Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([NH:21][CH2:22][C@H:23]([NH:28][S:29]([C:32]4[C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH:35]=[CH:34][CH:33]=4)(=[O:31])=[O:30])[C:24]([O:26]C)=[O:25])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[N:11]2)[N:3]=1.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([NH:21][CH2:22][C@H:23]([NH:28][S:29]([C:32]4[C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH:35]=[CH:34][CH:33]=4)(=[O:30])=[O:31])[C:24]([OH:26])=[O:25])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[N:11]2)[N:3]=1
Reactant: COC(=O)[C@H](CNC(=O)c1ccc2c(cnn2Cc2cc(=O)[nH]c(N)n2)c1)NS(=O)(=O)c1cccc2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(Cn2ncc3cc(C(=O)NC[C@H](NS(=O)(=O)c4cccc5ccccc45)C(=O)O)ccc32)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
Methyl 3-[1-[2-amino-4-oxopyrimidin-6-ylmethyl]-indazol-5-yl-carbonylamino]-2(S) -(1-naphthalenesulfonylamino)propionate. A mixture of the product prepared according to Example E-24 Part F (85 mg, 298 μmol) and the product prepared according to Example E-24 Part H (113 mg, 328 μmol) in N,N-dimethylformamide (3 mL) was treated sequentially with triethylamine (52 μL, 373 μmol), 1-hydroxybenzotriazole hydrate (40 mg, 298 μmol) and dicyclohexylcarbodiimide (68 mg, 328 μmol). The mixture was stirred at room temperature for 24 h and concentrated. The residue was purified by flash chromatography (dichloromethane-methanol, 97:3 then 9:1) to provide the title product (154 mg, 89%) as a gum: 1H NMR (MeOH-d4) d 8.64 (d, 1H), 8.15 (s, 2H), 7.92 (d, 1H), 7.89 (s, 1H), 7.71 (d, 1H), 7.6-7.3 (4H), 5.35 (s, 2H), 5.03 (s, 1H), 4.20 (dd, 1H), 3.64 (dd, 1H), 3.46 (dd, 1H); ester methyl signal obscured by residual MeOH signal.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=O.CC[N:15](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[Si](N[Si](C)(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([NH2:15])=[O:12]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)C1Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2-indancarboxylic acid (1.4 g, 8.63 mmol) was dissolved in anhydrous DMF (20 mL), and the following was added sequentially: DIPEA (3.02 mL, 17.26 mmol), HATU (3.94 g, 10.36 mmol), and HMDS (2.17 mL, 10.36 mmol) after 30 min of stirring at rt. After stirring for 20 h at rt, the solution was taken up in EtOAc and washed with 0.5M HCl (3×), water (3×), and 10% aq. sodium carbonate (3×). The organic phase was collected and dried over magnesium sulfate, and concentrated in vacuo. The solid residue was recrystallized from EtOH to afford the title compound as sharp, colorless crystals. (Yield: 861 mg, 5.06 mmol, 59%) 1H NMR (400 MHz, CDCl3) 7.34-7.12, 5.52, 3.41-3.08
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[N:16][NH:17][C:11]=3[C:10]3[S:18][CH:19]=[CH:20][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[C:25]1([CH3:34])[C:26]([C:31](Cl)=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=1>O1CCOCC1>[N:17]1[NH:16][CH:15]=[C:12]2[CH2:13][CH2:14][N:8]([C:6]([C:5]3[CH:21]=[CH:22][C:2]([NH:1][C:31](=[O:32])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH3:34])=[CH:3][CH:4]=3)=[O:7])[C:9]3[CH:20]=[CH:19][S:18][C:10]=3[C:11]=12
Reactant: Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3sccc32)cc1
Reactant: Cc1ccccc1C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCc3c[nH]nc3-c3sccc32)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 400 mg of 6-(4-aminobenzoyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]thieno[3,2-b]azepine in 12.0 ml of dioxane under argon is added 65 mg of sodium hydride (60% in mineral oil). After stirring for 15 minutes, 176 μl of o-toluoyl chloride is added. The reaction mixture is stirred at room temperature for 18 hours under argon. The reaction mixture is evaporated in vacuo to a residue which is dissolved in 40 ml of methylene chloride and washed with 20 ml each of water and brine. The organic layer is dried (Na2 SO4) and filtered. The filtrate is concentrated in vacuo to give a residue which is purified by chromatography on silica gel plates by elution with 1:1 ethyl acetate:hexane 100 mg of N-[4-[[4,5-dihydro-2-(2-methylbenzoyl)pyrazolo-[4,3-d]thieno[3,2-b]azepin-6(2H)-yl]carbonyl]phenyl-2-methylbenzamide as a white foam and 200 mg of the product as a white foam.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[C:17](OS(C(F)(F)F)(=O)=O)=[N:18][CH:19]=[C:20]([CH:25]=2)[C:21]([O:23][CH3:24])=[O:22])[CH:12]=[CH:13][C:14]=1[Cl:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[C:17]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[CH3:34])=[N:18][CH:19]=[C:20]([CH:25]=2)[C:21]([O:23][CH3:24])=[O:22])[CH:12]=[CH:13][C:14]=1[Cl:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cnc(OS(=O)(=O)C(F)(F)F)c(-c2ccc(Cl)c(OCc3ccccc3)c2)c1
Reactant: Cc1ccccc1B(O)O
Product: COC(=O)c1cnc(-c2ccccc2C)c(-c2ccc(Cl)c(OCc3ccccc3)c2)c1
Yield: 94.9 %

Procedure:
According to the method described in example 4.5, starting from 1.5 g (2.99 mmol) of methyl 5-[3-(benzyloxy)-4-chlorophenyl]-6-{[(trifluoromethyl)sulphonyl]oxy}nicotinate and of 508 mg (3.74 mmol) of 2-methylphenyl boronic acid, we obtain 1.26 g of methyl 5-[3-(benzyloxy)-4-chlorophenyl]-6-(2-methylphenyl)nicotinate in the form of oil.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12].IC.[C:16](=O)([O-])[O-].[K+].[K+].C([N+](CC)(CC)CC1C=CC=CC=1)C>C(#N)C>[CH3:16][O:1]/[N:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)Cc1ccccc1C=NO
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CO/N=C/c1ccccc1CC(=O)O
Reaction time: 8 h

Procedure:
1.8 g (10 mmoles) of 2-hydroxyiminomethyl-phenylacetic acid are reacted with 1.50 ml of iodomethane, 5 g of potassium carbonate and 10 mg of triethylbenzylammonium (TEBA) chloride in 20 ml of anhydrous acetonitrile. The system is left for 6 hours at +80° C. and overnight at ambient temperature.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1.[C@H:21]12[CH2:27][C@H:24]([NH:25][CH2:26]1)[CH2:23][N:22]2[CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][N:25]3[CH2:26][C@@H:21]4[CH2:27][C@H:24]3[CH2:23][N:22]4[CH2:28][C:29]3[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=3)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(Oc2ccc(-c3ncco3)cc2)cc1
Reactant: COC(=O)c1ccc(CN2C[C@@H]3C[C@H]2CN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc(CN2C[C@@H]3C[C@H]2CN3Cc2ccc(Oc3ccc(-c4ncco4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 99.6 %

Procedure:
4-[4-(2-oxazolyl)phenoxy]benzaldehyde (10.2 g, 38.5 mmol) and methyl 4-[[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoate (9.9 g, 40.4 mmol, 1.05 equiv.) were dissolved in dichloroethane (200 mL). After 75 minutes, sodium triacetoxyborohydride (9.8 g, 46.1 mmol, 1.2 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature. Then, 1N NaOH was added. The reaction mixture was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with 0.5 M H2SO4, and MeOH was added to the mixture until the precipitated gummy solid dissolved. The layers were separated and the aqueous layer was cooled to −5 C and saturated K2CO3 was added slowly enough to keep the temperature below 0 C to prevent ester hydrolysis. Once the pH was 11, the solution was extracted with EtOAc (2×), and the combined EtOAc fractions were dried and concentrated to give 19.0 g (100%) of methyl 4-[[(1S,4S)-5-[[4-[4-(2-oxazolyl)phenoxy]phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoate as the free base, which was 98% pure by HPLC; 1H NMR (300 MHz, CDCl3) δ 8.02 (d, 2H), 8.02 (d, 2H), 7.69 (d, 1H), 7.47 (d, 2H), 7.40 (d, 2H), 7.22 (d, 1H), 7.08 (d, 2H), 7.05 (d, 2H), 3.92 (s, 3H), 3.84 (d, 1H), 3.78 (d, 1H), 3.77 (d, 1H), 3.71 (d, 1H), 3.35 (s, 1H), 3.31 (s, 1H), 2.89 (d, 1H), 2.88 (d, 1H), 2.71 (dd, 1H), 2.70 (dd, 1H), 1.79 (s, 2H) ppm.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH2:24]([N:26]([CH2:39][CH3:40])[CH2:27][CH2:28][O:29][CH2:30][CH2:31][NH:32][C:33]1[CH2:37][S:36][C:35](=[O:38])[N:34]=1)[CH3:25].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:37]2/[C:33]([NH:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][N:26]([CH2:24][CH3:25])[CH2:39][CH3:40])=[N:34][C:35](=[O:38])[S:36]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CCN(CC)CCOCCNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CCN(CC)CCOCCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.21 g) in 2-propanol (15 mL) was added a solution of 4-({2-[2-(diethylamino)ethoxy]ethyl}amino)-1,3-thiazol-2(5H)-one (1.85 g) in 2-propanol (5 mL), and piperidinium acetate (0.52 g) was added. The reaction mixture was stirred at 60° C. overnight and concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (1.26 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([O:22][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc([N+](=O)[O-])cc3)c2)CC1
Yield: 67.6 %

Procedure:
Following the procedure of Example 69(b) {4-[3-(4-cyanophenoxy)-5-hydroxy-benzoylamino]cyclohexyl}carbamic acid tert-butyl ester 1.1 g (2.43 mmol) and 1-chloro-4-nitro-benzene (0.765 g, 4.86 mmol) were used to afford 0.94 g of the required product. NMR (DMSO-d6): δ 1.2 (4H, m), 1.40 (9H, s), 1.8 (4H, m), 3.2 (1H, m), 3.7 (1H, m), 6.7 (1H, d), 7.25 (5H, m), 7.55 (2H, m), 7.8 (2H, d), 8.3 (2H, d), 8.4 (1H, d).
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1[N:6]=[CH:7][N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=3)[C:9]=12.Cl.[CH3:24][NH:25][O:26][CH3:27].C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[CH:5]1[N:6]=[CH:7][N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([N:25]([O:26][CH3:27])[CH3:24])=[O:20])=[CH:21][CH:22]=3)[C:9]=12
Reactant: O=C(O)c1ccc(C2OCCn3cncc32)cc1
Reactant: CNOC
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc(C2OCCn3cncc32)cc1
Temperature: 2.5 °C
Reaction time: 16 h

Procedure:
9.30 mmol of thionyl chloride are added to a solution of 3.10 mmol of 4-(5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-8-yl)benzoic acid in 5 ml of chloroform. The reaction mixture is heated to reflux for 3 hours and then evaporated. The residue is stripped with toluene and then taken up in 10 ml of dichloromethane. The reaction solution is cooled to 0-5° C., and 3.10 mmol of N,O-dimethylhydroxylamine hydrochloride, followed by 15.5 mmol of diisopropylethylamine, are added. The reaction mixture is stirred at room temperature for 16 hours and filtered through Hyflo, and the filtrate is evaporated. The title compound is obtained as a yellowish oil from the residue by flash chromatography (SiO2 60F). Rf=0.13 (dichloromethane-2M ammonia in ethanol 97:3); Rt=4.00.
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[S:5][C:4]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:3]1.[OH:27][C@@H:28]([CH2:41][NH2:42])[CH2:29][O:30][C:31]1[C:39]2[NH:38][C:37](=[O:40])[NH:36][C:35]=2[CH:34]=[CH:33][CH:32]=1>>[OH:27][C@@H:28]([CH2:41][NH:42][CH:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[CH:13][C:8]([CH:7]=[C:6]3[S:5][C:4]([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:3][C:2]3=[O:1])=[CH:9][CH:10]=2)[CH2:15][CH2:16]1)[CH2:29][O:30][C:31]1[C:39]2[NH:38][C:37](=[O:40])[NH:36][C:35]=2[CH:34]=[CH:33][CH:32]=1
Reactant: O=C1CCN(c2ccc(C=C3SC(N4CCCCC4)=NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: O=C1N=C(N2CCCCC2)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1

Procedure:
The title compound was prepared from 1-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one (which was obtained in Intermediate 25) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (Jesudason, C. D., et al., EP 0 764 640) according to the procedure of Example 1 as a pale yellowish solid; mp>140° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.55-1.75 (m, 6 H), 1.80-2.00 (m, 2 H), 2.60-2.95 (m, 5 H), 3.50-4.10 (m, 9 H), 4.89 (brs, 1 H), 6.57 (d, J=7.8 Hz, 1 H), 6.62 (d, J=8.2 Hz, 1 H), 6.87 (t, J=8.1 Hz, 1 H), 7.01 (d, J=8.9 Hz, 2 H), 7.45 (d, J=8.9 Hz, 2 H), 7.51 (s, 1 H), 10.60 (s, 1 H), 10.70 (brs, 1 H); MS (ES) m/z: 289.1 ((M+2H)2+, 100%), 577.1 (MH+, 50%); HRMS Calcd. for C30H37N6O4S (MH+): 577.2597. Found: 577.2625.
Reaction SMILES: Br[CH:2]([C:4]1[O:5][C:6](=[O:23])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]([CH3:22])[CH3:21])[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].[N:24]1[C:32]([NH2:33])=[C:31]2[C:27]([NH:28][CH:29]=[N:30]2)=[N:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>>[NH2:33][C:32]1[N:24]=[CH:25][N:26]=[C:27]2[C:31]=1[N:30]=[CH:29][N:28]2[CH:2]([C:4]1[O:5][C:6](=[O:23])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]([CH3:22])[CH3:21])[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3]
Reactant: CC(Br)c1oc(=O)c2ccccc2c1-c1cccc(N(C)C)c1
Reactant: Nc1ncnc2[nH]cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(c1oc(=O)c2ccccc2c1-c1cccc(N(C)C)c1)n1cnc2c(N)ncnc21
Yield: 36.5 %

Procedure:
The title compound was made in a similar way as that of the compound of example 1, using 3-(1-bromoethyl)-4-(3-(dimethylamino)phenyl)-1H-isochromen-1-one (intermediate C8, 86 mg, 0.231 mmol), 9H-purin-6-amine (46.8 mg, 0.347 mmol) and K2CO3 (47.9 mg, 0.347 mmol) to give the title compound (36 mg, 37%). The resulting mixture was straightforward purified via reverse phase chromatography with a Biotage C18 SNAP column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%). The resulting product was further purified by Preparative HPLC (method 1) to give the title compound (12 mg, 12%).
Reaction SMILES: [C:1]([O:17][CH:18]1[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]1)(=[O:16])[CH2:2][C:3]([O:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]([CH3:15])([CH3:14])[CH2:7]1)=[O:4].[C:28]([C:32]1[CH:33]=[C:34]([CH:39]=[C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])[C:41]=1[OH:42])[CH2:35]N(C)C)([CH3:31])([CH3:30])[CH3:29].[NH2-].[Li+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:14][C:8]1([CH3:15])[CH2:7][CH:6]([O:5][C:3](=[O:4])[CH:2]([CH2:35][C:34]2[CH:33]=[C:32]([C:28]([CH3:29])([CH3:31])[CH3:30])[C:41]([OH:42])=[C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:39]=2)[C:1]([O:17][CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)=[O:16])[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9]1
Reactant: CC1(C)CC(OC(=O)CC(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: CN(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Li+]
Agent: [NH2-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC1(C)CC(OC(=O)C(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1

Procedure:
26 g (0.068 mole) of bis-(2,2,6,6-tetramethyl-4-piperidinyl) malonate and 17.8 g (0.068 mole) of N-(3,5-di-tert.butyl-4-hydroxybenzyl)dimethylamine are dissolved in 200 ml of toluene. After the addition of 0.5 g of lithium amide, the mixture is refluxed for 3 hours. After cooling, the mixture is neutralised with 1.5 ml of 1% acetic acid, and the organic phase repeatedly washed with water. After drying phase repeatedly washed with water. After drying over Na2SO4, the solution is concentrated in vacuo to obtain, as oily residue, 3,5-di-tert.butyl-4-hydroxybenzyl-malonic acid-bis(2,2,6,6-tetramethyl-4-piperidinyl)ester.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([OH:14])[C:6]([CH3:15])=[C:5]([C:16]([F:19])([F:18])[F:17])[N:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[CH:29]=[CH2:30].O>CN(C=O)C>[CH3:15][C:6]1[C:7]([O:14][CH2:30][CH:29]=[CH2:28])=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:3]([C:2]([F:20])([F:1])[F:21])=[N:4][C:5]=1[C:16]([F:19])([F:18])[F:17]
Reactant: C=CCBr
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1c(C)c(C(F)(F)F)nc(C(F)(F)F)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a mixture of 10 g (0.03 mol) of product of Example 35 with 9.7 g (0.07 mol) of K2CO3 in 100 ml of DMF was charged 8 g (0.07 mol) of allyl bromide. The resulting mixture was stirred at 25° C. for 4 days. The reaction mixture was poured into H2O, and extracted with duethyl ether. The ether phase was dried (MgSO4), and concentrated in vacuo to 10.2 g (95%) of product as a yellow oil: nD25 1.4334
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([CH:8]=O)=[CH:6][CH:7]=1.[C:10]1([CH2:16][CH2:17][CH2:18][NH:19][S:20]([CH2:23][C:24]#[N:25])(=[O:22])=[O:21])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:1][S:2][C:3]1[S:4][C:5](/[CH:8]=[C:23](/[S:20]([NH:19][CH2:18][CH2:17][CH2:16][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)(=[O:22])=[O:21])\[C:24]#[N:25])=[CH:6][CH:7]=1
Reactant: N#CCS(=O)(=O)NCCCc1ccccc1
Reactant: CSc1ccc(C=O)s1
Product: CSc1ccc(/C=C(\C#N)S(=O)(=O)NCCCc2ccccc2)s1

Procedure:
Reaction of 2-methylmercaptothiophen-5-carboxaldehyde and (3-phenyl-n-propyl)aminosulfonylacetonitrile as in Example 1 gave (E)-3-(2-methylmercaptothien-5-yl)-2-[(3-phenyl-n-propyl)aminosulfonyl]acrylonitrile
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([CH3:40])([CH2:20][CH2:21][C:22]1[N:23]([CH3:39])[C:24]([C:27](=[O:38])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:25][CH:26]=1)[CH:10]=[CH:11][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[C:1]([O:5][C:6]([NH:8][C@:9]([CH3:40])([CH2:20][CH2:21][C:22]1[N:23]([CH3:39])[C:24]([C:27](=[O:38])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:25][CH:26]=1)[CH2:10][CH2:11][P:12](=[O:19])([O:13][CH2:14][CH3:15])[O:16][CH2:17][CH3:18])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOP(=O)(C=C[C@@](C)(CCc1ccc(C(=O)CCCCc2ccccc2)n1C)NC(=O)OC(C)(C)C)OCC
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: CCOP(=O)(CC[C@@](C)(CCc1ccc(C(=O)CCCCc2ccccc2)n1C)NC(=O)OC(C)(C)C)OCC
Temperature: 50 °C
Reaction time: 5 h
Yield: 80.5 %

Procedure:
To a solution of diethyl (3R)-3-t-butoxycarbonylamino-3-methyl-5-[1-methyl-5-(5-phenylpentanoyl)pyrrol-2-yl]pent-1-enylphosphonate (145.4 mg, 0.25 mmol) obtained in Example (44b) in ethanol (2.5 ml) was added chlorotris(triphenylphosphine)rhodium(I) (23.7 mg, 0.026 mmol), and the resulting mixture was stirred at 50° C. under a hydrogen atmosphere for 5 hours. After cooling, to the reaction mixture was added furthermore chlorotris(triphenylphosphine)rhodium(I) (24.3 mg, 0.026 mmol), and the resulting mixture was stirred at 50° C. under a hydrogen atmosphere for 5 hours. After stirring, the reaction mixture was evaporated in vacuo, and the residue was purified by chromatography on a silica gel column using ethyl acetate as the eluent to afford the crude product (154.0 mg). Furthermore, the crude product obtained was purified using a preparative reversed phase HPLC column [Inertsil ODS-3 (2.0 cm×25 cm), GL Science, mobile phase: acetonitrile/water (80:20), flow rate: 10 ml/min] to afford the title compound (116.1 mg, yield: 80%).
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][CH2:9][CH2:10]C2C=C3C(=O)NC(=O)C3=CC=2)=[CH:3][CH:2]=1.O.[NH2:29]N>C(O)C>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][CH2:9][CH2:10][NH2:29])=[CH:3][CH:2]=1
Reactant: NN
Reactant: O=C1NC(=O)c2cc(CCC=Cc3ccc(-c4ccccc4)cc3)ccc21
Solvent: O
Solvent: CCO
Product: NCCC=Cc1ccc(-c2ccccc2)cc1

Procedure:
A mixture of 280 ml of ethanol, 7.9 g of the product of Stage A and 1.3 ml of hydrazine hydrate was refluxed and then allowed to return to ambient temperature. The precipitate was filtered off and washed with ethanol. After concentration, the product was poured into a 2N hydrochloric acid solution and extraction was carried out with ethyl acetate. The organic phase was washed with water, dried, filtered and concentrated under reduced pressure to obtain 2.89 g of the desired product melting at approximately 188°-194° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]([C:10]1[CH:11]=[CH:12][N:13]2[C:17]([CH:18]=1)=[C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[CH3:33])=[CH:14]2)=[O:9].[C:34]([O-])(=[O:36])C.[Na+]>CN(C=O)C.O>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[CH:12][N:13]2[C:17]([CH:18]=1)=[C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[CH3:33])=[C:14]2[CH:34]=[O:36])=[O:9]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1ccn2cc(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccn2c(C=O)c(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 58.3 %

Procedure:
To phosphorus oxychloride (0.35 ml, 3.82 mmol) cooled at 0° C. under argon, was added dropwise anhydrous DMF (0.34 ml, 4.46 mmol) and the mixture was stirred for 5 min forming a precipitate. 1.5 ml of DMF were added and stirring was continued at 0° C. for 15 min. To this mixture was added dropwise a solution of the compound of step 2 (0.476 g, 1.27 mmol) in 5 ml of DMF, and the mixture was heated at 60° C. for 1.5 h and then stirred at room temperature overnight. A solution of sodium acetate (0.837 g) in 6.5 ml water was added, the mixture was heated at 50° C. for 1 h, and evaporated to dryness under reduced pressure. The residue was dissolved in EA, the solution was washed with a saturated solution of sodium hydrogencarbonate, water and brine, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EA, 100:0, then 90:10) to give 0.297 g of the title compound.