Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]12[C@@H:11]3[CH2:12][CH2:13][C@@:14]4([O:19][C@@H:20]5[O:25][C@H:24]([CH2:26]O)[C@@H:23]([OH:28])[C@H:22]([OH:29])[C@H:21]5[O:30][C@@H:31]5[O:36][C@H:35]([CH2:37][OH:38])[C@@H:34]([OH:39])[C@H:33]([O:40][C@@H:41]6[O:46][C@H:45]([CH2:47][OH:48])[C@@H:44]([OH:49])[C@H:43]([OH:50])[C@H:42]6[OH:51])[C@H:32]5[OH:52])[C:16]([CH2:18][C@@:10]3([CH2:15]4)[CH2:9][CH2:8][C@@H:7]1[C@@:6]([C:54]([O:56][C@@H:57]1[O:62][C@H:61]([CH2:63][OH:64])[C@@H:60]([OH:65])[C@H:59]([OH:66])[C@H:58]1[OH:67])=[O:55])([CH3:53])[CH2:5][CH2:4][CH2:3]2)=[CH2:17].[OH-].[K+].OS(O)(=O)=O>CO>[CH3:26][C@H:24]1[O:25][C@@H:20]([O:19][C@:14]23[C:16](=[CH2:17])[CH2:18][C@:10]4([CH2:15]2)[C@H:11]([C@@:2]2([CH3:1])[C@H:7]([CH2:8][CH2:9]4)[C@@:6]([C:54]([O:56][C@@H:57]4[O:62][C@H:61]([CH2:63][OH:64])[C@@H:60]([OH:65])[C@H:59]([OH:66])[C@H:58]4[OH:67])=[O:55])([CH3:53])[CH2:5][CH2:4][CH2:3]2)[CH2:12][CH2:13]3)[C@@H:21]([O:30][C@@H:31]2[O:36][C@H:35]([CH2:37][OH:38])[C@@H:34]([OH:39])[C@H:33]([O:40][C@@H:41]3[O:46][C@H:45]([CH2:47][OH:48])[C@@H:44]([OH:49])[C@H:43]([OH:50])[C@H:42]3[OH:51])[C@H:32]2[OH:52])[C@@H:22]([OH:29])[C@@H:23]1[OH:28]
Reactant: C=C1C[C@@]23CC[C@H]4[C@@](C)(CCC[C@@]4(C)C(=O)O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)[C@@H]2CC[C@]1(O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H]1O)C3
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=C1C[C@@]23CC[C@H]4[C@@](C)(CCC[C@@]4(C)C(=O)O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)[C@@H]2CC[C@]1(O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O)[C@@H]1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H]1O)C3
Yield: 78.9 %

Procedure:
Rebaudioside A (0.2 mmol, 183 mg) was transferred to a 15 ml flask. Four ml each of 10% KOH and methanol were added and the resultant mixture heated to yield a homogeneous solution which was refluxed for 1.5 hours. Reaction was then judged complete by TLC analysis. After cooling to 0°; the reaction mixture was acidified to pH 3 with 10% H2SO4. The resultant mixture was then concentrated to dryness and the residue recrystallized from water to give 150 mg (99%) of pure rebaudioside C.
Reaction SMILES: [NH2:1][C:2](=[O:42])[CH2:3][C:4]1[CH:41]=[CH:40][CH:39]=[CH:38][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][N:26]3C(OC(C)(C)C)=O)=[CH:21][CH:20]=2)[N:9]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH:25]1[C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:10]2[N:9]=[C:8]([CH2:7][CH2:6][C:5]3[CH:38]=[CH:39][CH:40]=[CH:41][C:4]=3[CH2:3][C:2]([NH2:1])=[O:42])[C:13]([C:14]([F:17])([F:15])[F:16])=[CH:12][N:11]=2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1c1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCCCN3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 22 h
Yield: 88.2 %

Procedure:
tert-Butyl 2-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I41) (0.087 g, 0.15 mmol) was dissolved in dry DCM (5 mL) under an atmosphere of nitrogen. Trifluoroacetic acid (0.351 mL, 4.58 mmol) was added to the solution and the reaction was stirred at room temperature for 22 hours. Volatiles were removed in vacuo, EtOAc (20 mL) and sat. aq. NaHCO3 (15 mL) were added to the residue and the layers were separated. The aqueous layer was extracted with EtOAc (15 mL), the combined organics were washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo to give a pale yellow solid which was taken up in DCM (˜10 mL) and methanol (˜1 mL) and concentrated in vacuo. The process was repeated with only DCM twice to give the title compound (8) (0.064 g, 89% yield) as a pale yellow solid;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.C([O-])(=O)C.[NH4+].[N+:20]([CH2:23][CH3:24])([O-:22])=[O:21]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:23]([N+:20]([O-:22])=[O:21])[CH3:24])[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1cc(C=C(C)[N+](=O)[O-])cc(OC)c1OC
Temperature: 105 °C
Yield: 50 %

Procedure:
5.00 g (25.5 mmol) 3,4,5-trimethoxybenzaldehyde (Aldrich, Milwaukee, Wis.), 9.82 g (127 mmol) ammonium acetate (Fluka), and 50 g (670 Mmol) nitroethane, 98% (Aldrich) were combined in a 100 ml round bottom flask equipped with magnetic stirrer and nitrogen inlet. The reaction mixture was heated to 105° C. for 90 minutes and the solvent was removed under vacuum to give a crude product which was recrystallized from cold methyl alcohol three times to give yellow needles in 50% yield. 1H NMR spectra is shown in FIG. 4.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:51])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C@@H:16]([CH2:47][C:48]([OH:50])=O)[CH2:15]2)=[CH:10][CH:9]=1.[CH2:52]([NH:54][CH2:55][CH3:56])[CH3:53]>>[CH2:52]([N:54]([CH2:55][CH3:56])[C:48](=[O:50])[CH2:47][C@H:16]1[CH2:15][C@H:14]([C:11]2[CH:12]=[CH:13][C:8]([CH2:7][O:6][CH2:5][C@@H:4]([CH3:51])[CH2:3][O:2][CH3:1])=[CH:9][CH:10]=2)[C@@H:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[CH2:18][N:17]1[S:37]([C:40]1[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][CH:45]=1)(=[O:39])=[O:38])[CH3:53]
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)O)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Reactant: CCNCC
Product: CCN(CC)C(=O)C[C@H]1C[C@H](c2ccc(COC[C@@H](C)COC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1S(=O)(=O)c1ccc(C)cc1

Procedure:
According to general procedure D, 1.0 mmol of [(2R,4R,5R)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-acetic acid (example 1g) are reacted with diethylamine to afford the title compound which is identified based on its Rf-value.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[CH:26]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)[CH2:29][C:30]([OH:32])=[O:31].N1CCCCC1.Cl>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:19][CH:20]=2)=[CH:11][C:10]=1/[CH:26]=[CH:29]/[C:30]([OH:32])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc(-c2ccc(OC(F)(F)F)cc2)ccc1OCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)/C=C/c1cc(-c2ccc(OC(F)(F)F)cc2)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 110.1 %

Procedure:
A mixture of 4-benzyloxy-4′-(trifluoromethoxy)biphenyl-3-carbaldehyde (4.0 g, 9.336 mmol), malonic acid (2.137 g, 20.539 mmol), pyridine (4.3 ml) and piperidine (184 μl, 1.867 mmol) was refluxed for 1 hour under argon atmosphere. The reaction mixture was cooled to room temperature, adjusted to pH 1 by addition of 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1) to give the title compound (4.26 g, 97.0%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH:28][C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:19][CH:18]=1)=[O:22]
Reactant: NCc1cccc(Cl)c1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4cccc(Cl)c4)cc3)c2)o1

Procedure:
N-(3-Chlorobenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 3-chlorobenzylamine using method N. NMR; δH [2H6]—DMSO 9.19,(1H, t), 8.00,(2H, t), 7.90,(1H, dd), 7.77,(1H, d), 7.56-7.52,(3H, m), 7.39-7.29,(4H, m), 4.51,(2H, d), 2.56,(3H, s), 2.31,(3H, s). LCMS; retention time 3.56 min, MH+ 418/420.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[CH2:15](OCC)[CH3:16]>>[CH2:15]([CH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[NH:6]1)[CH3:16]
Reactant: CCOCC
Reactant: c1ccc2c(c1)cnc1ccccc12
Product: CCC1Nc2ccccc2-c2ccccc21
Temperature: 25 °C

Procedure:
A stirred solution of phenanthridine (25 g, 139 mmol) in anhydrous diethyl ether (100 mL) was cooled to −78° C., and treated drop-wise under nitrogen via syringe with a solution of 0.62 M ethyllithium1 in diethyl ether (225 mL, 139 mmol). The yellow solution was warmed to room temperature and stirred for three to four hours. The reaction was cooled to −78° C., and quenched with water. After warming to room temperature, the reaction mixture was extracted with diethyl ether, and the organic phase was washed sequentially with water and a saturated, aqueous, sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent evaporated in vacuo, to yield 6-ethyl-5,6-dihydrophenanthridine as a crude solid (26 g, 124 mmol, 89%).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]1>CCCCO>[Br:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:22]2)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cnccn1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cnccn4)c23)C1
Temperature: 155 °C
Yield: 37.9 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazine-2-carboxamide (0.180 g, 0.536 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (0.322 g, 1.61 mmol) were placed in n-BuOH (2 mL) and heated to 155° C. in a sealed tube. The reaction was then cooled to room temperature and concentrated to dryness. The resulting residue was purified by reverse phase HPLC (5 to 95% ACN in water, Gilson system) to give the product, (R)-tert-butyl 1-(5-bromo-3-(pyrazine-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.105 g, 38% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([CH2:21]Cl)[CH:18]=[CH:17][C:3]=1[O:4][CH2:5][C:6]1[N:7]=[C:8]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[O:9][C:10]=1[CH3:11].[CH2:23]([N:30]1[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:32]([OH:40])=[N:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([N:30]1[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:32]([O:40][CH2:21][C:19]2[CH:18]=[CH:17][C:3]([O:4][CH2:5][C:6]3[N:7]=[C:8]([C:12]4[O:13][CH:14]=[CH:15][CH:16]=4)[O:9][C:10]=3[CH3:11])=[C:2]([Cl:1])[CH:20]=2)=[N:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1O
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(Cl)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
A mixture of 4-(2-chloro-4-chloromethylphenoxy)methyl-2-(2-furyl)-5-methyl-1,3-oxazole (2.00 g), ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-carboxylate (1.45 g), potassium carbonate (0.82 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl 1-benzyl-3-[(3-chloro-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate as colorless crystals (3.09 g, yield 96%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 153-154° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]([C:25]1[S:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[CH:29]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]([C:25]2[S:26][C:27]3[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=3[CH:29]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CCOC(=O)C(N)c1cc2ccccc2s1
Product: CCOC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1cc2ccccc2s1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl 2-amino-2-(benzothiophen-2-yl)acetate [CAS No. 98800-64-7], the title compound was prepared as a solid (mp=189-190° C.). The product was purified by preparative LC 2000 chromatography using 2:8 EtOAc/hexanes as the eluent.
Reaction SMILES: Cl.[S:2]([Cl:8])([CH2:5][CH2:6][NH2:7])(=[O:4])=[O:3].[N-:9]=[N+:10]=[N-:11].[Na+].[Cl-].[Na+]>O>[ClH:8].[S:2]([N:9]=[N+:10]=[N-:11])([CH2:5][CH2:6][NH2:7])(=[O:4])=[O:3]
Reactant: NCCS(=O)(=O)Cl
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NS(=O)(=O)CCN
Temperature: 5 °C

Procedure:
Tauryl chloride hydrochloride and sodium azide were reacted with one another in a ratio of 1:1 in water. For this purpose, the calculated stoichiometric amount of sodium azide was dissolved in water and the solution was cooled to 5° C. Tauryl chloride hydrochloride was added while stirring and the reaction mixture was stirred for 15 min. By stripping off the water, a solid mixture of crystalline sodium chloride and taurylazide hydrochloride was obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:13]2[N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:8]=2[C:7]([C:18](Cl)=O)=[CH:6][CH:5]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([NH2:30])[CH:24]=1>>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:18]2[NH:29][C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][C:25]=3[N:30]=2)=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]([F:15])([F:16])[F:17])[CH:10]=[CH:9]2
Reactant: COc1ccc(N)c(N)c1
Reactant: COc1ccc(C(=O)Cl)c2ccc(C(F)(F)F)nc12
Agent: Cl
Product: COc1ccc2[nH]c(-c3ccc(OC)c4nc(C(F)(F)F)ccc34)nc2c1

Procedure:
Prepared from 8-methoxy-2-trifluoromethylquinoline-5-carbonyl choride, hydrochloride (Intermediate 35 of PCT/GB97/01359) and 4-methoxy-1,2-phenylenediamine; purification by column chromatography eluting with 50%-70% ethyl acetate in hexane afforded the title compound as a pale yellow solid (1.32 g).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[NH:4][CH:3]=1.[Br:14][C:15]1[CH:22]=[C:21](F)[CH:20]=[CH:19][C:16]=1[C:17]#[N:18].[H-].[Na+].O>CN(C)C=O>[Br:14][C:15]1[CH:22]=[C:21]([N:4]2[C:5]3[CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8][C:9](=[O:11])[C:10]=3[C:2]([CH3:1])=[CH:3]2)[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: Cc1c[nH]c2c1C(=O)CC(C)(C)C2
Reactant: N#Cc1ccc(F)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(C#N)c(Br)c2)c2c1C(=O)CC(C)(C)C2
Temperature: 55 °C
Reaction time: 1 h

Procedure:
The title compound of Example 1 (9.8 g, 55.3 mmol) and 2-bromo-4-fluorobenzonitrile (13.27 g, 66.4 mmol) were dissolved in anhydrous dimethylformamide (DMF, 300 mL). To this was added sodium hydride (95%, 2.79 g, 111 mmol) and the reaction was stirred at 55° C. for 1 hour. The reaction mixture was cooled to room temperature and water was added. A tan solid precipitated which was filtered, washed with water and ether and then dried in vacuo (16.5 g, 84%). LCMS m/z: (M+H)=358.1.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:25])([CH3:24])[C@@H:11]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:12]=C)(=[O:7])=[O:6].O=O.[O:28]=[O+][O-].CSC>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:25])[C@@H:11]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH:12]=[O:28])(=[O:6])=[O:7]
Reactant: O=[O+][O-]
Reactant: C=C[C@H](OCc1ccc(OC)cc1)C(C)(C)COS(=O)(=O)CCCCl
Agent: O=O
Solvent: CSC
Solvent: ClCCl
Product: COc1ccc(CO[C@@H](C=O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Yield: 66 %

Procedure:
Following the general procedure for the preparation of aldehydes from alkenes of Description 11, (3S)-3-[(4-methoxyphenyl)methoxy]-2,2-dimethylpent-4-enyl (3-chloropropyl)sulfonate (13a) (3.0 g, 7.7 mmol) dissolved in 100 mL of dichloromethane (DCM) was treated with a mixture of oxygen and ozone (O2/O3). Upon completion of the reaction, 2 mL (1.69 g, 27.2 mmol) of dimethyl sulfide (DMS) was added. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 2.0 g (66% yield) of the title compound (13b) as a colorless oil. Rf=0.49 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=1.08 (s, 6H), 2.27-2.33 (m, 2H), 3.24-3.28 (m, 2H), 3.53 (d, J=2.4 Hz, 1H), 3.65-3.68 (m, 2H), 3.82 (s, 3H), 4.00 (d, J=9.2 Hz, 1H), 4.13 (d, J=9.2 Hz, 1H), 4.44 (d, J=11.2 Hz, 1H), 4.60 (d, J=11.2 Hz, 1H), 6.88 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 9.69 (d, J=2.4 Hz, 1H) ppm. MS (ESI) m/z 415.11 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.CCN(CC)CC.[Si:29]([O:36][C@@H:37]([CH3:65])[C@@H:38]([NH:53][C:54]1[C:62]2[CH:61]=[CH:60][S:59][C:58]=2[C:57]([C:63]#[N:64])=[CH:56][CH:55]=1)[C:39]([NH:41][NH:42][C:43](=O)[C:44]1[CH:49]=[CH:48][C:47]([C:50]#[N:51])=[CH:46][CH:45]=1)=[O:40])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C(Cl)Cl>[Si:29]([O:36][C@@H:37]([CH3:65])[C@@H:38]([NH:53][C:54]1[C:62]2[CH:61]=[CH:60][S:59][C:58]=2[C:57]([C:63]#[N:64])=[CH:56][CH:55]=1)[C:39]1[O:40][C:43]([C:44]2[CH:49]=[CH:48][C:47]([C:50]#[N:51])=[CH:46][CH:45]=2)=[N:42][N:41]=1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)NNC(=O)c1ccc(C#N)cc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c2sccc12)c1nnc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.3 %

Procedure:
To a solution of triphenylphosphine (275 mg, 1.43 mmol) in DCM (24 mL) was added I2 (363 mg, 1.43 mmol) at 0° C. After I2 was dissolved completely, Et3N (0.40 mL, 2.87 mmol) was added, followed by a solution of N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(7-cyanobenzo[b]thiophen-4-ylamino)butanoyl)-4-cyanobenzohydrazide (380 mg, 0.71 mmol) in DCM (12 mL). After addition, the reaction mixture was allowed to warm to room temperature and stirred for additional 10 min. The reaction was quenched with saturated sodium thiosulfate (3 mL) and diluted with DCM (100 mL). The organic layer was separated and washed with water, brine and dried over Na2SO4. Removal of the solvent gave a residue, which was purified by flash chromatography to provide the title compound 4-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)propylamino)benzo[b]thiophene-7-carbonitrile (360 mg, 98%). 1H NMR (400 MHz, CDCl3, δ in ppm) 8.22 (d, J=8.4 Hz, 2H), 7.93 (d, J=8.4 Hz, 2H), 7.73 (d, J=5.5 Hz, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.55 (d, J=5.5 Hz, 1H), 6.63 (d, J=8.2 Hz, 1H), 5.89 (d, J=8.6 Hz, 1H), 5.12 (m, 1H), 4.74 (m, 1H), 1.61 (d, J=6.2 Hz, 3H), 1.05 (s, 9H), 0.26 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: [CH2:1](N)C.Cl[C:5]1[C:14]([C:15]([C:17](=[CH:23][N:24](C)[CH3:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16])=[CH:13][C:12]2[C:7](=[C:8]([F:29])[C:9]([F:28])=[C:10]([F:27])[CH:11]=2)[N:6]=1.N12CCCN=C1CCCCC2>C(O)C>[CH2:21]([O:20][C:18]([C:17]1[C:15](=[O:16])[C:14]2[CH:13]=[C:12]3[CH:11]=[C:10]([F:27])[C:9]([F:28])=[C:8]([F:29])[C:7]3=[N:6][C:5]=2[N:24]([CH2:25][CH3:1])[CH:23]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)c(F)c2nc1Cl
Reactant: CCN
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCOC(=O)c1cn(CC)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Reaction time: 1 h
Yield: 62.2 %

Procedure:
4.5 g of ethylamine are added in the course of 10 minutes, at between 5° and 10° C., to a stirred suspension of 7.1 g of ethyl 2-(2-chloro-6,7,8-trifluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate in 100 cm3 of ethanol kept at a temperature close to 5° C., the mixture is stirred for 1 hour at between 5° and 10° C. and the temperature is allowed to rise to about 20° C. 4 g of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) are added to the solution obtained and the mixture is heated at a temperature close to 75° C. for 1 hour and a half. After cooling to a temperature close to 20° C., the product is drained and washed with twice 30 cm3 of ethanol and twice 50 cm3 of diisopropyl ether. 4 g of 3-ethoxycarbonyl-1-ethyl-7,8,9-tri fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a cream solid melting at 284° C., which is used for the subsequent steps without further purification.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:12]3[N:13]([CH:18]=[CH:19][N:20]=3)[C:14]([Br:17])=[CH:15][N:16]=2)=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1.O>[Br:17][C:14]1[N:13]2[CH:18]=[CH:19][N:20]=[C:12]2[C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:21])=[O:2])=[CH:9][CH:8]=2)=[N:16][CH:15]=1
Reactant: COC(=O)c1ccc(Nc2ncc(Br)n3ccnc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Nc2ncc(Br)n3ccnc23)cc1

Procedure:
A solution of 4-(5-bromoimidazo[1,2-a]pyrazin-8-ylamino) benzoic acid methyl ester (6.02 g, 17.3 mmol) and LiOH (7.3 g, 174 mmol) in THF (200 mL) and water (200 mL) is stirred at 25° C. for 18 hours. The majority of the solvents are removed in vacuo, then to the remaining aqueous solution is added EtOAc. The aqueous layer is separated, then washed once more EtOAc. The aqueous phase is separated, acidified to pH 5 using concentrated hydrochloric acid and the resultant solid filtered and dried in the vacuum oven. The solid is identified as the desired title acid.
Reaction SMILES: [OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:34][N:35]([CH3:41])[C@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][CH2:40][C@H:36]([N:35]([CH3:41])[CH3:34])[CH2:37]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1
Reactant: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@H](N(C)C)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and (S)—N,N-dimethylpyrrolidin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 4.00 (t, 2H), 3.80 (t, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.22 (s, 6H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27 (t, 1H), 1.07 (t, 1H), 0.83 (d, 3H). m/z: 446 [M+H]