H, t, J=7.2 Hz), 2.88 (2H, q, J=7.2 Hz), 7.67 (1H, d, J=8.0 Hz), 8.15 (1H, dd, J=1.6, 8.0 Hz), 8.36 (1H, d, J=1.6 Hz).