Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][C@H:6]1[CH2:10][CH2:9][C@@H:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:7]1)(=O)=O.[CH:17]1([CH2:20][NH:21][C:22](=[O:42])[CH2:23][N:24]2[C:33](=[O:34])[C:32]3[C:27](=[CH:28][CH:29]=[C:30](O)[CH:31]=3)[N:26]=[C:25]2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:19][CH2:18]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[CH:17]1([CH2:20][NH:21][C:22](=[O:42])[CH2:23][N:24]2[C:33](=[O:34])[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:5][C@H:6]4[CH2:10][CH2:9][C@H:8]([N:11]5[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]5)[CH2:7]4)[CH:31]=3)[N:26]=[C:25]2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:18][CH2:19]1
Reactant: CS(=O)(=O)O[C@H]1CC[C@@H](N2CCCCC2)C1
Reactant: O=C(Cn1c(-c2ccccc2)nc2ccc(O)cc2c1=O)NCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(Cn1c(-c2ccccc2)nc2ccc(O[C@H]3CC[C@H](N4CCCCC4)C3)cc2c1=O)NCC1CC1
Temperature: 80 °C
Yield: 14.5 %

Procedure:
A mixture of crude (1S,3R)-3-piperidin-1-ylcyclopentyl methanesulphonate (INTERMEDIATE XII.1) (90 mg, 0.4 mmol), N-cyclopropylmethyl-2-(6-hydroxy-4-oxo-2-phenyl-4H-quinazolin-3-yl)acetamide (INTERMEDIATE IV.6) (71 mg, 0.2 mmol) and Cs2CO3 (326 mg, 1.0 mmol) in DMSO (0.3 mL) was heated at 80° C. for 16 h. The mixture was then cooled and diluted with water. The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel with methanol:dichloromethane (1:9, v/v) as eluent to afford N-cyclopropylmethyl-2-[4-oxo-2-phenyl-6-((1S,3S)-3-piperidin-1-ylcyclopentyloxy)-4H-quinazolin-3-yl]acetamide (EXAMPLE 5a) (14 mg, 0.029 mmol, 14%).
Reaction SMILES: O=P(Cl)(Cl)Cl.[C:6]1([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN([CH:20]=[O:21])C>>[CH:20]([C:9]1[CH:10]=[CH:11][C:6]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:7][CH:8]=1)=[O:21]
Reactant: c1ccc(N2CCCC2)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
POCl3 (6.13 g) was added to stirred DMF (7 ml) at 0° C. and the mixture was stirred for 30 minutes at room temperature. The mixture was added dropwise to a solution of 1-phenylpyrrolidine (5.0 g) in DMF (30 ml) at 0° C. and the resulting solution was stirred overnight at room temperature. The reaction mixture was poured into an ice water mixture and extracted with Et2O. The Et2O layer was washed with saturated NaCl solution, dried over MgSO4 and the solution was concentrated in vacuo. The resulting crystalline mass was washed with Et2O-hexane, yielding 1-(4-formylphenyl)pyrrolidine (3.28 g). ##STR6##
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.Br[CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C:3]3[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:2]=3[NH:1][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:6][CH:7]=2)[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Oc3cc(Cl)ccc3N)cc2)CC1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCNc1ccc(Cl)cc1Oc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 60 °C
Reaction time: 72 h
Yield: 71.1 %

Procedure:
A mixture of tert-butyl 4-[4-(2-amino-5-chlorophenoxy)phenyl]piperazine-1-carboxylate (3.8 g, 9.5 mmols), ethyl 4-bromobutyrate (2.7 ml, 19 mmols), potassium carbonate (1.3 g, 9.5 mmols) and N,N-dimethylformamide (30 ml) was stirred at 60° C. for 72 hours. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an oil of ethyl 4-[2-[4-(4-tert-butoxycarbonyl-1-piperazinyl)phenoxy]-4-chlorophenyl]aminobutyrate (3.5 g, 71%).
Reaction SMILES: C[O:2][C:3](=[O:28])/[CH:4]=[CH:5]/[CH:6]=[C:7](/[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)\[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH-].[Na+]>CO>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20](/[C:7](/[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:6]/[CH:5]=[CH:4]/[C:3]([OH:28])=[O:2])=[CH:25][CH:24]=1
Reactant: CCCCCCCCCCCC/C(=C\C=C\C(=O)OC)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCC/C(=C\C=C\C(=O)O)c1ccc(OC)cc1
Yield: 68.5 %

Procedure:
As described in Example 99, (E,E)-5-(4-methoxyphenyl)-2,4heptadecadienoic acid methyl ester (11.9 g) was saponified in a refluxing mixture of methanol (30 mL) and 2N NaOH (30 mL). After 2,5 hours the crude acid was isolated in the usual way and was crystallized from hexane to give 7.86 g of (E,E)-5-(4-methoxyphenyl)-2,4-heptadecadienoic acid. A sample was recrystallized from the same solvent to afford the analytical specimen mp 85°-88° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:7]=1[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:5])[CH3:2].[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([C:32]([F:43])([F:42])[F:31])[CH:38]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=2)[C:7]=1[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(C(C)C)cc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3cccc(C(F)(F)F)c3)ccc2n1-c1ccc(C(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-isopropylphenyl)indole-3-carboxylic acid ethyl ester (150 mg, 0.37 mmol, see step (b) Example 10) and 3-trifluoromethylphenylboronic acid (140 mg, 0.74 mmol), pyridine. Yield 130 mg (65%).
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([C:12]1[C:13](Cl)=[C:14]([Cl:24])[C:15]2[O:19][CH:18]([C:20]([OH:22])=[O:21])[CH2:17][C:16]=2[CH:23]=1)(=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>N1C=CC=CC=1>[Cl:24][C:14]1[C:13]2[O:3][N:2]=[C:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:12]=2[CH:23]=[C:16]2[CH2:17][CH:18]([C:20]([OH:22])=[O:21])[O:19][C:15]=12
Reactant: O=C(c1ccccc1)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)C1Cc2cc3c(-c4ccccc4)noc3c(Cl)c2O1
Reaction time: 48 h
Yield: 32.3 %

Procedure:
Hydroxylamine hydrochloride (15.19 g, 0.2186 mol.) and (3a) (10.84 g., 0.0322 mol.) were heated at reflux in 75 ml. of dry pyridine for 5 hours. On cooling, the pyridine was removed on a rotary evaporator and chased with ethanol. The residue, a yellow gum, was taken up in ethyl acetate and washed with dilute aqueous hydrochloric acid and brine, then dried over anhydrous magnesium sulfate and evaporated to a gum containing both E and Z isomers of the oxime. Without further purification, the gum was taken up in 20 ml. of absolute ethanol and treated with 120 ml. of 1M alcoholic potassium hydroxide at reflux on a steam bath for 3 hours then refrigerated at 0°-5° C. for 48 hours. The resulting precipitate was collected by filtration, washed with hexane, dried, and dissolved in 300 ml. warm distilled water. Acidification to pH 2.0 by addition of 4.0 M aqueous hydrochloric acid gave a gelatinous precipitate which was extracted into ethyl acetate, dried with anhydrous magnesium sulfate, decolorized with Darco, and evaporated. Recrystallization from ethyl acetate with hexane afforded the furobenzisoxazole (4a) in 32.3% yield, m.p. 214°-215° C. Analysis (C16H10ClNO4) C,H,N,Cl.
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[CH2:9][C:10]1[CH:25]=[CH:24][C:13]([O:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:12][CH:11]=1.CCN(CC)CC.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(Cl)Cl>[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[O:14][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:3]2[CH2:4][C@@H:5]3[CH2:8][C@H:2]2[CH2:7][N:6]3[C:33](=[O:35])[CH3:34])=[CH:25][CH:24]=1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2sc(Oc3ccc(CN4C[C@@H]5C[C@H]4CN5)cc3)nc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc(Oc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (S,S)-2-[4-(2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenoxy]-benzothiazole hydrochloride (109 mg, 0.27 mmol) and Et3N (150 μL, 1.1 mmol) in CH2Cl2 (4 mL) was added acetic anhydride (40 μL, 0.4 mmol), and the resulting solution was then stirred at rt for 18 h. The resulting white suspension was partitioned between CH2Cl2 (150 mL) and satd. aq. NaHCO3 (50 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated. Purification by silica gel flash chromatography (0% to 5% CH3OH in CH2Cl2) afforded the title compound as a viscous, colorless oil (93 mg, 92%). MS (ESI): mass calcd. for C21H21N3O2S, 379.14; m/z found, 380.2 [M+H]+. 1H NMR (500 MHz, CDCl3, mixture of rotamers): 7.73 (d, J=7.5 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.44-7.36 (m, 3H), 7.33-7.24 (m, 3H), 4.78 (br m, 0.5H), 4.23 (m, 0.5H), 3.78-3.73 (br m, 2.5H), 3.56 (m, 1.5H), 3.32 (dd, J=9.3, 2.2 Hz, 0.5H), 3.27 (dd, J=11.4, 2.3 Hz, 0.5H), 3.01 (dd, J=9.1, 2.2 Hz, 0.5H), 2.84 (dd, J=9.7, 2.1 Hz, 0.5H), 2.77 (br d, J=9.9 Hz, 0.5H), 2.56 (dd, J=9.9, 1.2 Hz, 0.5H), 2.08 (s, 1.5H), 2.00 (s, 1.5H), 1.98 (br m, 0.5H), 1.91 (br m, 0.5H), 1.80 (br m, 0.5H), 1.66 (br m, 0.5H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:4].[NH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+]>CO>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4])[N:6]=1)#[N:24]
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(C#N)c2c(Oc3ccccc3)cccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2cccc(Oc3ccccc3)c12
Temperature: 25 °C
Yield: 97.4 %

Procedure:
A mixture of 1-cyano-4-hydroxy-8-phenoxy-isoquinoline-3-carboxylic acid methyl ester (322 mg, 1.0 mmol), glycine (1.51 g, 20.1 mmol), and a 0.5 M sodium methoxide solution in methanol (38.2 mL) was refluxed for 31 h before it was cooled to room temperature and concentrated in vacuo. Water (75 mL) was added and the pH of the yellow suspension was adjusted to 10 with aqueous 1 N HCl. A clear yellow solution was obtained after 5 minutes of sonication. The solution was washed with dichloromethane (2×50 mL). The remaining aqueous layer was acidified to pH=3 with aqueous 1 N HCl. The white precipitate formed was separated by filtration, washed with water and dried in vacuo to give the title compound as a white solid (354 mg): 1H NMR (DMSO-d6, 200 MHz): δ=12.86 (bs, 1H), 9.56 (t, 1H), 8.09 (m, 1H), 7.88 (t, J=8.2 Hz, 1H), 7.47 (m, 2H), 7.21 (m, 4H), 4.05 (d, J=5.8 Hz, 2H).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]#[N:17])=[CH:6][CH:5]=1.[OH-:18].[NH4+].[OH-].[K+]>O.C(Cl)Cl>[ClH:1].[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]([C:16]([NH2:17])=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: [OH-]
Reactant: N#Cc1ccccc1-c1ccc(CN)cc1
Agent: Cl
Agent: [K+]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: NCc1ccc(-c2ccccc2C(N)=O)cc1
Temperature: 72.5 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
4-Aminomethyl-2′-cyanobiphenyl hydrochloride (XVII) (100 g, 0.408 mole) was suspended in a mixture of water (500 ml) and methylene chloride (200 ml) at 25-30° C. and adjusted the pH to 9.0-9.5 with ammonium hydroxide (65 ml, 20% w/w) at 25-30° C. to get a clear solution. Organic layer was separated, washed with water (100 ml) and dried over sodium sulfate. Thereafter, organic layer was concentrated at below 60° C. and tert.butanol (300 ml) was added to the residue. The reaction mass was heated to 70-75° C. Thereafter, powdered potassium hydroxide (32.35 g, 0.491 mole) was added and heated to reflux for completion of the reaction. Water (400 ml) was added and aqueous layer was separated and extracted with methylene chloride (500 ml). The combined organic layer was washed with water (200 ml) and dried over sodium sulfate. Methylene chloride solution was cooled to 2-5° C. and the pH adjusted to 1.2-1.4 with hydrochloric acid. The precipitated product was stirred for one hour and filtered, washed with methylene chloride to afford the title compound as white powder (90 g, 84.1% yield).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)([O:3][CH3:4])=[O:2].S(Cl)(Cl)=O.[I-].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Zn+]>O1CCCC1>[CH3:4][O:3][C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([C:11](=[O:13])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[F:19])[CH2:9][CH2:10]1)=[O:2]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: Fc1ccccc1[Zn+]
Agent: [I-]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)C1CCC(C(=O)c2ccccc2F)CC1
Temperature: 25 °C
Yield: 67.3 %

Procedure:
In an oven dried 1 neck round bottom flask with reflux condenser and stirbar, trans-4-carbomethoxycyclohexane-1-carboxylic acid (840 mg; 4.5 mmol) was heated to reflux in the presence of 15 mL thionyl chloride. After 3 hours reflux, mixture cooled to 40° C. under nitrogen flow, and excess thionyl chloride was removed at reduced pressure. Residue was taken up in 5 mL of dry tetrahydrofuran and added to a 0° C. mixture of 2-fluorophenylzinc iodide (9.0 mL; 4.5 mmol), tetrakis(triphenylphospine)palladium (0) (272 mg; 0.2 mmol) in 10 mL anhydrous tetrahydrofuran. Mixture was allowed to warm to room temperature over 16 hours. Reaction was quenched with 6 mL 1N HCl and ethyl acetate was taken in. Organics separated and aqueous re-extracted with 20 mL ethyl acetate. Combined organics were washed with sat. NaHCO3, water, brine and dried over MgSO4. Material was purified via flash silica plug (10:1) using 15% ethyl acetate in hexanes isocratic to give 800 mg of title compound. (67% yield)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:29][CH2:30][OH:31])[O:14][CH2:13][CH2:12][N:11]([C:15](=[O:28])[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([O:31][CH2:30][CH2:29][C:9]1([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:14][CH2:13][CH2:12][N:11]([C:15](=[O:28])[C:16]2[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=2)[CH2:10]1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)N2CCOC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCOC(CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
388 mg (0.83 mmole) of 2-[2-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethanol [prepared as described in step (e) above] were dissolved in 5 ml of methylene chloride, and 126 mg (1.25 mmole) of triethylamine and 0.078 ml (1.01 mmole) of methanesulfonyl chloride were added to the resulting solution. The mixture was then stirred at room temperature for 2 hours. The reaction mixture was then diluted with methylene chloride, after which it was washed with 1 N aqueous hydrochloric acid and with a saturated aqueous solution of sodium chloride, in that order. The organic extract was dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography, using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 1:4 to 0:1 by volume as the eluent, to obtain 424 mg of the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]([NH:14][NH2:15])=O)=[CH:8][CH:9]=2)[CH:4]=[N:3][CH:2]=1.Cl[C:17]1[N:18]=[N:19][C:20]([C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)=[CH:21][CH:22]=1>C(O)CCC>[CH3:28][N:26]1[CH:27]=[C:23]([C:20]2[CH:21]=[CH:22][C:17]3[N:14]([C:12]([CH2:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][N:3]=[CH:4]5)=[N:19][N:18]=3)[N:15]=2)[CH:24]=[N:25]1
Reactant: NNC(=O)Cc1ccc2ncncc2c1
Reactant: Cn1cc(-c2ccc(Cl)nn2)cn1
Solvent: CCCCO
Product: Cn1cc(-c2ccc3nnc(Cc4ccc5ncncc5c4)n3n2)cn1
Temperature: 25 °C
Yield: 5.7 %

Procedure:
Quinazolin-6-yl-acetic acid hydrazide (0.032 g, 0.158 mmol) and 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-pyridazine (0.031 g, 0.158 mmol) were heated to 165° C. in butanol (2 mL) for five hours. The reaction was cooled to room temperature, evaporated in vacuo and purified via silica gel column chromatography eluting with 5% methanol in dichloromethane to give 0.0031 g (7%) of 6-[6-(1-methyl-1H -pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl]-quinazoline. 1H NMR (400 MHz, CD3OD) δ 8.45 (s, 1H), 8.29 (s, 1H), 8.06 (d, 2H, J=9.6 Hz), 7.60 (d, 2H, J=9.6 Hz), 7.55 (m, 1H), 7.17 (d, 1H, J=8.0 Hz), 6.08 (s, 1H), 4.58 (m, 2H), 3.89 (s, 3H). Mass spectrum (LCMS, ESI pos.): Calcd for C18H14N8; found: 343.3 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12](Cl)[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:19]=[N+:20]=[N-:21].[Na+].C(Cl)Cl>CN(C=O)C>[N:19]([C:12]1[C:11]2[CH2:10][CH2:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:17][C:16]=2[N:15]=[CH:14][CH:13]=1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: Clc1ccnc2c1CCN(Cc1ccccc1)C2
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ccnc2c1CCN(Cc1ccccc1)C2
Temperature: 70 °C
Yield: 55.1 %

Procedure:
7-Benzyl-4-chloro-5,6,7,8-tetrahydro-[1,7]naphthyridine (0.417 mmol) was treated with 5 equiv. of NaN3 (135 mg) in DMF (0.5 ml) and heated to 70° C. for 4 h. The residue was dissolved on 50 ml of DCM and washed with brine. The organic layer was concentrated to afford a black oil, which was purified by column chromatography to afford the desired azide (61 mg), which was used directly in the next step.
Reaction SMILES: Cl.CC1(C)[O:7][C@H:6]2[CH2:8][CH2:9][CH2:10][C@H:11]([NH:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5[CH:34]=[CH:33][C:32]6[C:31]([CH3:36])([CH3:35])[CH2:30][CH2:29][C:28]([CH3:38])([CH3:37])[C:27]=6[CH:26]=5)[N:20]=4)[CH2:15][CH2:14]3)[C@H:5]2[O:4]1>CO>[CH3:35][C:31]1([CH3:36])[CH2:30][CH2:29][C:28]([CH3:37])([CH3:38])[C:27]2[CH:26]=[C:25]([C:21]3[N:20]=[C:19]([N:16]4[CH2:15][CH2:14][CH:13]([NH:12][C@H:11]5[CH2:10][CH2:9][CH2:8][C@H:6]([OH:7])[C@@H:5]5[OH:4])[CH2:18][CH2:17]4)[CH:24]=[CH:23][CH:22]=3)[CH:34]=[CH:33][C:32]1=2
Reactant: CC1(C)O[C@@H]2[C@@H](NC3CCN(c4cccc(-c5ccc6c(c5)C(C)(C)CCC6(C)C)n4)CC3)CCC[C@@H]2O1
Agent: Cl
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCC(N[C@H]5CCC[C@H](O)[C@@H]5O)CC4)n3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10 ml of 1.25 N HCl in methanol are added to 168 mg of ((3aR,4S,7aS)-2,2-dimethylhexahydrobenzo-1,3-dioxol-4-yl)-[6′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-3,4,5,6-tetrahydro-2H-1,2′-bipyridinyl-4-yl]amine, and the mixture is stirred at room temperature overnight. The reaction mixture is evaporated and dried under high vacuum. The product is in the form of the hydrochloride.
Reaction SMILES: C(OC([N:8]([CH2:26][C@H:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:37][C:38]3[CH:47]=[CH:46][C:41]([C:42]([O:44]C)=[O:43])=[CH:40][CH:39]=3)[CH:33]=2)[O:28]1)[CH2:9][C@@H:10]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[O:11][SiH2]C(C)(C)C(C)(C)C)=O)(C)(C)C.[Li+].[OH-].CO.P(=O)(O)(O)O>O1CCCC1>[OH:11][C@H:10]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:9][NH:8][CH2:26][C@H:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:37][C:38]3[CH:47]=[CH:46][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=3)[CH:33]=2)[O:28]1
Reactant: COC(=O)c1ccc(Cc2ccc3c(c2)CC[C@H](CN(C[C@H](O[SiH2]C(C)(C)C(C)(C)C)c2cccnc2)C(=O)OC(C)(C)C)O3)cc1
Agent: O=P(O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(Cc2ccc3c(c2)CC[C@H](CNC[C@H](O)c2cccnc2)O3)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 77.2 mg (0.11 mmol) methyl 4-[((2R)-2-{[(tert-butoxycarbonyl)((2R)-2-(3-pyridinyl)-2-{[([(1,1,2,2-tetramethylpropyl)silyl]oxy}ethyl)amino]-methyl}-3,4-dihydro-2H-chromen-6-yl)methyl]benzoate (Example 167) in 1 mL of tetrahydrofuran was added 0.54 mL of 1 M LiOH and 0.27 mL methanol. The mixture was stirred at room temperature for 3 hours after which point 0.5 mL of 1N phosphoric acid was added to the solution. The mixture was partitioned between ethyl acetate (3×5 mL) and water (5 mL). The organic layer was washed with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated. To the residue was added 0.4 mL of hydrochloric acid in dioxane. This solution was stirred at room temperature for 0.5 hour. The solution was then washed with water and concentrated in vacuo, followed by purification by preparative HPLC (gradient of 100:0 0.1% TFA/H2O:acetonitrile to 30:70 0.1% TFA/H2O:acetonitrile) to obtain 16.4 mg of product as the TFA salt. MH+ 419.3.
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].C(C1(C2C=CC(OC)=C(C=2)[CH:27]=[O:28])CC1)#N>>[C:1]([C:3]1([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:10]=2)[CH:27]=[O:28])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2]
Reactant: COc1ccc(C2(C#N)CC2)cc1C=O
Reactant: COc1ccc(C2(C#N)CCCCC2)cc1
Product: COc1ccc(C2(C#N)CCCCC2)cc1C=O

Procedure:
This compound was prepared from 4-(1-Cyanocyclohexyl)anisole in the same manner of Compound 2.
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)/[C:3]([OH:5])=[O:4].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=1.N1CCCCC1>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:2]([CH3:1])[C:3]([OH:5])=[O:4])=[CH:21][CH:20]=1
Reactant: COc1ccc(S)cc1
Reactant: C/C(=C\CCCCc1ccccc1)C(=O)O
Solvent: C1CCNCC1
Product: COc1ccc(SC(CCCCc2ccccc2)C(C)C(=O)O)cc1
Temperature: 85 °C
Yield: 25.1 %

Procedure:
(E)-2-Methyl-7-phenyl-hept-2-enoic acid (2.2 g, 10 mmol), 4-methoxybenzenethiol (2.8 g, 20 mmol) and piperidine (0.1 mL, 1 mmol) are combined and heated at 85° C. for 12 hours. The reaction is cooled and purified by gradient elution chromatography (silica, 35 to 100% ether in petroleum ether) to yield (±)-3-(4-Methoxyphenylsulfanyl)-2-methyl-7-phenylheptanoic acid (0.9 g, 25%) as a 50/50 mixture of diastereomers: 1H NMR (300 MHz, CDCl3) δ 7.39-7.34 (m, 2H), 7.29-7.25 (m, 2H), 7.20-7.11 (m, 3H), 6.81 (m, 2H), 3.79 (s, 1.5H), 3.78 (s, 1.5H), 3.30-3.16 (m, 1H), 2.70-2.54 (m, 3H), 1.72-1.40 (m, 6H), 1.28 (d, J=7.0 Hz, 1.5H), 1.22 (d, J=7.0 Hz, 1.5H); MS (FAB) m/e 359 (M+H)+.