Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:14])[C:9](=[O:13])[C:10]([CH3:12])([CH3:11])[C:5]2=[CH:4][CH:3]=1.[CH3:15][O-:16].[Na+].O>CN(C=O)C>[CH3:15][O:16][C:2]1[N:7]=[C:6]2[N:8]([CH3:14])[C:9](=[O:13])[C:10]([CH3:12])([CH3:11])[C:5]2=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: CN1C(=O)C(C)(C)c2ccc(Cl)nc21
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(n1)N(C)C(=O)C2(C)C
Temperature: 145 °C

Procedure:
A mixture of 0.3 g (1.4 mmol) 6-chloro-1,3,3-trimethyl-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one, 0.6 ml (2.8 mmol) of sodium methoxide (4.6M in methanol), and 1.2 mg of Cul in 6 ml of DMF was heated to 145° C. for 18 hours. The reaction mixture was cooled to room temperature and added to 25 ml of water. The mixture was extracted with ethyl acetate. The ethyl acetate extract were was washed with 25 ml of saturated sodium bisulfite, dried (Na2SO4) and evaporated. The residue was triturated twice with hot hexane, and the hexane decanted. The residue 6-methoxy-1,3,3-trimethyl-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (0.25 g) was used without further purification. TLC: Rf=0.7 (5:1 hexane/ethyl acetate). 1H NMR (CDCl3) δ 7.35 (d, 1H), 6.38 (d, 1H), 3.92 (s, 3H), 3.22 (s, 3H), 1.33 (s, 3H). Mass spectrum: m/e=207.3 (p+1).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH:22](=[O:30])[C:23]1[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=1)[OH:25].C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[CH2:8][O:7][C:6]1[CH:5]=[C:4]([CH:21]=[CH:20][CH:19]=1)[CH2:3][O:25][C:24]1[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=1[CH:22]=[O:30]
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: O=Cc1ccccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=Cc1ccccc1OCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C

Procedure:
2-(3-Chloromethyl-phenoxymethyl)-quinoline (371 mg, 1.3 mmol, example 49) and salicylaldehyde (133 μL, 1.25 mmol) are dissolved in acetone (10 mL). K2CO3 (525 mg, 3.75 mmol) is added and the contents are heated to reflux for 16 hrs. The reaction is cooled to r.t., poured into water (100 mL) and extracted with ethyl ether (3×50 mL). The ether layers are combined and washed with Brine (3×75 mL) and dried over MgSO4. The crude material is preadsorbed onto silica gel and purified by flash chromatography (silica, 20 to 25% ethyl acetate in hexanes) to give the title compound. MS (ion spray) 370 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([CH3:20])=[CH:6]2.[H-].[Na+].F[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=1>CN(C=O)C>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=1)=[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([CH3:20])=[CH:6]2
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Reactant: COc1ccc2c(O)c(-c3ccccc3)c(C)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2cc(O)ccc2c(Oc2ccc(C=O)c(C(F)(F)F)c2)c1-c1ccccc1
Temperature: 0 °C
Yield: 90 %

Procedure:
Compound 7 (215 mg, 0.81 mmol, 1 equiv) was dissolved in DMF (5 mL) and cooled to 0° C. under N2. Sodium hydride, 60% dispersion (36 mg, 0.89 mmol, 1.1 equiv), followed by 4-fluoro-2-(trifluoromethyl)benzaldehyde (312 mg, 1.63 mmol, 2 equiv) were added and the entire reaction mixture was heated to 70° C. for 3 days. The mixture was then partitioned between EtOAc (50 mL) and H2O (50 mL). The organic layer was washed with saturated aqueous NaCl (100 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel flash column chomatography (10% EtOAc in hexanes) to provide 20 (308 mg, 87%) as a clear oil. 1HNMR (400 MHz, DMSO-d6): δ 10.01 (s, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.78 (s, 1H), 7.60 (d, J=9.1 Hz, 1H), 7.39 (d, J=2.4 Hz, 1H), 7.32-7.10 (m, 7H), 6.95 (dd, J=8.6, 2.4 Hz, 1H), 3.88 (s, 3H), 2.20 (s, 3H). MS m/z 473.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[H-].[Na+].[N+:11]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1Cl)([O-:13])=[O:12].Cl>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:8])[CH:5]([C:6]#[N:7])[C:19]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[N+:11]([O-:13])=[O:12])[CH3:2]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CCOC(=O)CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C#N)c1ccncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
Ethylcyanoacetate (3.75 g, 38 mmol) in 3 mL DMF was added dropwise at 0° C. to a suspension of sodium hydride (1.5 g, 60% in mineral oil, 38 mmol) in DMF (9 mL). The reaction mixture was stirred at room temperature for 30 minutes then cooled to ° C. and 3-nitro-4-chloropyridine (2.63 g, 19 mmol, 1 eq) in DMF (3 mL) added slowly. 2 M HCl (20 mL) and ethyl acetate (20 mL) were added after 2 hours stirring at room temperature and the organic layer was washed with water and brine, before being dried over sodium sulphate and concentrated to give a red/orange oil. The crude oil was triturated with ethyl acetate and the resultant solid collected by filtration to give the title compound (2.88 g, 48%). 1H NMR (d6-DMSO) δ 13.2 (s, br), 8.70 (1H, s), 7.88 (1H, dd, J=7.1, 1.0), 4.06 (2H, q, J=7.1), 1.18 (3H, t, J=7.1); LC-MS (1) Rt 1.13 min; m/z (ES−) 190, 234.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][C:25]=1[C:33]([F:36])([F:35])[F:34].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:24]([F:23])=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:26]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccc(F)c(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccc(F)c(C(F)(F)F)c4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) and 4-fluoro-3-trifluoromethyl-benzoyl chloride (0.6 g, 2.8 mmol) in dry methylene chloride (60 mL), was added diisopropylethylamine (0.7 g, 5.4 mmol). After stirring at room temperature overnight, the reaction mixture was quenched with methanol (1 mL). The resulting suspension was filtered, and the solid was washed with methyene chloride to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-4-fluoro-3-trifluoromethyl-benzamide (0.8 g, 79%) as a white solid: mp 171-173° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=7.5 min. (99%); 1H NMR (DMSO-d6) δ 2.06-2.12 (m, 1H), 2.54-2.65 (m, 2H), 2.85-2.98 (m, 1H), 4.97 (d, J=5.7 Hz, 2H), 5.15-5.21 (dd, J=5.4 and 12.5 Hz, 1H), 7.68 (t, J=8.9 Hz, 1H), 7.76-7.84 (m, 3H), 8.28-8.35 (m, 2H), 9.43 (t, J=5.7 Hz, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 21.91, 30.86, 38.43, 48.82, 116.20 (116.37, 116.64, 116.80), 117.35 (117.63), 120.50 (124.10), 121.92, 126.51 (126.56), 127.14, 130.65 (130.70), 131.48, 133.22, 134.58, 134.71 (134.77), 138.70, 158.78 (162.21), 164.19, 166.87, 167.44, 169.75, 172.68; Anal. Calcd. for C22H15N3O5F4+0.2H2O: C, 54.94; H, 3.23; N, 8.74; F, 15.80. Found: C, 54.68; H, 3.17; N, 8.63; F, 15.72.
Reaction SMILES: [C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][CH2:17][O:18]S(C)(=O)=O)[C:14](=[O:23])[O:13][CH2:12][C@H:11]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:10](=[O:32])[O:9][C@H:8]1[CH3:33])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Na+].[I-].[C:36]([O-])(O)=[O:37].[Na+].CCOC(C)=O>CN(C=O)C>[C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][CH2:17][O:18][CH:36]=[O:37])[C:14](=[O:23])[O:13][CH2:12][C@H:11]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:10](=[O:32])[O:9][C@H:8]1[CH3:33])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CCOS(C)(=O)=O
Reactant: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CCOC=O
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a solution (3S,6S,7R,8R)-3-(tert-butoxycarbonylamino)-6-methyl-8-(2(methylsulfonyloxy)ethyl)-4,9-dioxo-1,5-dioxonan-7-yl isobutyrate (510 mg, 1.03 mmol) in DMF (3 mL) at room temperature (about 22° C.) was added NaI (1 g, 6.7 mmol). The resulting reaction mixture was heated to 80° C. and stirred for 48 h. After cooling to room temperature, saturated NaHCO3 solution (30 mL) and EtOAc (25 mL) were added. The phases were separated and the aqueous phase was extracted with EtOAc (2×25 mL). The combined EtOAc extracts were dried over Na2SO4, filtered, and concentrated to dryness. The crude residue was purified via column chromatography (SiO2, hexanes/EtOAc gradient) to afford the title compound (228 mg, 50%) as a white solid (228 mg, 50%): mp 103-104; 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 5.43-5.15 (m, 2H), 5.06 (t, J=9.9 Hz, 1H), 4.93-4.77 (m, 2H), 4.19 (dt, J=11.1, 5.5 Hz, 1H), 4.05 (ddd, J=11.4, 8.9, 4.8 Hz, 1H), 3.60 (s, 1H), 2.71 (td, J=11.4, 2.8 Hz, 1H), 2.67-2.53 (m, 1H), 2.17-2.02 (m, 1H), 1.73 (dt, J=14.7, 7.4 Hz, 1H), 1.45 (s, J=15.6 Hz, 9H), 1.28 (d, J=6.3 Hz, 3H), 1.21 (dd, J=7.0, 0.5 Hz, 6H); ESIMS m/z 468 ([M+Na]+).
Reaction SMILES: C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)[C:10](OC2C=CC=CC=2)=[O:11])C=CC=CC=1.Cl.Cl.Cl.[CH3:53][N:54]([CH3:65])[CH:55]1[CH2:58][N:57]([CH:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)[CH2:56]1.C(N(CC)CC)C>CN(C)C=O>[CH3:53][N:54]([CH3:65])[CH:55]1[CH2:56][N:57]([CH:59]2[CH2:64][CH2:63][N:62]([C:10]([NH:9][C:19]3[CH:24]=[C:23]([O:25][C:26]4[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]5([C:38]([NH:39][C:40]6[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=6)=[O:47])[CH2:37][CH2:36]5)=[O:34])=[CH:28][C:27]=4[F:48])[CH:22]=[CH:21][N:20]=3)=[O:11])[CH2:61][CH2:60]2)[CH2:58]1
Reactant: CN(C)C1CN(C2CCNCC2)C1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C1CN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccc(F)cc6)CC5)cc4F)ccn3)CC2)C1
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of [4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (66 mg) in N,N-dimethylformamide (1.0 ml) were added 4-(3-dimethylaminoazetidin-1-yl)piperidine trihydrochloride (116 mg) and triethylamine (0.168 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (57.5 mg, 91%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[CH3:8][O:9][C:10]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][NH:13]1)=[O:11].O([CH2:30][CH2:31][N:32]1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42])S(C(F)(F)F)(=O)=O>O.C(Cl)Cl>[C:33]1(=[O:42])[N:32]([CH2:31][CH2:30][N:13]2[CH2:14][C@@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:17][C@@H:12]2[C:10]([O:9][CH3:8])=[O:11])[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]12
Reactant: O=C1c2ccccc2C(=O)N1CCOS(=O)(=O)C(F)(F)F
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)OC)NC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@H](C(=O)OC)N(CCN2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To a well-stirred bi-phasic mixture consisting of sodium carbonate (500 g, 4.72 mol) in water (3 liters) and trans-2,5-piperidine dicarboxylate dimethyl ester hydrochloride (280 g, 1.18 mol) in methylene chloride (4.5 liters), a solution of 2-phthalimido-ethyl triflate (417 g, 1.29 mol) in methylene chloride (3 liters) was added in a steady stream over a 3 hour period. The organic layer was separated, and the aqueous layer was extracted with fresh methylene chloride (3 liters). The combined organic extracts were washed with water (3 liters), then with brine (3 liters), dried with anhydrous magnesium sulfate and finally, concentrated in vacuo to a solid. The entire residue was triturated in refluxing ether (3 liters), with vigorous stirring, for 15 minutes. After cooling to ambient temperature, the solution was poured into hexanes (3 liters), and the resulting mixture was stirred for 18 hours. The resulting colorless solid was collected by filtration, and the filter cake was washed with hexanes (1 liter). In vacuo drying afforded 437.3 g (99.1% yield) of the title compound as a colorless solid. TLC Rf (ethyl acetate/methylene chloride=1:1 in volume; iodoplatinate spray): 0.5.
Reaction SMILES: [CH:1]([C@H:4]1[C:8](=[O:9])[O:7][C@H:6]([C@@H:10]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:11][C@H:12]([CH2:16][C:17]2[CH:25]=[C:24]3[C:20]([CH:21]=[N:22][N:23]3[CH2:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:19][CH:18]=2)[CH:13]([CH3:15])[CH3:14])[CH2:5]1)([CH3:3])[CH3:2].OC1C=CC=CN=1.[NH2:46][CH2:47][C:48]([CH3:53])([CH3:52])[C:49]([NH2:51])=[O:50]>CCN(CC)CC>[NH2:51][C:49](=[O:50])[C:48]([CH3:53])([CH3:52])[CH2:47][NH:46][C:8]([C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][C@H:6]([OH:7])[C@@H:10]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:11][C@H:12]([CH2:16][C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[N:22][N:23]2[CH2:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:19][CH:18]=1)[CH:13]([CH3:14])[CH3:15])=[O:9]
Reactant: CC(C)(CN)C(N)=O
Reactant: COCCCn1ncc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H]3C[C@@H](C(C)C)C(=O)O3)C(C)C)cc21
Agent: Oc1ccccn1
Solvent: CCN(CC)CC
Product: COCCCn1ncc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@H](C(=O)NCC(C)(C)C(N)=O)C(C)C)C(C)C)cc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
A mixture of tert-butyl (1S,3S)-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-3-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-4-methylpentylcarbamate (120 mg, 0.25 mmol), Et3N (1.5 mL), 2-hydroxypyridine (71.3 mg, 0.75 mmol), and 3-amino-2,2-dimethylpropanamide (87 mg, 0.75 mmol) was stirred at 80° C. overnight. The mixture was evaporated and purified by flash chromatography on silica gel to give tert-butyl (3S,5S,6S,8S)-8-(3-amino-2,2-dimethyl-3-oxopropylcarbamoyl)-6-hydroxy-3-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-2,9-dimethyldecan-5-ylcarbamate (120 mg, 65%). MS: 646 (M++1)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH:18]([CH2:20]Cl)[CH2:17][C:16]2=[O:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:23]#[N:24].[Na+].[I-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:16](=[O:22])[CH2:17][CH:18]([CH2:20][C:23]#[N:24])[CH2:19]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(CCl)CN1c1ccc(OCc2ccccc2)cc1
Reactant: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCC1CC(=O)N(c2ccc(OCc3ccccc3)cc2)C1
Yield: 36.8 %

Procedure:
123 mg (0.39 mmol) (RS)-1-(4-benzyloxy-phenyl)-4-chloromethyl-pyrrolidin-2-one is dissolved in 2.5 ml N,N-dimethylformamide. After addition of 29 mg (0.58 mmol) sodium cyanide and 6 mg (0.04 mmol) sodium iodide, the mixture is hold at 120° C. for 15 min. Dilution with water and extraction with ethyl acetate yields 44 mg (37%) of a brownish solid. MS: m/e=307.3 (M+H)+.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[NH2:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH3:23])([CH3:22])[C:16](=[O:21])[N:17]2[CH3:20])=[CH:13][CH:12]=1>>[CH3:20][N:17]1[C:18]2[C:14](=[CH:13][CH:12]=[C:11]([NH:10][C:1](=[O:9])[C:2]3[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=3)[CH:19]=2)[C:15]([CH3:22])([CH3:23])[C:16]1=[O:21]
Reactant: CN1C(=O)C(C)(C)c2ccc(N)cc21
Reactant: O=C(O)c1cccnc1
Product: CN1C(=O)C(C)(C)c2ccc(NC(=O)c3cccnc3)cc21

Procedure:
Prepared in analogy to example 1b from nicotinic acid and 6-amino-1,3,3-trimethylindolin-2-one (W. von der Saal et al., J. Med. Chem. 1989, 32(7), 1481-1491). The title compound was obtained as light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH:12]=O)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:14][N+:15]([O-:17])=[O:16]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH:12]=[CH:14][N+:15]([O-:17])=[O:16])[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: Cn1c(C=O)cc2ccc(Br)cc21
Product: Cn1c(C=C[N+](=O)[O-])cc2ccc(Br)cc21
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 6-bromo-1-methyl-1H-indole-2-carbaldehyde (422 mg, 1.77 mmol) and NH4OAc (137 mg, 1.77 mmol) in MeNO2 (10.0 mL) was heated to reflux for 2 h. The mixture was cooled to room temperature and partitioned between water and EtOAc. The aqueous phase was separated and extracted with EtOAc (3×). The organic extracts were dried over Na2SO4, filtered and concentrated to give title compound (490 mg, 99%) as an orange solid: 1H NMR (500 MHz, CDCl3) δ 8.12 (d, J=13.0 Hz, 1H), 7.67 (d, J=13.5 Hz, 1H), 7.53 (s, 1H), 7.50 (d, J=8.5 Hz, 1H), 7.26 (dd, J=8.5, 1.5 Hz, 1H), 7.05 (s, 1H), 3.84 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:17])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.C(O[B:30]1[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]1)(C)C>O1CCCC1.C1COCC1.CCCCCC>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:17])=[C:9]1[B:30]1[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)n(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 462 mg 3-Methyl-indole-1-carboxylic acid tert-butyl ester in 2.5 ml anhydrous tetrahydrofuran at −78° C. under argon is added 1.2 ml of a 2M LDA solution in THF/hexane and stirred at 0° C. for 30 min to complete the deprotonation. The reaction mixture is cooled to −78° C., 0.6 ml 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane are added, and stirred at 0° C. for 60 min. The reaction is quenched by the addition of 2 ml MeOH/water (1:1), diluted into water and extracted with ethylacetate. After evaporation of the solvent and purification on silica gel, 385 mg of 3-Methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indole-1-carboxylic acid tert-butyl ester are obtained.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([CH:14]3[O:19][CH2:18][CH2:17][NH:16][CH2:15]3)[O:11][N:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1.Cl>ClCCl>[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([N:16]2[CH2:17][CH2:18][O:19][CH:14]([C:12]3[O:11][N:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=4)[N:13]=3)[CH2:15]2)=[O:33])=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Fc1ccc(-c2noc(C3CNCCO3)n2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)N1CCOC(c2nc(-c3ccc(F)cc3)no2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a suspension of 2-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-morpholine hydrochloride (0.15 g, 0.53 mmol) in anhydrous dichloromethane (6 mL), under nitrogen atmosphere, triethylamine (155 mL, 1.1 mmol) and 4-fluorobenzoyl chloride (62 mL, 0.53 mmol) were subsequently added at 0° C. The reaction mixture was allowed to warm at room temperature and stirred overnight. HCl 1N (6 mL) was added and the phases were separated. The organic layer was washed sequentially with HCl 1N (6 mL), NaOH 1N (6 mL×2 times) and with water, then was dried over sodium sulphate and evaporated under reduced pressure. The crude was purified by flash chromatography (silica gel, eluent: hexane/ethyl acetate 7/3) to afford 120 mg of (4-fluoro-phenyl)-{2-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-morpholin-4-yl}-methanone as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.[CH2:28]([NH:30][CH3:31])[CH3:29].CCCP(=O)=O>O1CCCC1.C(OCC)(=O)C>[CH2:28]([N:30]([CH3:31])[C:25]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([NH:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:17]=[C:11]2[CH:10]=1)=[O:24])=[O:27])[CH3:29]
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reactant: CCNC
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(C)C(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (600 mg, 1.66 mmol), N-ethylmethylamine (427 ul, 4.97 mmole), N-diisopropylethylamine (868 ul, 4.97 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 2.44 ml, 4.14 mmol) in tetrahydrofurane (30 ml) is stirred for 2 hours at 70° C. The cooled solution is diluted with ethyl acetate, washed once with sat. aqueous sodium bicarbonate solution, once with brine, dried with magnesium sulfate and evaporated to dryness. Two successive crystallizations of the residue (680 mg white solid) from ethyl acetate afford N4-ethyl-N4,1-dimethyl-N5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (365 mg, 54.6%) as a white solid. mp.: 193-4° C. MS: m/z=404.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][C@@H:17]([CH3:19])[NH:16][C@@H:15]([CH3:20])[C:14]3=[O:21])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[Cl:29][C:30]1[S:34][C:33]([CH:35]=[CH:36][S:37](Cl)(=[O:39])=[O:38])=[CH:32][CH:31]=1>C(Cl)Cl>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][C@@H:17]([CH3:19])[N:16]([S:37]([CH:36]=[CH:35][C:33]4[S:34][C:30]([Cl:29])=[CH:31][CH:32]=4)(=[O:39])=[O:38])[C@@H:15]([CH3:20])[C:14]3=[O:21])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: C[C@@H]1CN(Cc2ccc3c(N)ncnc3c2)C(=O)[C@H](C)N1
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(Cc2ccc3c(N)ncnc3c2)C(=O)[C@H](C)N1S(=O)(=O)C=Cc1ccc(Cl)s1
Reaction time: 8 h
Yield: 2.3 %

Procedure:
(3S,5R)-1-(4-Amino-quinazolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one (43 mg, 0.123 mmol), minor epimer from EXAMPLE 88, Part D, is taken up in methylene chloride to this is added triethylamine (0.034 ml, 0.25 mmol) followed by 2-(5-chloro-thiophen-2-yl)-ethenesulfonyl chloride (40 mg, 0.16 mmol), EXAMPLE 3. The reaction is stirred overnight, and the crude material is purified by preparative thin layer chromatography (15% methanol/CH2Cl2). The product (1.4 mg, 2.3%) is isolated as a yellow wax. C21H22ClN5O3S2 MS m/z: 492, 494. 1H NMR (CD3OD) δ8.36 (s, 1H); 8.03 (d, 1H, J=7.5 Hz); 7.61 (s, 1H); 7.49-7.44 (m, 2H); 7.19 (d, 1H, J=3.83 Hz); 6.98 (d, 1H, J=3.75 Hz); 6.76 (d, 1H, J=15.1 Hz); 4.86-4.71 (m, 2H); 4.45-4.39 (m, 1H); 4.13-4.09 (m, 1H); 3.64-3.7 (m, 2H); 1.63 (d, 3H, J=7.09 Hz); 1.33 (d, 3H, J=6.80 Hz).