Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:14]([CH2:33][OH:34])[O:13][C@@H:10]1[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([O:38][C@H:39]1[C@@H:44]([CH2:45][O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[O:43][C@H:42](Cl)[C@H:41]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C@H:40]1[O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)(=[O:37])[CH3:36].CC1C=C(C)C=C(C)N=1>CCOCC.Cl([O-])(=O)(=O)=O.[Ag+]>[C:35]([O:38][C@H:39]1[C@@H:44]([CH2:45][O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[O:43][C@H:42]([O:34][CH2:33][C@H:14]2[O:13][C@H:10]([O:11][CH3:12])[C@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:16]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@@H:15]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:41]([O:55][CH2:56][C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C@H:40]1[O:63][CH2:64][C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1)(=[O:37])[CH3:36]
Reactant: CO[C@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: CC(=O)O[C@@H]1[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H](Cl)O[C@@H]1COCc1ccccc1
Agent: [Ag+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: Cc1cc(C)nc(C)c1
Product: CO[C@H]1O[C@H](CO[C@H]2O[C@H](COCc3ccccc3)[C@H](OC(C)=O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
Ethereal silver perchlorate (0.08M, 76.9 mL, 6.15 mmol) was added with stirring at -30° C. to a solution of methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside (2.078 g, 4.48 mmol), 4-O-acetyl-2,3,6-tri-O-benzyl-α-D-galactopyranosyl chloride (2.859 g, 5.6 mmol) and 2,4,6-trimethylpyridine (0.81 mL, 6.15 mmol) in ether (20 mL). The mixture was stirred 15 min at -30° C. and silver chloride precipitated. The mixture was filtered through a celite pad, the solids were washed with ether, the filtrate was concentrated under reduced pressure. The residue was dissolved in methylene chloride and the organic layer was washed successively with aqueous sodium thiosulfate and water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a foam. Flash chromatography on silica gel and elution with a graded mixture of hexane and ethyl acetate afforded methyl 6-O-(4-O-acetyl-2,3,6-tri-O-benzyl-α-D-galactopyranosyl) -2,3,4-tri-O-benzyl-α-D-glucopyranoside (2.314 g, 55%) as a foam.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=O.C1([C:11]2[N:15](C)[C:14]([CH:17]=[O:18])=[CH:13]N=2)CC1>>[C:2]([C:3]1[N:15]([CH3:11])[C:14]([CH:17]=[O:18])=[CH:13][N:5]=1)([CH3:7])([CH3:6])[CH3:1]
Reactant: CC(C)(C)C(N)=O
Reactant: Cn1c(C=O)cnc1C1CC1
Product: Cn1c(C=O)cnc1C(C)(C)C

Procedure:
2-tert-Butyl-3-methyl-3H-imidazole-4-carbaldehyde was prepared from trimethyl acetamide in the same manner as 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).
Reaction SMILES: [Br-].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](C[P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:3]1.[N:31]1([C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[C:39]([N+:45]([O-:47])=[O:46])[CH:38]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.[C:48](=O)([O-])[O-].[K+].[K+].O>CO>[N:31]1([C:37]2[CH:44]=[CH:43][C:40]([CH:41]=[CH:48][N:2]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[N:3]3)=[C:39]([N+:45]([O-:47])=[O:46])[CH:38]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(N2CCOCC2)cc1[N+](=O)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1cc(N2CCOCC2)ccc1C=Cn1ncc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
(1H-Indazol-3-ylmethyl)triphenylphosphonium bromide (0.64 g, 1.3 mmol) was dissolved in methanol (8.0 mL) and the solution was added with 4-(morpholin-4-yl)-2-nitrobenzaldehyde (0.35 g, 1.5 mmol) and potassium carbonate (0.37 g, 2.7 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with water and the precipitated solid was collected by filtration and dried. The obtained solid was triturated in methanol to obtain (E)-3-([2-[4-(morpholin-4-yl)-2-nitrophenyl]vinyl]-1H-indazole (0.41 g, 86%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Cl[C:31](OC1C=CC([N+]([O-])=O)=CC=1)=[O:32].[CH3:43][CH:44]([CH3:47])[CH2:45][NH2:46]>C1COCC1.O>[CH2:45]([NH:46][C:31]([N:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:9]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=1)=[O:32])[CH:44]([CH3:47])[CH3:43]
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Reactant: CC(C)CN
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CNC(=O)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
To a stirred mixture of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (0.100 g, 0.36 mmol) and DIEA (0.082 mL, 0.47 mmol) in THF (2 mL) was added 4-nitrophenyl chloroformate (0.080 g, 0.40 mmol). The reaction mixture was stirred for 30 min, 2-methylpropan-1-amine (0.036 mL, 0.36 mmol) was added and stirring was continued for 14 h, then heated at reflux for 24 h, cooled, taken up in H2O, extracted with EtOAc (3×), dried over MgSO4, concentrated and purified by ISCO (20% EtOAc/hexanes) to give the title compound. MS (ESI, positive ion) m/z: 377 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[OH:38][CH2:39][CH2:40][NH:41][CH2:42][CH2:43][OH:44]>>[OH:38][CH2:39][CH2:40][N:41]([CH2:42][CH2:43][OH:44])[C:21]([N:11]1[C:12]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([CH3:37])[N:9]=[C:10]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:26][C:25]=1[O:34][CH2:35][CH3:36])=[O:22]
Reactant: OCCNCCO
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N(CCO)CCO

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with bis-(2-hydroxyethyl)-amine (Sigma) to give the title compound. HR-MS (ES, m/z) calculated for C31H33N3O4F3Cl2 [(M+H)+] 638.1795, observed 638.1797.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:31]=O)[N:12]3[C:17]4[CH:18]=[CH:19][N:20]([S:21]([C:24]5[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=5)(=[O:23])=[O:22])[C:16]=4[N:15]=[CH:14][C:13]=23)=[CH:5][CH:4]=1.CC(O)=O.[CH:37]1([NH2:40])[CH2:39][CH2:38]1.C([BH3-])#N>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:31][NH:40][CH:37]3[CH2:39][CH2:38]3)[N:12]3[C:17]4[CH:18]=[CH:19][N:20]([S:21]([C:24]5[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=5)(=[O:23])=[O:22])[C:16]=4[N:15]=[CH:14][C:13]=23)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nc(C=O)n3c2cnc2c3ccn2S(=O)(=O)c2ccc(C)cc2)cc1
Reactant: NC1CC1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc(-c2nc(CNC3CC3)n3c2cnc2c3ccn2S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
3-(4-Methoxyphenyl)-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine-1-carbaldehyde (0.075 g, 0.17 mmol), AcOH (0.048 mL, 0.84 mmol), and cyclopropanamine (0.026 mL, 0.37 mmol) were added in DCE (1.68 mL). The mixture was stirred at rt for 30 min. MP-Cyanoborohydride (0.23 g, 0.50 mmol, 2.15 mmol/g, Biotage™) was added in one portion. The mixture was stirred at 25° C. for 72 h. The mixture was purified directly by flash chromatography (40 g silica gel column, MeOH/DCM 0% to 10%) to give N-((3-(4-methoxyphenyl)-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)methyl)cyclopropanamine (0.050 g, 61%): LC/MS (Table 2, Method c) Rt=1.49 min; MS m/z: 488 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29]C)=[O:28])=[C:22]([F:31])[CH:21]=1)[CH3:2].O[Li].O.CC(=O)OCC>C1COCC1.O>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[C:22]([F:31])[CH:21]=1)[CH3:2]
Reactant: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)OC)c(F)c1
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)O)c(F)c1
Temperature: 60 °C
Reaction time: 10 h
Yield: 86.7 %

Procedure:
To a solution of methyl 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetate (210 g, 519 mmol) in THF (500 mL) was added a solution of LiOH.H2O (52 g, 1.23 mol) in H2O (700 mL). The mixture was stirred at 60° C. for 10 h. TLC (PE/EA=5:1, Rf=0.3) showed the reaction was finished. The mixture was concentrated and neutralized with 1.0 M HCl to pH=7.0. Then the mixture was filtered, and the solid was washed with water and dry in vacuo to give 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (183.3 g, 0.45 mol, 93% yield): 1H NMR (400 MHz, CD3OD) δ 7.94 (s, 1H), 7.41-7.28 (m, 3H), 7.24 (d, J=9.6 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 6.44 (s, 1H), 5.26 (s, 2H), 4.11 (q, J=6.8 Hz, 2H), 3.78 (s, 3H), 3.67 (s, 2H), 1.36 (t, J=7.2 Hz, 3H); ES-LCMS m/z 412 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=O)=[CH:4][CH:3]=1.[C:15]([Mg]Cl)([CH3:18])([CH3:17])[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]2[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Reactant: CC(C)(C)[Mg]Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CC(C)(C)C1=CCC(C)(C)c2ccc(Br)cc21

Procedure:
Reaction Scheme 9 discloses the preferred method of synthesis of a starting material from which certain examples for compounds of the invention within the scope of Formula 6 are preferably made. In accordance with this scheme 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G) is reacted with t-butylmagnesium chloride in tetrahydrofuran in the presence of 1,3-dimethyl-3,4,5,6-tetrahydro-2(H)-pyrimidinone (DMPU). Thereafter, the resulting intermediate tertiary alcohol is heated in the presence of acid (p-toluenesulfonic acid) to give 7-bromo-1-(1,1-dimethylethyl)-3,4-dihydro-4,4-dimethylnaphthalene (Compound C42). Compound C42 is reacted with 1-ethoxyvinyltributyltin (EVTB) in the presence of Pd(0) catalyst to yield after acidic work-up 7-acetyl-1-(1,1-dimethylethyl)-3,4-dihydro-4,4-dimethylnaphthalene (Compound C43). Compound C43 is subjected to a sequence of reactions of the type described above in connection with Reaction Scheme 8, starting with a Horner Emmons reaction with diethyl cyanomethylphosphonate, to eventually provide ethyl 7-[4,4-dimethyl-3,4-dihydro-1-(1,1-dimethylethyl)-naphth-7-yl]-3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate (Compound C46). Compound C46 of the invention is within the scope of Formula 6.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[S:11][C:10]([CH:12]3OCC[O:13]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C.O>CO>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[S:11][C:10]([CH:12]=[O:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cc2ccc(C3OCCO3)s2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=Cc1ccc(Cc2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(5-(4-fluoro-benzyl)-thiophen-2-yl)-[1,3]dioxolane described in Preparation Example 36 (560 mg, 2.04 mmol) in methanol (20 mL) was added citric acid aqueous solution (20 mL), and the solution was stirred at room temperature for 30 minutes. Ethyl acetate and water were added to the reaction solution, which was then partitioned, the organic layer was washed with water twice, dried over anhydrous sodium sulfate, the solvent was evaporated in vacuo, and title compound (460 mg, 2.09 mmol) was obtained as a brown oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH:18]=[O:19].O.[SH-].[Na+]>C(O)C>[CH:18]([C:3]1[CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:5][C:6]2[C:11]([CH:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:19]
Reactant: O=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Agent: [Na+]
Agent: [SH-]
Solvent: O
Solvent: CCO
Product: O=CC1=Cc2ccccc2OC1c1ccccc1
Reaction time: 8 h

Procedure:
A mixture of 26 g 4-chloro-3-formyl-flav-3-ene and 7.1 g sodium hydrosulfide hydrate in 400 ml ethanol is refluxed for 3 hours and allowed to stand overnight at room temperature. The reaction mixture is evaporated to dryness and the residue dissolved in methylene chloride. The precipitate is filtered and the organic solution is evaporated. The residue is recrystallized in a mixture of hexane and toluene. Pure 4-(2"H-3"-formyl-2"-phenyl-1"-benzopyran-4"-yl-thio)-3-formyl-flav-3-ene is obtained as yellow crystals; m.p. 193°-194° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.Br[C:11]1[O:15][CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:11]2[O:15][CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(S)cc1
Reactant: O=C(O)c1coc(Br)c1
Solvent: CN(C)C=O
Product: COc1ccc(Sc2cc(C(=O)O)co2)cc1
Yield: 42.5 %

Procedure:
By the procedure of Example 11, p-methoxythiophenol (4.39 g., 31.4 mmoles) and cuprous oxide (2.25 g., 15.7 mmoles) heated at 135° C. for 2 hours were reacted with 5-bromofuran-3-carboxylic acid (3 g., 15.7 mmoles) in 60 ml. of dimethylformamide, and crude product (1.67 g. ) isolated. Recrystallization from methylene chloride/hexane gave purified 5-(4-methoxphenylthio)furan-3-carboxylic acid (825 mg., m.p. 115°-117° C., m/e 250).
Reaction SMILES: Cl.CN.[N:4]1C=CC=C[CH:5]=1.Cl[C:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12]>CN(C)C=O>[CH3:5][NH:4][C:11](=[O:12])[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: c1ccncc1
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)Oc1ccccc1
Yield: 53.5 %

Procedure:
Methylamine hydrochloride (16.9 g, 250 mmol) was dissolved in N,N-dimethylformamide (250 ml), pyridine (44 ml, 275 mmol) was added thereto, and the reaction mixture was stirred. The reaction mixture was cooled with ice, phenyl chloroformate (35 ml, 275 mmol) was added dropwise thereto, and the reaction mixture was then stirred at room temperature for 24 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crystals were suspended in diethylether, diluted with hexane, filtered off, washed with the diethylether:hexane=1:1, and dried by evacuation, to yield the title compound (22.3 g, 147 mmol, 59.1%) as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][CH:18]([CH3:20])[CH3:19])[N:16]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[C:23]([O:27][C:28](=[O:38])[NH:29][CH2:30][CH2:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28](=[O:38])[NH:29][CH2:30][CH2:31][CH:32]1[CH2:33][CH2:34][N:35]([C:11]([C:10]2[CH:14]=[C:15]([O:17][CH:18]([CH3:20])[CH3:19])[N:16]=[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:22][CH:21]=3)[CH:9]=2)=[O:13])[CH2:36][CH2:37]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)Oc1cc(C(=O)O)cc(Oc2ccc(C#N)cc2)n1
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Product: CC(C)Oc1cc(C(=O)N2CCC(CCNC(=O)OC(C)(C)C)CC2)cc(Oc2ccc(C#N)cc2)n1
Yield: 35.2 %

Procedure:
2-(4-cyano phenoxy)-6-isopropoxy isonicotinic acid (0.20 g, 0.67 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.16 g, 0.7 mmol) were coupled using the procedure of Example 5(c) to afford 0.12 g of the required product. 1H NMR (DMSO-d6): δ 1.12 (2H, m), 1.15 (6H, d), 1.4 (9H, s), 1.6 (2H, m), 1.75 (1H, m), 2.7 (1H, m), 2.98 (3H, m), 3.5 (1H, m), 4.45 (1H, m), 4.8 (1H, m), 6.48 (1H, s), 6.58 (1H, s), 6.8 (1H, brs), 7.38 (2H, d), 7.9 (2H, d).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:8][CH:7]2[C:9](=[O:10])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH2:11](O)[CH2:12][OH:13].CCN(CC)CC.[O-]S([O-])(=O)=O.[Mg+2]>C1C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[CH2:12]1[O:13][C:9]2([CH:7]3[CH2:6][CH2:5][CH:4]2[CH2:3][C:2](=[CH2:1])[CH2:8]3)[O:10][CH2:11]1
Reactant: OCCO
Reactant: C=C1CC2CCC(C1)C2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=C1CC2CCC(C1)C21OCCO1
Temperature: 25 °C
Yield: 112 %

Procedure:
To a solution of 3-methylene bicyclo[3,2,1]octan-8-one (0.14 g, 1.04 mmol, 1.0 eq.) in benzene (10 mL) was added ethylene glycol (0.65 g, 16 eq.) and PTSA (0.01 g, 0.06 eq.). The reaction was equipped with a Dean-Stark and heated at reflux overnight. After cooling to room temperature, Et3N (0.15 mL) was introduced and the resulting mixture was passed through a cake of SiO2 and MgSO4. The cake was washed with CH2Cl2 and the combined filtrates were concentrated to give 3-methylene bicyclo[3,2,1]octan-8-one ethylene ketal (0.21 g, >100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[N:31]([CH2:38][CH2:39]O)([CH2:35][CH2:36][OH:37])[CH2:32][CH2:33][OH:34]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:39][CH2:38][N:31]([CH2:35][CH2:36][OH:37])[CH2:32][CH2:33][OH:34])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: OCCN(CCO)CCO
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)OCCN(CCO)CCO)cc4CCC3C2C2CCCC2)cc1Cl

Procedure:
The title compound was prepared from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and triethanolamine according to Method E. 1H NMR (400 MHz, CDCl3) δ ppm 1.17-1.66 (m, 7H), 1.70-1.82 (m, 1H), 1.88-2.02 (m, 1H), 2.06-2.18 (m, 1H), 2.23-2.45 (m, 1H), 2.79-2.85 (m, 4H), 2.86-2.97 (m, 1H), 3.03 (t, J=5.50 Hz, 2H), 3.07-3.17 (m, 1H), 3.48 (ddd, J=13.90, 9.47, 4.83 Hz, 1H), 3.63-3.70 (m, 4H), 4.48 (t, J=5.50 Hz, 2H), 4.63 (dd, J=9.40, 5.37 Hz, 1H), 7.01 (dd, J=8.86, 2.15 Hz, 1H), 7.29 (d, J=2.15 Hz, 1H), 7.45 (d, J=8.86 Hz, 1H), 7.82-7.99 (m, 2H), 8.15 (d, J=8.59 Hz, 1H). ES-MS m/z 551 (M+H)
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:24]=[CH:23][C:6]2[C:7]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][NH2+:19][CH2:18]3)=[N:8][C:9]3[CH:10]=[CH:11][NH:12][C:13](=[O:15])[C:14]=3[C:5]=2[CH:4]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:56]([CH2:58][C:59](O)=[O:60])#[N:57]>CN(C=O)C>[F:2][C:3]1[CH:24]=[CH:23][C:6]2[C:7]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:59](=[O:60])[CH2:58][C:56]#[N:57])[CH2:18]3)=[N:8][C:9]3[CH:10]=[CH:11][NH:12][C:13](=[O:15])[C:14]=3[C:5]=2[CH:4]=1
Reactant: O=c1[nH]ccc2nc(N[C@@H]3CCC[NH2+]C3)c3ccc(F)cc3c12
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCC(=O)N1CCC[C@@H](Nc2nc3cc[nH]c(=O)c3c3cc(F)ccc23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3R)-3-[(9-fluoro-1-oxo-1,2-dihydrobenzo[c]-1,6-naphthyridin-6-yl)amino]piperidinium chloride (40 mg, 0.09 mmol) in DMF (2 mL) were added triethylamine (0.13 mL, 0.94 mmol), HATU (0-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate) (36 mg, 0.094 mmol), and cyanoacetic acid (40 mg, 0.47 mmol). The solution was stirred at room temperature overnight. The crude solution was filtered and purified by reverse phase HPLC. LRMS (ESI) calc'd for (C20H19FN5O2) [M+H]+, 380.2; found 380.1.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=1>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:2]2[N:3]=[CH:4][C:5]([C:16]3[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=3)=[C:6]3[C:11]=2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]3)=[N:25][CH:26]=1
Reactant: OB(O)c1cccnc1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Reactant: Nc1ccc(F)cn1
Product: Cc1ccc2c(-c3cccnc3)cnc(Nc3ccc(F)cn3)c2n1

Procedure:
The title compound, MS: m/e=332.2 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 3-pyridineboronic acid and 2-amino-5-fluoropyridine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:26]=[C:25]([CH2:27][CH3:28])[S:24][C:15]=2[N:16]=[C:17]([C:19]2[O:23][N:22]=[CH:21][CH:20]=2)[N:18]=1>>[O:23]1[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[CH:26]=[C:25]([CH2:27][CH3:28])[S:24][C:15]=3[N:16]=2)=[CH:20][CH:21]=[N:22]1
Reactant: CCc1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: CCc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(isoxazol-5-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3-nitrobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:33]=[CH:34][CH:35]=[C:36]3[C:40]([CH2:41][O:42][CH2:43][CH3:44])=[C:39]([CH3:45])[NH:38][C:37]=23)=[CH:28][CH:27]=1.[CH2:46](Br)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>O1CCCC1>[ClH:25].[CH2:46]([N:38]1[C:37]2=[C:32]([C:29]3[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][CH:30]=3)[N:33]=[CH:34][CH:35]=[C:36]2[C:40]([CH2:41][O:42][CH2:43][CH3:44])=[C:39]1[CH3:45])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: BrCc1ccccc1
Reactant: CCOCc1c(C)[nH]c2c(-c3ccc(Cl)cc3)nccc12
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOCc1c(C)n(Cc2ccccc2)c2c(-c3ccc(Cl)cc3)nccc12
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
18-Crown-6 (2 mg, 0.006 mmol) and potassium tert-butoxide (7 mg, 0.066 mmol) were added to a solution of 7-(4-chlorophenyl)-3-ethoxymethyl-2-methyl-1H-pyrrolo[2,3-c]pyridine (20 mg, 0.066 mmol) prepared in Example 466 in anhydrous tetrahydrofuran (1 ml). The reaction mixture was stirred for 30 minutes at room temperature and then benzyl bromide (11.8 μl, 0.099 mmol) was added thereto. The reaction mixture was stirred overnight and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 10 mg of the titled compound as a white solid.