Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:25]1[CH2:29][CH:28]=[N:27][C:26]1=[O:30]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:27]4[CH2:28][CH2:29][O:25][C:26]4=[O:30])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][C:18]([CH3:24])=[C:19]([CH3:23])[CH:20]=1
Reactant: O=C1N=CCO1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(I)cc3)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3)CC2)nc1C
Yield: 29.9 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using (4-iodophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (435 mg) described in Preparation Example 176 and oxazolin-2-one (104 mg), the title compound (118 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:3]=1.II.[I:22](O)(=O)(=O)=O>CO>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[N:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:3]=1[I:22]
Reactant: COC(=O)c1cc(N)c(F)c(-c2ccc(Cl)cc2)n1
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Solvent: CO
Product: COC(=O)c1nc(-c2ccc(Cl)cc2)c(F)c(N)c1I
Yield: 234 %

Procedure:
A 250 mL round bottom flask was loaded with methyl 4-amino-6-(4-chlorophenyl)-5-fluoropicolinate (25 g, 0.08906 mol), iodine (18 g, 0.07125 mol), and periodic acid (H5IO6; 7.3 g, 0.03206 mol). CH3OH (100 mL) was added. The reaction mixture was stirred at reflux for 16 h. The reaction mixture was concentrated under vacuum and then dissolved in Et2O (500 mL). The ether solution was washed with 10% sodium thiosulfate (3×100 mL), water (3×100 mL) and then brine. The organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give an orange solid. Crystallisation from EtOAc-hexane (3:7) gave a pale orange solid (30.5 g, 83%): mp 113.7-115.2° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H), 6.73 (br s, 2H), 3.87 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 167.50, 151.48 (d, JF-C=5 Hz), 145.95 (d, JF-C=13 Hz), 144.05 (d, JF-C=257 Hz), 140.75 (d, JF-C=9 Hz), 134.56, 133.42 (d, JF-C=5 Hz), 130.63 (d, JF-C=6 Hz), 129.02, 112.44 (d, JF-C=5 Hz), 77.52, 53.05; 19F NMR (376.5 MHz, DMSO-d6) δ −140.62; ESIMS m/z 407 ([M]+). Anal. Calcd. For C13H9ClFIN2O2: C, 38.40; H, 2.23; N, 6.89. Found: C, 38.40; H, 2.31; N, 6.85.
Reaction SMILES: [SH:1][C:2]1[N:3]([C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH2:20])[C:18]=2[N:19]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6].[CH3:21][CH2:22][CH2:23][CH:24]([O:33][C:34]([C:36]1([CH:46]=[CH:45][CH:44]=[CH:43][CH2:42]1)OCC1OC1)=[O:35])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>N1C(C)=CC=CC=1C.C(O)C>[OH:6][CH:5]([CH2:4][O:12][C:46]1[CH:45]=[CH:44][CH:43]=[CH:42][C:36]=1[C:34]([O:33][CH:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:23][CH2:22][CH3:21])=[O:35])[CH2:7][S:1][C:2]1[N:3]([C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH2:20])[C:18]=2[N:19]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6]
Reactant: Nc1ncnc2c1nc(S)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CCCCCCCCC(CCC)OC(=O)C1(OCC2CO2)C=CC=CC1
Solvent: Cc1cccc(C)n1
Solvent: CCO
Product: CCCCCCCCC(CCC)OC(=O)c1ccccc1OCC(O)CSc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 114.2 %

Procedure:
A suspension of 8-mercapto-adenosine (4.9 g, 16.4 mmole), 1-(4-dodecyloxycarbonyl)phenoxy-2,3-epoxy-propane (5.4 g, 14,9 mmole), 2,6-lutidine (5 drops) and absolute ethanol (100 ml) is heated at reflux temperature for a couple of hours, then the obtained solution is allowed to cool slowly under stirring. The white crystalline precipitate which forms is recovered by filtration, washed with ethanol (about 25 ml) and dried under vacuum yielding 6.2 g of the compound of the title with m.p. 163°-65° C.; [α]D20 -39.98° (c=1 in dimethylformamide).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:17]=2[F:26])=[CH:14][CH:15]=1)=O)C.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH:41]C(C3C4N=CC=NC=4C(C4C(Cl)=C(OC)C=C(OC)C=4Cl)=CC=3)=O)=[N:39][CH:40]=2)[CH2:30][CH2:29]1>C(Cl)Cl.CO>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH:41][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:17]=4[F:26])=[CH:14][CH:15]=3)=[O:3])=[N:39][CH:40]=2)[CH2:30][CH2:29]1
Reactant: CCOC(=O)c1ccc(-c2cc(OC)cc(OC)c2F)c2nccnc12
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1Cl
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1
Reaction time: 1 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 143.1), 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31; purified by silica gel column chromatography), and stirring the reaction mixture for 1 h at reflux. Title compound: ESI-MS: 517.1 [M+H]+; tR=3.37 min (System 1); TLC: Rf=0.11 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH2:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][NH:20]1)[CH3:18].CCN(C(C)C)C(C)C>CS(C)=O>[CH2:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]1[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)[CH3:18]
Reactant: CCC1CCCCN1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC1CCCCN1c1nc2cc(C(=O)OC)ccc2[nH]c1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (500 mg, crude) in DMSO (5 mL) was added 2-ethylpiperidine (475 mg, 4.20 mmol) and DIEA (542 mg, 4.19 mmol). The resulting solution was stirred overnight at 80° C. in an oil bath and then quenched by the addition of water (50 mL), extracted with dichloromethane (5×20 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (1%-10% ethyl acetate in petroleum ether) to afford methyl 3-(2-ethylpiperidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as yellow oil (150 mg).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[C:18]3[C:24]2[NH:25][CH:26]=[CH:27][CH:28]=2)[CH:12]=[N:13][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[NH:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[C:18]1[C:17]2[C:21](=[CH:22][CH:23]=[C:15]([C:11]3[CH:10]=[C:9]([OH:8])[CH:14]=[N:13][CH:12]=3)[CH:16]=2)[NH:20][N:19]=1
Reactant: c1ccc(COc2cncc(-c3ccc4[nH]nc(-c5ccc[nH]5)c4c3)c2)cc1
Agent: [Pd]
Solvent: CO
Product: Oc1cncc(-c2ccc3[nH]nc(-c4ccc[nH]4)c3c2)c1
Reaction time: 24 h
Yield: 79.6 %

Procedure:
A mixture of 5-(5-benzyloxy-pyridin-3-yl)-3-(1H-pyrrol-2-yl)-1H-indazole (Preparation #16c, E and F (using 5-benzyloxy-3-bromopyridine), 0.015 g, 0.4 mmol) in MeOH (5 mL) and 10 wt. % Pd/C (3 mg) was shaken under an atmosphere of hydrogen (about 40 psi) for about 24 hours. The crude product was filtered and the solvent was removed under reduced pressure to yield 5-[3-(1H-pyrrol-2-yl)-1H-indazol-5-yl]-pyridin-3-ol (0.088 g, 80%); RP-HPLC (Table 1, Method e) Rt=1.78 min; m/z: (M+H)+ 277, (M−H)− 275.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]#[N:26])=[CH:19][C:18]=3[CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:13][C:12]=2[CH:31]([CH3:33])[CH3:32])=[CH:7][C:6]=1[CH2:34][CH:35]([CH3:37])[CH3:36])#[N:2].[ClH:38]>CCO>[ClH:38].[ClH:38].[NH2:2][CH2:1][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][NH2:26])=[CH:19][C:18]=3[CH2:27][CH:28]([CH3:29])[CH3:30])=[CH:13][C:12]=2[CH:31]([CH3:33])[CH3:32])=[CH:7][C:6]=1[CH2:34][CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)Cc1cc(-c2ccc(-c3ccc(CCC#N)cc3CC(C)C)cc2C(C)C)ccc1OCC#N
Agent: Cl
Solvent: CCO
Product: CC(C)Cc1cc(-c2ccc(-c3ccc(CCCN)cc3CC(C)C)cc2C(C)C)ccc1OCCN
Reaction time: 8 h
Yield: 91 %

Procedure:
3-[4″-(cyanomethoxy)-2,3″-diisobutyl-3′-isopropyl-1,1′:4′,1″-terphenyl-4-yl]propanenitrile (8f) (19.0 mg, 0.038 mmol) was dissolved in 5 ml of EtOH containing 10% Pd/C (15 mg) and 0.1 ml HCl (cone.). The solution was stirred overnight under 20 psi of H2. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to yield 20 mg of a white solid (91%): 1H NMR (500 MHz, CD3OD) δ 0.75 (d, J=6.6 Hz, 6H), 0.93 (d, J=6.9 Hz, 6H), 1.14 (d, J=6.9, 6H), 1.68 (m, 2H), 1.96 (m, 1H), 1.99 (m, 1H), 2.54 (d, J=6.6 Hz, 2H), 2.62 (d, J=6.9 Hz, 2H), 2.76 (t, J=7.4, 2H), 2.96 (t, J=6.8 Hz, 2H), 3.11 (m, 1H), 3.41 (t, J=4.5 Hz, 2H), 4.29 (t, J=5.0 Hz, 2H), 7.13 (m, 9H); 13C NMR (125 MHz, CD3OD) δ 22.85, 22.96, 24.61, 30.15, 30.53, 30.54, 30.81, 33.34, 40.12, 40.53, 40.70, 43.42, 66.06, 112.90, 126.84, 127.50, 127.67, 129.06, 130.75, 131.25, 131.29, 131.33, 133.29, 136.26, 140.46, 140.49, 140.59, 141.95, 142.56, 147.13, 156.52; HRMS (FAB, M+H) Calcd for C34H49N2O: 501.3845. Found 501.3845.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[CH2:14]([O:16][C:17]([CH:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:21][CH:22]=O)=[O:18])[CH3:15]>>[CH2:14]([O:16][C:17]([CH:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:21][CH:22]1[C:6]2[NH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]=2[CH2:4][CH2:3][N:2]1[CH3:1])=[O:18])[CH3:15]
Reactant: CCOC(=O)C(CCC=O)C(=O)OCC
Reactant: CNCCc1c[nH]c2ccccc12
Product: CCOC(=O)C(CCC1c2[nH]c3ccccc3c2CCN1C)C(=O)OCC
Yield: 55.2 %

Procedure:
1.78 g of N-methyl-tryptamine (i.e., 3-(2-methylaminoethyl)-indole) and 3.1 g of 4,4-bis(ethoxycarbonyl)-butanal were treated in the same manner as described in Example 21-(1). 2.1 g of 1,2,3,4-tetrahydro-1-[3,3-bis-(ethoxycarbonyl)propyl]-2-methyl-β-carboline were thereby obtained. Yield: 55.0%
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:7]([NH:9][NH2:10])=[O:8])([O-:3])=[O:2].[CH2:18](OC(OCC)(OCC)C)[CH3:19]>>[CH3:18][C:19]1[O:8][C:7]([C:6]2[CH:11]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[N:9][N:10]=1
Reactant: NNC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: CCOC(C)(OCC)OCC
Product: Cc1nnc(-c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)o1
Reaction time: 12 h
Yield: 82.4 %

Procedure:
A mixture of 3-nitro-5-(trifluoromethyl)benzohydrazide (20 g, 80 mmol) in 1,1,1-triethoxyethane (156 g, 963 mmol) was heated to reflux and stirred for 12 h. Then the solvent was concentrated to yield a black solid of 2-methyl-5-(3-nitro-5-(trifluoromethyl)phenyl)-1,3,4-oxadiazole (20 g, 65.9 mmol, 82% yield): 1H NMR (400 MHz, CD3OD) δ 9.04 (s, 1H), 8.71 (s, 1H), 8.66 (s, 1H), 2.67 (s, 1H); ES-LCMS m/z 274 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:5]=[C:4]([NH:14][CH:15]=[O:16])[CH:3]=1.C([O-])(=O)C.[Na+]>C(O)C.[Pd]>[CH:15]([NH:14][C:4]1[CH:3]=[CH:2][N:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:5]=1)=[O:16]
Reactant: CCOC(=O)Cc1nc(Cl)cc(NC=O)n1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cc1nccc(NC=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To a solution of ethyl 2-(6-chloro-4-formamidopyrimidin-2-yl)acetate (2.3 g.) and sodium acetate (0.93 g.) in 80% ethanol (50 ml.) was added 10% palladium on carbon (0.2 g.), and the mixture was stirred under a hydrogen atmosphere for 8 hours at ambient temperature. The reaction mixture was filtered and the filtrate was concentrated. To the residue were added ethyl acetate and a small amount of water and the ethyl acetate layer was separated. The remaining aqueous layer was extracted with ethyl acetate. The ethyl acetate layers were combined together, washed with water and dried over magnesium sulfate and then the solvent was distilled off. Thus obtained oily substance (2.2 g.) was purified by column chromatography on silica gel (40 g.) using a mixture of benzene and ethyl acetate as an eluent to give a pale brown solid of ethyl 2-(4-formamidopyrimidin-2-yl)acetate (1.3 g.), mp. 80° to 93° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[CH3:17][C:18]([C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)([C:20]1[O:21][CH:22]=[CH:23][N:24]=1)[CH3:19]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:31]([C:28]2[CH:27]=[CH:26][C:25]([C:18]([CH3:19])([C:20]3[O:21][CH:22]=[CH:23][N:24]=3)[CH3:17])=[CH:30][CH:29]=2)(=[O:32])=[O:33])=[C:3]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:4]=1
Reactant: CC(C)(c1ccc(S(=O)(=O)Cl)cc1)c1ncco1
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccnc1
Product: CC(C)(c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2cccnc2)cc1)c1ncco1

Procedure:
The title compound was prepared from (2-Amino-5-chloro-phenyl)-pyridin-3-yl-methanone and 4-(1-methyl-1-oxazol-2-yl-ethyl)-benzenesulfonyl chloride following the general procedure described for the preparation of N-aryl-benzenesulfonamides. MS: m/z 482 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22]I)=[CH:14][CH:13]=3)[CH:10]([CH2:24][CH2:25][CH:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[OH:27])[C:9]2=[O:35])=[CH:4][CH:3]=1.[CH3:36][NH:37][CH2:38][CH:39]([OH:48])[CH:40]([OH:47])[CH:41]([OH:46])[CH:42]([OH:45])[CH2:43][OH:44]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:37]([CH3:36])[CH2:38][CH:39]([OH:48])[CH:40]([OH:47])[CH:41]([OH:46])[CH:42]([OH:45])[CH2:43][OH:44])=[CH:14][CH:13]=3)[CH:10]([CH2:24][CH2:25][CH:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[OH:27])[C:9]2=[O:35])=[CH:4][CH:3]=1
Reactant: CNCC(O)C(O)C(O)C(O)CO
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCCCCI)cc2)N1c1ccc(F)cc1
Solvent: CN(C)C=O
Product: CN(CCCCOc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)CC(O)C(O)C(O)C(O)CO
Temperature: 50 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
100 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-(4-iodobutoxy)phenyl]azetidin-2-one are dissolved in 5 ml of absolute dimethylformamide. 132 mg of 6-methylaminohexane-1,2,3,4,5-pentaol are then added, and the reaction solution is stirred at 50° C. for 2 h. After concentration using a rotary evaporator and oil pump vacuum at 40° C., the residue is purified by preparative HPLC. The product (89 mg) is obtained as an oil. C35H44F2N2O8 (658) MS (ESI): M+
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4]([CH2:12][CH2:13][NH2:14])=[CH:5][NH:6]2.[F:15][C:16]([F:28])([F:27])[CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O.S([O-])([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+]>C(O)(=O)C.C(O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4]([CH2:12][CH2:13][NH:14][CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([O:18][CH2:17][C:16]([F:15])([F:27])[F:28])[CH:20]=1)=[CH:5][NH:6]2
Reactant: O=Cc1cccc(OCC(F)(F)F)c1
Reactant: NCCc1c[nH]c2c(F)ccc(F)c12
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: Fc1ccc(F)c2c(CCNCc3cccc(OCC(F)(F)F)c3)c[nH]c12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Combine 2-(4,7-difluoro-1H-indol-3-yl)ethylamine (483 mg, 2.46 mmol) and ethanol (45 mL) and stir. After 10 minutes treat with 3-(2,2,2-trifluoroethoxy)benzaldehyde (502 mg, 2.46 mmol) and anhydrous sodium sulfate (3.5 g) and stir under nitrogen and heat at 70° C. After 2 h., cool the reaction vacuum filter to remove the sodium sulfate and treat with sodium borohydride (279 mg, 7.38 mmol) in a 500 mL round bottom flask equipped with magnetic stirring. Allow the solution to stir for 2 hours at room temperature and then carefully treat with three drops of glacial acetic acid to quench the excess hydride. Remove the solvent in vacuo and re-dissolve the crude material in methanol. Purify by a 10 g SCX column by washing thoroughly with methanol, eluting with 2N ammonia in methanol, and concentrating in vacuo to give the title compound as a straw colored oil. Prepare the hydrochloride salt by dissolving the free base (800 mg, 2.08 mmol) in methanol (15 mL) and treating with a solution of ammonium chloride (111 mg, 2.08 mmol) in methanol (5 mL). Sonicate the mixture for 10 minutes before concentrating in vacuo to give a white solid. Recrystallize from ethyl acetate to obtain the hydrochloride salt of the title compound: mp 208.5–210.0° C.; 1H NMR (400 MHz, dmso-d6): 11.79 (br s, 1H), 9.21 (br s, 2H), 7.39 (t, 1H, J=7.8 Hz), 7.32 (d, 1H, J=2.0 Hz) 7.30 (s, 1H), 7.18 (d, 1H, J=8.0 Hz), 7.11 (dd, 1H, J=2.6, 8.2 Hz), 6.85–6.91 (m, 1H), 6.67–6.73 (m, 1H), 4.77 (q, 2H, J=8.8 Hz), 4.16 (s, 4H), 3.12–3.16 (m, 4H); MS (APCI): m/e 385.1 (M+1); CHN (for C19H17F5N2O.HCl) calcd: C, 54.23, H 4.31, N, 6.66; found: C, 54.20, H 4.30, N 6.66.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])=[CH:10][CH2:11][C:5]2=[N:4][N:3]=1.C[O-:25].[Na+]>CO>[Cl:23][C:20]1[CH:21]=[CH:22][C:7]2[N:6]3[C:2](=[O:25])[NH:3][N:4]=[C:5]3[CH2:11][CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:8]=2[CH:19]=1
Reactant: C[O-]
Reactant: Fc1ccccc1C1=CCc2nnc(Br)n2-c2ccc(Cl)cc21
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]nc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=CC2

Procedure:
3.9 g of 1-bromo-8-chloro-6-(2-fluorophenyl)-4H-s-triazolo[4,3-a][1]benzazepine are suspended in 90 ml of methanol and treated with 1.62 of g of sodium methylate. The mixture is heated to boiling under reflux for 20 hours and then evaporated. The residue, which contains predominantly 8-chloro-6-(2-fluorophenyl)-1-methoxy-4H-s-triazolo[4,3-a][1]benzazepine, is heated to boiling under reflux for 4.5 hours in 100 ml of 48% hydrobromic acid. The mixture is diluted with water, made weakly alkaline with sodium carbonate and extracted with methylene chloride. The methylene chloride solution is evaporated and the residue is chromatographed on 120 g of aluminium oxide (activity grade III). Impurities are separated by elution with benzene/chloroform (9:1 to 1:4). By elution with chloroform which contains 1% to 10% methanol and two-fold recrystallization of the resulting material from benzene there is obtained 8-chloro-6-(2-fluorophenyl)-2,4-dihydro-1H-s-triazolo[4,3-a][1]benzazepin-1-one of melting point 223°-225°.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12]([CH3:14])=[O:13].P(=O)(O)(O)O>>[CH3:1][C:2]1[CH:3](/[CH:10]=[CH:11]/[C:12]([CH3:14])=[O:13])[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH:7]=1
Reactant: CC(=O)/C=C/C1=C(C)CCCC1(C)C
Agent: O=P(O)(O)O
Product: CC(=O)/C=C/C1C(C)=CCCC1(C)C

Procedure:
The same procedure was used as for β-ionone except phosphoric acid was used as the cyclizing agent. Boiling point 63°-65° C./0.1 mm; nD25 1.4960; yield 3.8 g.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]=[C:8]1[CH2:12][CH2:11][O:10][C:9]1=[O:13]>>[CH:1]1([NH:6][CH2:7][CH:8]2[CH2:12][CH2:11][O:10][C:9]2=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: C=C1CCOC1=O
Product: O=C1OCCC1CNC1CCCC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 88.1 %

Procedure:
A mixture of 4.44 g (0.0521 mole) of cyclopentylamine and 5.12 g (0.0521 mole) of dihydro-3-methylene-(3H)-furanone was stirred at room temperature for 40 minutes and then distilled under vacuum to give 8.41 g of (rac)-3-[(cyclopentylamino)methyl]dihydro-2(3H)-furanone, b.p. 120-128 degrees, 0.3 mm Hg.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:24])[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[CH:14]=1)[C:9]([OH:11])=O.[CH2:25]([O:27][C:28](=[O:37])[CH2:29][S:30][C:31]1[S:35][C:34]([NH2:36])=[N:33][CH:32]=1)[CH3:26]>>[CH2:25]([O:27][C:28](=[O:37])[CH2:29][S:30][C:31]1[S:35][C:34]([NH:36][C:9](=[O:11])[C:8]2[CH:12]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)[CH:14]=[C:6]([O:5][C@@H:4]([CH3:24])[CH2:3][O:2][CH3:1])[CH:7]=2)=[N:33][CH:32]=1)[CH3:26]
Reactant: COC[C@H](C)Oc1cc(Oc2cccc(OC)c2)cc(C(=O)O)c1
Reactant: CCOC(=O)CSc1cnc(N)s1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(Oc3cccc(OC)c3)cc(O[C@@H](C)COC)c2)s1

Procedure:
The title compound was prepared from 3-((S)-2-methoxy-1-methyl-ethoxy)-5-(3-methoxy-phenoxy)-benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@H:13]([CH2:14][OH:15])[CH2:12][N:11]3[N:16]=[C:17]([CH2:19][O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:18]=[C:10]3[C:9]2=[O:27])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:31]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@H:13]([CH2:14][O:15][CH3:31])[CH2:12][N:11]3[N:16]=[C:17]([CH2:19][O:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:18]=[C:10]3[C:9]2=[O:27])=[CH:4][CH:3]=1
Reactant: O=C1c2cc(COc3ccccc3)nn2C[C@@H](CO)N1c1ccc(F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@@H]1Cn2nc(COc3ccccc3)cc2C(=O)N1c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 65.5 %

Procedure:
A solution of (S)-5-(4-fluoro-phenyl)-6-hydroxymethyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (0.135 g, 0.36 mmol) in THF (0.5 mL) was added to a suspension of a 60% dispersion of sodium hydride in mineral oils (17 mg, 0.44 mmol) in THF (0.5 mL) at 0° C. The mixture was stirred for 10 minutes at 0° C., then iodomethane (0.046 mL, 0.73 mmol) was added. The reaction was heated at 120° C. for 10 minutes under microwave irradiation. Then the mixture was quenched with a saturated solution of NH4Cl and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 20/80). Desired fractions were collected and the solvents evaporated in vacuo. The residue was triturated with DIPE to yield (S)-5-(4-fluoro-phenyl)-6-methoxymethyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (90 mg, 64% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.26 (s, 3H), 3.36 (t, J=9.2 Hz, 1H), 3.51 (dd, J=9.5, 3.9 Hz, 1H), 4.21 (dtd, J=9.0, 4.5, 4.5, 2.3 Hz, 1H), 4.59 (dd, J=13.3, 4.7 Hz, 1H), 4.74 (dd, J=13.3, 2.2 Hz, 1H), 5.13 (s, 2H), 6.94-7.00 (m, 1H), 7.00-7.04 (m, 3H), 7.10-7.19 (m, 2H), 7.27-7.36 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[C:9]3[CH:10]=[C:11]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[CH:12]=[CH:13][C:14]=3[O:15][C:6]=2[CH:5]=[CH:4][N:3]=1.C([O-])(=[O:25])C.[NH4+]>C(O)(=O)C>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:11]2[CH:12]=[CH:13][C:14]3[O:15][C:6]4[CH:5]=[CH:4][NH:3][C:2](=[O:25])[C:7]=4[C:8](=[O:22])[C:9]=3[CH:10]=2)[CH:17]=1
Reactant: CC(=O)[O-]
Reactant: O=c1c2cc(-c3cccnc3)ccc2oc2ccnc(Cl)c12
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=c1[nH]ccc2oc3ccc(-c4cccnc4)cc3c(=O)c12
Temperature: 65 °C
Reaction time: 20 h

Procedure:
A resealable tube was charged with 1-chloro-8-(pyridin-3-yl)-10H-chromeno[3,2-c]pyridin-10-one (0.500 g, 1.620 mmol) and acetic acid (12.5 mL). Ammonium acetate (1.248 g, 16.20 mmol) was added, the system was purged with argon, and the tube was sealed. The mixture stirred at 65° C. for 20 h. The reaction mixture was filtered and washed with water. The filter cake was concentrated down from heptanes to afford 8-(pyridin-3-yl)-1H-chromeno[3,2-c]pyridine-1,10(2H)-dione as an off-white solid. MS m/z=291.0 [M+H]+. Calcd for C17H10N2O3: 290.07.