Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9](=O)[NH:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(C3CCCC3)n[nH]c(=O)c2c1
Product: COc1ccc2c(C3CCCC3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-cyclopentyl-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride. The product is too impure for a description by NMR. It is used as obtained in the following amination reaction.
Reaction SMILES: [CH3:1][C:2]12[CH2:29][CH:5]([C:6]3([CH3:28])[C:10]1([CH3:11])[C:9]1[CH:12]=[C:13]([C:16]([C:18]4[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=4)=[O:17])[CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2.[CH2:30](O)[CH2:31][OH:32].CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH3:1][C:2]12[CH2:29][CH:5]([C:6]3([CH3:28])[C:10]1([CH3:11])[C:9]1[CH:12]=[C:13]([C:16]4([C:18]5[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][CH:27]=5)[O:32][CH2:31][CH2:30][O:17]4)[CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2
Reactant: COC(=O)c1ccc(C(=O)c2ccc3c(c2)C2(C)C4(C)CCC(C4)C2(C)O3)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)c1ccc(C2(c3ccc4c(c3)C3(C)C5(C)CCC(C5)C3(C)O4)OCCO2)cc1

Procedure:
2 g (5.12 mmol) of the ketone obtained in Example 8, in 20 ml of benzene, were treated with 0.5 ml of ethylene glycol and 10 mg of TsOH. The reaction mixture was heated at reflux for 24 hours and was then neutralized with a saturated sodium bicarbonate solution. After extraction with ethyl ether, the organic phase was washed with water, dried over magnesium sulfate, filtered and evaporated to yield, after chromatography on silica in a hexane/EtOAc (90/10) mixture and triturating in hexane, 910 mg (41%) of the expected compound, melting at 136°-137° C.
Reaction SMILES: [NH:1]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[C@H:2]([C:12]([NH:14][C@H:15]([C:21]([NH:23][C@H:24]([C:35]([N:37]1[CH2:80][CH2:79][CH2:78][C@H:38]1[C:39]([NH:41][C@H:42]([C:47]([NH:49][C@H:50]([C:54]([NH:56][C@H:57]([C:68](OCC1C=CC=CC=1)=[O:69])[C@@H:58]([CH3:67])[O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:55])[CH:51]([CH3:53])[CH3:52])=[O:48])[CH2:43][CH:44]([CH3:46])[CH3:45])=[O:40])=[O:36])[C@@H:25]([CH3:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:22])[CH2:16][CH2:17][C:18](=[O:20])[NH2:19])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:88][NH2:89]>CN(C=O)C.CO>[NH:1]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[C@H:2]([C:12]([NH:14][C@H:15]([C:21]([NH:23][C@H:24]([C:35]([N:37]1[CH2:80][CH2:79][CH2:78][C@H:38]1[C:39]([NH:41][C@H:42]([C:47]([NH:49][C@H:50]([C:54]([NH:56][C@H:57]([C:68]([NH:88][NH2:89])=[O:69])[C@@H:58]([CH3:67])[O:59][CH2:60][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)=[O:55])[CH:51]([CH3:53])[CH3:52])=[O:48])[CH2:43][CH:44]([CH3:46])[CH3:45])=[O:40])=[O:36])[C@@H:25]([CH3:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:22])[CH2:16][CH2:17][C:18](=[O:20])[NH2:19])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)[C@@H](C)OCc1ccccc1)C(=O)N[C@H](C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)OCc1ccccc1)C(C)C
Reactant: NN
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)[C@@H](C)OCc1ccccc1)C(=O)N[C@H](C(=O)N[C@H](C(=O)NN)[C@@H](C)OCc1ccccc1)C(C)C

Procedure:
Compound XIV (1.6 g, 1.32 mmol) was dissolved in DMF/MeOH (5:3; 16 ml) and treated with H2NNH2 (0.78 ml) for 72 hrs at 25° C. The white solid was filtered and washed with MeOH and water, yield 1.05 g (70.5%); mp 210°-210.5° C; [α]D25 -22.5° (c 1, DMF). Anal. Calcd for C58H84N10O13 (1129.37): C, 61.68; H, 7.50; N, 12.40. Found: C, 61.72; H, 7.26; N, 12.30.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[N:3]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(#N)C>[CH2:11]([NH:18][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[N:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Fc1cc(F)c(F)nc1F
Reactant: NCc1ccccc1
Solvent: CC#N
Product: Fc1cc(F)c(NCc2ccccc2)nc1F
Yield: 84.6 %

Procedure:
To 50 ml of acetonitrile were added 12.0 g of 2,3,5,6-tetrafluoropyridine and 18.0 g of benzylamine, and the mixture was stirred under reflux condition for 2 hours, and the solvent and the like were distilled off. To the residue was added 150 ml of ethyl acetate, and the mixture was washed twice with 150 ml of distilled water and 150 ml of 10% aqueous solution of citric acid. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 16.0 g of the title compound as a pale yellow oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][N:12]=[C:13]([C:16]#[N:17])[C:14]#[N:15].NC1C=CC2C(=CC=CC=2)C=1.C(#N)CC#N.O.[NH2:35][NH2:36]>>[NH2:15][C:14]1[C:13](=[N:12][NH:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[C:16]([NH2:17])=[N:36][N:35]=1
Reactant: N#CC(C#N)=NNc1ccc2ccccc2c1
Reactant: NN
Agent: Nc1ccc2ccccc2c1
Solvent: N#CCC#N
Solvent: O
Product: NC1=NN=C(N)C1=NNc1ccc2ccccc2c1
Yield: 67 %

Procedure:
The title compound was prepared using 110 mg (0.5 mmol) of 2-[(naphthalen-2-yl)hydrazono]malononitrile, which was derived from 2-aminonaphthalene (143 mg, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. The hydrazine hydrate was added to the solution at a temperature of 75° C. despite the fact that the starting material had not fully dissolved. The solution cleared briefly and then a precipitate formed. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 86 mg (67%) of the title compound as a tan coloured solid.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[CH:21][C:20]([CH2:23][C:24]([NH2:26])=[O:25])=[C:19]([NH:27][CH2:28][C:29]4[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=4)[CH:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.C(=O)([O-])[O-].[K+].[K+].O.[CH3:44][NH2:45].C(O)C>>[F:35][C:33]1[CH:34]=[C:29]([CH:30]=[C:31]([F:36])[CH:32]=1)[CH2:28][NH:27][C:19]1[CH:18]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([N:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:45][CH3:44])[CH2:5][CH2:6]3)=[CH:15][CH:14]=2)[N:22]=[CH:21][C:20]=1[CH2:23][C:24]([NH2:26])=[O:25]
Reactant: CN
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCN(CCCl)CC3)cc2)cc1NCc1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CNCCN1CCN(c2ccc(Nc3cc(NCc4cc(F)cc(F)c4)c(CC(N)=O)cn3)cc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
42 mg of 6-({4-[4-(2-chloroethyl)piperazin-1-yl]phenyl}amino)-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide (the compound of Example 250) was dissolved in a 30% methylamine-ethanol solution, to which 23 mg of potassium carbonate was added, and stirred at 80° C. for 8 hours. After cooling, water was added to the reaction mixture, extracted with chloroform, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel thin layer chromatography (chloroform:ammonia methanol=10:1), and crystallized by adding ether to obtain 8 mg (15%) of the title compound as a slight yellow solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:6]1[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH2:11][CH:10]([CH2:18][O:19][Si](C(C)(C)C)(C)C)[CH2:9][N:8]3[CH:7]=1)=O.[F:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([CH2:38][C:39]([NH2:41])=[O:40])=[CH:34][NH:35]2)=[CH:31][CH:30]=1>>[F:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([CH:38]3[CH:4]([C:6]4[C:16]5=[C:17]6[C:12](=[CH:13][CH:14]=[CH:15]5)[CH2:11][CH:10]([CH2:18][OH:19])[CH2:9][N:8]6[CH:7]=4)[C:3](=[O:2])[NH:41][C:39]3=[O:40])=[CH:34][NH:35]2)=[CH:31][CH:30]=1
Reactant: NC(=O)Cc1c[nH]c2cc(F)ccc12
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CC(CO[Si](C)(C)C(C)(C)C)C2
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CC(CO)C3)C1c1c[nH]c2cc(F)ccc12

Procedure:
Beginning with (5-(tert-butyldimethylsilyloxymethyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester and (6-fluoro-1H-indol-3-yl)acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([OH:27])[CH:25]=4)[NH:20][CH:19]=3)[CH2:11][CH2:10]2)=[N:5][CH:6]=[N:7][CH:8]=1.[CH3:28][N:29]=[C:30]=[O:31]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:27][C:30](=[O:31])[NH:29][CH3:28])[CH:25]=4)[NH:20][CH:19]=3)[CH2:11][CH2:10]2)=[N:5][CH:6]=[N:7][CH:8]=1
Reactant: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(O)cc23)CC1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)Oc1ccc2[nH]cc(CCCN3CCN(c4ncncc4OC)CC3)c2c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 61.5 %

Procedure:
To a solution of 3-[3-[4-(5-methoxy-4-pyrimidinyl)-1-piperazinyl]propyl]-5-hydroxyindole (0.170 g, 0.46 mmol) in 6 mL of CH2Cl2 was added methyl isocyanate (60 μL, 1.0 mmol) and the mixture was stirred at room temperature for 4 days. The mixture was then evaporated and the resulting pinkish-gray foam was triturated with isopropanol-ether to give a light grey solid. This material was chromatographed (SiO2 /EtOAc-MeOH, 95:5; then 90:10) to give the title compound (0.120 g, 60%) as a light gray solid, m.p. 120°-122° C. IR (KBr) 3400, 3220, 1730 cm-1 ; 1H NMR (CDCl3, 200 MHz) δ 8.33 (s, 1H), 8.06 (br s, 1H), 7.88 (s, 1H), 7.34-7.26 (m, 2H), 6.99-6.91 (m, 2H), 5.00 (br m, 1H), 3.85 (s, 3H), 3.79 (t, J=4.7 Hz, 4H), 2.91 (d, J=4.8 Hz, 3H), 2.75 (t, J=7.4 Hz, 2H), 2.54 (t, J=4.8 Hz, 4H), 2.45 (t, J=7.6 Hz, 2H), 2.04-1.83 (m, 2H). Anal. Calcd. for C22H28N6O3.0.8H2O: C, 60.20; H, 6.80; N, 19.15. Found: C, 60.13; H, 6.40; N, 18.75.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13]C)[CH:9]([C:15]1([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)[CH2:18][CH2:17][CH2:16]1)[NH:8][CH2:7][CH2:6]2.C=O.[C:31]([BH3-])#N.[Na+].Br>C(O)(=O)C.C(#N)C>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[CH:9]([C:15]1([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)[CH2:16][CH2:17][CH2:18]1)[N:8]([CH3:31])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)C(C1(c3ccc4ccccc4c3)CCC1)NCC2
Reactant: [BH3-]C#N
Agent: Br
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN1CCc2cc(O)c(O)cc2C1C1(c2ccc3ccccc3c2)CCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 6,7-dimethoxy-1-[1-(2-naphthyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinoline (4.74 g prepared as described in Example RB20), 37-40% aqueous formaldehyde solution (5.1 ml), acetonitrile (120 ml) and sodium cyanoborohydride (1.3 g) was stirred at ambient temperature for 15 minutes. The mixture was neutralised by addition of glacial acetic acid and stirred for 45 minutes. The mixture was concentrated by evaporation and basified with 2N aqueous potassium hydroxide solution. The resulting mixture was extracted with ether. The extracts were washed with aqueous potassium hydroxide solution and extracted with aqueous hydrochloric acid. The acid extract was basified and extracted with ether. The ether extract yielded a residue, a portion (3.86 g) of which was mixed with 48% aqueous hydrobromic acid (40 ml) and glacial acetic acid (40 ml) and heated at 100° C. for two days. The solvent was removed by evaporation and the residue dried by azeotropic distillation with propan-2-ol. The residue was washed with ether and decolourised with charcoal in propan-2-ol. The mixture was filtered and yielded 6,7-dihydroxy-2-methyl-1-[1-(2-naphthyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinoline 1.1 hydrobromide (m.p. 150°-153° C.) which was dried in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][C@H:19]([C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=2)[CH3:20])=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH2:40])(=[O:39])=[O:38])=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)=[C:4]([CH:3]=1)[C:16]([NH:18][C@H:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:40][S:37]([C:34]2[CH:33]=[CH:32][C:31]([Cl:30])=[CH:36][CH:35]=2)(=[O:39])=[O:38])=[O:27])=[CH:23][CH:22]=1)[CH3:20])=[O:17]
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)O)cc1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 103 from 4-[(1S)-1-({[5-chloro-2-(4-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid (step 5 of Example 44) and 4-chlorobenzenesulfonamide: 1H-NMR (CDCl3) δ 8.51 (1H, d, J=2.6 Hz), 8.13 (1H, d, J=2.6 Hz), 8.16–8.03 (1H, m), 8.08 (2H, d, J=8.7 Hz), 7.75 (2H, d, J=8.2 Hz), 7.52 (2H, d, J=8.7 Hz), 7.43 (2H, d, J=8.2 Hz), 7.21–7.08 (4H, m), 5.39–5.24 (1H, m), 1.57 (3H, d, J=7.4 Hz); MS (ESI) m/z 588 (M+H)+, 586 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:11]=[C:10]([CH2:12][NH2:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:20][CH:21]([CH3:25])[C:22](O)=[O:23].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:5]2[N:11]=[C:10]([CH2:12][NH:13][C:22](=[O:23])[CH:21]([CH3:25])[CH3:20])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: NCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Reactant: CC(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Reaction time: 8 h

Procedure:
(2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methanamine from Example 145 (0.1 g) was added to a pre-stirred (15 minutes) solution of 2-methylpropanoic acid (1.2 eq), 1-hydroxybenzotriazole (1.1), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.1), triethylamine (2 eq) in N,N-dimethylformamide (2.77 mL). The reaction was stirred overnight then extracted with Ethyl Acetate and brine. The organic layer was dried (Mg2SO4), filtered and concentrated to give quantitative yield of N-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)isobutyramide.
Reaction SMILES: [CH2:1]([C:3]([CH2:9][CH3:10])([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].[Si:11]([O:18][C@H:19]1[CH2:28][C@H:27]([OH:29])[C@H:26]2[C:21]([CH:22]=[CH:23][C@H:24]([CH3:47])[C@@H:25]2[CH2:30][CH2:31][C@H:32]2[O:37][C:36](=[O:38])[CH2:35][C@H:34]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH2:33]2)=[CH:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1(C2C=CN=CC=2)CCCC1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Si:11]([O:18][C@H:19]1[CH2:28][C@H:27]([O:29][C:4](=[O:5])[C:3]([CH2:9][CH3:10])([CH2:7][CH3:8])[CH2:1][CH3:2])[C@H:26]2[C:21]([CH:22]=[CH:23][C@H:24]([CH3:47])[C@@H:25]2[CH2:30][CH2:31][C@H:32]2[O:37][C:36](=[O:38])[CH2:35][C@H:34]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:41])[CH3:42])[CH2:33]2)=[CH:20]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:13])[CH3:12]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CCC(CC)(CC)C(=O)Cl
Agent: c1cc(N2CCCC2)ccn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCC(CC)(CC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 89.4 %

Procedure:
1.48 g (9.1 mmol) of 2,2-diethylbutyryl chloride were added to a solution of 1.0 g (1.8 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] 1.67 g (11.3 mmol) of 4-(1-pyrrolidinyl)pyridine and 1.0 ml (7.1 mmol) of triethylamine in 10 ml of toluene, and the resulting mixture was heated under reflux for 10 hours. At the end of this time the reaction mixture was worked-up following a procedure similar to that described in Example 5, above, to give 1.09 g (89% yield) of the title compound.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[CH:12]=[CH:13][C:14]=1[CH3:15].[Cl:27][CH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:17]([NH:16][C:11]2[CH:12]=[CH:13][C:14]([CH3:15])=[C:9]([NH:8][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([CH2:28][Cl:27])=[CH:30][CH:31]=3)[CH:10]=2)=[O:26])=[CH:19][CH:20]=1)#[N:25]
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1NC(=O)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
Triethylamine (0.55 ml) was added to a suspension of N-(3-amino-4-methylphenyl)-4-cyanobenzamide (0.40 g), 4-(chloromethyl)benzoyl chloride (0.45 g) and 4-dimethylaminopyridine (0.019 g) in methylene chloride (12 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was triturated with water. The resultant solid was isolated and washed in turn with 2N hydrochloric acid and a saturated aqueous sodium bicarbonate solution. The solid was dried under vacuum at 55° C. to give the required starting material (0.64 g); NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 4.82 (s, 2H), 7.23 (d, 1H), 7.58 (m, 3H), 7.84 (s, 1H), 7.99 (m, 4H), 8.1 (d, 2H), 9.91 (s, 1H), 10.46 (s, 1H); Mass Spectrum: M−H− 402.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CC(C)=O>[CH2:23]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1)[CH:22]=[CH2:21]
Reactant: O=C1CCC(c2cccc(O)c2)=NN1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cccc(C2=NNC(=O)CC2)c1

Procedure:
i. A stirred mixture of finely powdered 6-(3-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (13.1g, 0.07 mole), potassium carbonate (9.5g, 0.07 mole), allyl bromide (11.75 ml, 0.14 mole), and dry acetone (250 ml) was heated under reflux for 18 hours. Evaporation of the filtered solution under reduced pressure gave 6-(3-allyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone which was washed with ether (13.66g, 86%, m.p. 111°-113° C). Crystallisation from a small volume of ethanol gave the pure pyridazinone m.p. 112°-114° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([Sn](C)(C)C)[N:15]=3)[NH:10][C:9](=[O:21])[CH2:8]2)[CH2:3][CH2:2]1.Br[C:23]1[CH:24]=[CH:25][C:26]([C:29]2[N:33]=[CH:32][N:31]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][O:35]3)[N:30]=2)=[N:27][CH:28]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C)C=O>[O:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH:34]1[N:31]1[CH:32]=[N:33][C:29]([C:26]2[N:27]=[CH:28][C:23]([C:14]3[N:15]=[C:16]4[N:7]([CH:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[CH2:8][C:9](=[O:21])[NH:10][C:11]4=[N:12][CH:13]=3)=[CH:24][CH:25]=2)=[N:30]1
Reactant: Brc1ccc(-c2ncn(C3CCCCO3)n2)nc1
Reactant: C[Sn](C)(C)c1cnc2c(n1)N(C1CCOCC1)CC(=O)N2
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CN(C2CCOCC2)c2nc(-c3ccc(-c4ncn(C5CCCCO5)n4)nc3)cnc2N1
Temperature: 95 °C
Yield: 39 %

Procedure:
A mixture of 4-(tetrahydro-2H-pyran-4-yl)-6-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1 equiv), 5-bromo-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)pyridine (1.2 equiv), tris(dibenzylideneacetone)dipalladium (0.1 equiv), tri-o-tolylphosphine (0.2 equiv), triethylamine (3 equiv) and N,N-dimethylformamide was heated at 95° C. for 3 h under nitrogen. Concentration and chromatography purification give the desired product in 39% yield. MS (ESI) m/z 463.1 [M+1]+.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21]([OH:23])=O)[C:12]=3[CH:13]=[N:14][CH:15]=2)=[CH:6][CH:5]=1.C(N1C=CN=C1)([N:28]1C=CN=C1)=O.N>CN(C=O)C.C(Cl)Cl>[F:24][C:3]([F:2])([F:25])[C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]3[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21]([NH2:28])=[O:23])[C:12]=3[CH:13]=[N:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: O=C(O)COC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)COC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
To a solution of (rac)-2-(4-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yloxy)acetic acid hydrochloride (example 99) (34.6 mg, 0.093 mmol) in DMF (1 mL) was added N,N-triethylamine (31 μL, 0.22 mmol) and 1,1′-carbonyldiimidazole (18.0 mg, 0.11 mmol). The reaction was stirred at room temperature for 2 h, cooled (0°) and treated with aq. 25% ammonia solution (0.87 mL, 5.55 mmol) and evaporated after 30 min to give a 1:1 mixture of starting material and product. The residue was dissolved in CH2Cl2, dried (Na2SO4) and evaporated. The oil was again dissolved in DMF (1 mL) and N,N-triethylamine (15.5 μL, 0.11 mmol) and 1,1′-carbonyldiimidazole (18.0 mg, 0.11 mmol) were added. The reaction was stirred at room temperature for 2 h, cooled (0°) and treated with aq. 25% ammonia solution (0.87 mL, 5.55 mmol) and evaporated after 30 min at room temperature. The solution was evaporated, dried in vacuo and purified by flash chromatography (20 g SiO2, Telos-cartridge, 3% MeOH in CH2Cl2) to give the title compound (15 mg, 48%) as off-white solid. MS: 337.1 (M+H+).
Reaction SMILES: [N:1]([CH2:4][C:5]1([CH2:8][O:9][C:10]2[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:11]=2[C:20]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:21]=2[CH2:22][CH2:23][C:24]3=[O:29])[CH2:7][CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][C:5]1([CH2:8][O:9][C:10]2[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:11]=2[C:20]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:21]=2[CH2:22][CH2:23][C:24]3=[O:29])[CH2:6][CH2:7]1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN=[N+]=[N-])CC2)c1OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN)CC2)c1OC
Temperature: 80 °C

Procedure:
To a stirring solution of 4-(2-((1-(azidomethyl)cyclopropyl)methoxy)-3,4-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-one (1.5 g, 3.947 mmol) in tetrahydrofuran (50 mL), were added triphenylphosphine (4.14 g, 15.78 mmol) and the reaction mixture was stirred at RT for 2 h. water (5 mL) was added to the above reaction mixture and the resultant reaction was heated to 80° C. for 1 h. The reaction mixture was concentrated under reduced pressure and the obtained residue was acidified with 1N hydrochloric acid solution. Then extracted with ethyl acetate (3×) and the aq layer was basified with sodium bicarbonate solution and extracted with ethyl acetate and the combined ethyl acetate layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afforded the title compound as a liquid.