Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:7][C:8]1([F:19])[O:12][C:11]2[CH:13]=[CH:14][C:15]([CH:17]=O)=[CH:16][C:10]=2[O:9]1>[OH-].[OH-].[Pd+2].CO>[F:19][C:8]1([F:7])[O:12][C:11]2[CH:13]=[CH:14][C:15]([CH2:17][N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[CH:16][C:10]=2[O:9]1
Reactant: C1CNCCN1
Reactant: O=Cc1ccc2c(c1)OC(F)(F)O2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: FC1(F)Oc2ccc(CN3CCNCC3)cc2O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 2 L Erlenmeyer flask was charged with piperazine (185.1 g, 2.15 mol), 2,2-difluoro-benzo[1,3]dioxole-5-carbaldehyde (100.0 g, 0.537 mol), and methanol (1.08 L). The solution was stirred at room temperature for 18 h then passed twice through an H-Cube Midi™ (ThalesNano, Budapest, Hungary) with a new 20% Pd(OH)2/C MidiCart cartridge, at the following settings: 70° C., 1 atm pressure, 6 mL/min flow rate, and 10% excess H2 production. The aldehyde starting material was >90% consumed after the first pass, and completely consumed after the second pass as indicated by HPLC analysis. The methanol was evaporated, toluene (1.20 L) was added and the mixture was stirred at room temperature for 18 h. The resulting white suspension was filtered and the solid was rinsed with toluene (200 mL). The combined filtrate was washed with water (2×300 mL), dried over Na2SO4, filtered, and concentrated to afford the product as a colorless oil. The oil was dissolved in heptane (100 mL) and the product was allowed to crystallize at room temperature. For subsequent synthesis experiments, addition of a small amount of seed crystals was used to quicken the crystallization process. The suspension was cooled to 0° C., filtered and the solid was dried in vacuum oven at 50° C. for 24 h to give the title compound as a white solid (108.0 g, 78%). The heptane filtrate was concentrated to approximately 20 mL followed by addition of product seed crystals. The solution then was stirred overnight. The second batch of the title compound was obtained as a white solid after filtration and drying (6.7 g, 5%). The combined yield was (115 g, 83%). MS (ESI+): calcd for C12H14F2N2O2 m/z 256.1. found 256.9 (M+H)+. 1H NMR (400 MHz, CDCl3) δ: 7.11 (d, J=0.9 Hz, 1H), 6.99 (dd, J=9.0, 0.9 Hz, 1H), 6.95 (d, J=9.0 Hz, 1H), 3.45 (s, 2H), 2.92-2.83 (m, 4H), 2.39 (s, 4H); 13C NMR (101 MHz, CDCl3) δ: 143.89, 142.72, 134.68, 131.65 (t, JC-F=255.3), 123.88, 110.13, 108.82, 63.10, 54.38, 46.07.
Reaction SMILES: ClC1N=C2NC(=O)[C@]3(C4(CCC(C)(C)CC4)[N:17]4[C@@H](C(=O)[O:14][C@@H:15](C5C=CC=CC=5)[C@H:16]4[C:26]4[CH:31]=[CH:30][CH:29]=CC=4)[C@@H]3C3C=CC=C(Cl)C=3F)C2=CC=1.[CH2:48]([O:55][C:56](Cl)=[O:57])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.Cl.[OH-:60].[Na+]>>[CH2:48]([O:55][C:56]([NH:17][C@@H:16]1[CH2:26][CH2:31][C@@H:30]([CH2:29][OH:60])[O:14][CH2:15]1)=[O:57])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: [OH-]
Reactant: CC1(C)CCC2(CC1)N1[C@H](c3ccccc3)[C@H](c3ccccc3)OC(=O)[C@H]1[C@H](c1cccc(Cl)c1F)[C@@]21C(=O)Nc2nc(Cl)ccc21
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Product: O=C(N[C@@H]1CC[C@@H](CO)OC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
The compound (3.5 g, 21.0 mmol) obtained in Step 1 above was dissolved in 5N aqueous sodium hydroxide solution (40 ml) and benzyloxycarbonyl chloride (3.3 ml, 23.0 mmol) was added dropwise at 0° C. After stirring at room temperature for 16 hours, the reaction mixture was rendered acidic by addition of 1N hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, diethyl ether and hexane were added to the residue obtained and then the slurry was filtered and dried to give 2.06 g (37%) of the title compound as a colorless solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([S:20](Cl)(=[O:22])=[O:21])=[CH:15][CH:16]=2)[CH2:11]1)(=[O:9])[CH3:8].C(NC(C)C)(C)C.Cl.N1(S(C2C=C3C(CCNC3)=CC=2)(=O)=O)CCOCC1>C1COCC1>[C:7]([N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([S:20]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)(=[O:21])=[O:22])=[CH:15][CH:16]=2)[CH2:11]1)(=[O:9])[CH3:8]
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2C1
Reactant: C1COCCN1
Agent: Cl
Agent: O=S(=O)(c1ccc2c(c1)CNCC2)N1CCOCC1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(=O)N1CCc2ccc(S(=O)(=O)N3CCOCC3)cc2C1

Procedure:
was obtained as described in Example 4A by reacting morpholine with 2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride in the presence of diisopropylamine in THF and by heating with 50% concentrated hydrochloric acid and, after alkaline workup, converted into the corresponding 7-(morpholin-4-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([C@@H:10]2[C@@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([N:17]3[CH:25]=[N:24][C:23]4[C:18]3=[N:19][CH:20]=[N:21][C:22]=4Cl)[O:11]2)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[C:1]([C:5]1[O:9][C:8]([C@@H:10]2[C@@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([N:17]3[CH:25]=[N:24][C:23]4[C:18]3=[N:19][CH:20]=[N:21][C:22]=4[NH:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[O:11]2)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CCOCC1
Reactant: CC(C)(C)c1nnc([C@H]2O[C@@H](n3cnc4c(Cl)ncnc43)[C@H](O)[C@@H]2O)o1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nnc([C@H]2O[C@@H](n3cnc4c(NC5CCOCC5)ncnc43)[C@H](O)[C@@H]2O)o1
Yield: 77.1 %

Procedure:
(2S,3S,4R,5R)-2-(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-5-(6-chloro-purin-9-yl)-tetrahydro-furan-3,4-diol (41 mg) was heated under reflux with 4-aminotetrahydropyran hydrochloride (59 mg), diisopropylethylamine (0.11 ml), and isopropanol (5 ml) for 15 h. The solvent was evaporated in vacuo and the residue purified by chromatography on silica gel, eluting with ethyl acetate:methanol 100:0-90:10, to give the title compound (37 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[Cl:21][C:22]1[C:23]([C:30](O)=[O:31])=[N:24][N:25]([CH:27]([F:29])[F:28])[CH:26]=1>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:16])([F:17])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C:23]3[C:22]([Cl:21])=[CH:26][N:25]([CH:27]([F:29])[F:28])[N:24]=3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reactant: O=C(O)c1nn(C(F)F)cc1Cl
Product: C[C@@]1(c2cc(NC(=O)c3nn(C(F)F)cc3Cl)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1

Procedure:
The coupling of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1) and 4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxylic acid [D. Banner et al. WO2011069934 (2011)] following General Procedure F yielded the title compound as an off-white solid. MS: m/z=470.4 [M+H]+.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]3C(O)[C:21]4[C:26]([C:8]=23)=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=4)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COP([C:36](=[CH2:41])[C:37]([O:39][CH3:40])=[O:38])(OC)=O.[C:42](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=3[N:9]3[CH2:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:42][C:21]4[CH:22]=[C:23]([O:27][CH3:28])[CH:24]=[CH:25][C:26]=4[C:8]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C(O)c1cc(OC)ccc1-3
Reactant: C=C(C(=O)OC)P(=O)(OC)OC
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A solution of methyl 11-cyclohexyl-6-hydroxy-8-methoxy-6H-isoindolo[2,1-a]indole-3-carboxylate (2.9 g, 7.4 mmol), methyl 2-(dimethoxyphosphoryl)acrylate (2.6 g, 11 mmol), cesium carbonate (3.6 g, 11 mmol) in DMF (20 mL) was heated at 60° C. for 2 h and cooled to rt. The stirring reaction mixture was diluted with H2O (50 mL) and the precipitates were collected by filtration to yield dimethyl 13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylate (3.3 g, 7.1 mmol, 97%) as a yellow solid which was used without further purification. LCMS: m/e 460 (M+H)+, ret time 3.35 min, column B, 3 minute gradient.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].I[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([CH:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5])=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: CC(=O)CC(C)=O
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)C(C(C)=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 60.4 %

Procedure:
A mixture of pentane-2,4-dione (4.41 g, 40 mmol), 1-iodo-4-nitrobenzene (5 g, 20 mmol) and potassium carbonate (11 g, 80 mmol) were heated in DMSO (15 ml) at 120° C. for 3 hr. The reaction mixture was cooled to room temperature, diluted with water (100 ml), and then extracted with ethyl acetate. The organic layer was washed with water, brine and dried. Evaporation gave a residue which was chromatographed over silica gel eluting with ethyl acetate/pet ether (5:95) to give 3-(4-nitrophenyl)-pentane-2,4-dione (2.67 g, 60%) as solid.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:11]([C:16]1[CH:26]=[CH:25][CH:24]=[C:18]2C(N[C:22](=[O:23])[C:17]=12)=O)(OCC)=[O:12].Cl>C([O-])([O-])=O.[Na+].[Na+].O>[CH:25]1[CH:26]=[C:16]2[C:11]([N:1]([C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[C:22](=[O:23])[C:17]2=[CH:18][CH:24]=1)=[O:12]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: CCOC(=O)c1cccc2c1C(=O)NC2=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O

Procedure:
In a solution of Na2CO3 (51.5 g) in water (350 ml) at 5° C. was dissolved L-glutamic acid (29.4 g). Carboethoxy phthalimide (59.6 g) was added to the solution and suspended therein and thereafter reacted at 350° C. for 30-40 minutes. Then the solution was freed from insoluble matter, adjusted to pH 2.5 with 6N-HCl, and allowed to stand at 0° C. The resulting precipitate was filtered, and recrystallized from water to give N,N-phthaloylglutamic acid, yield 35.7 g, 64.4%; specific rotation [α]D25 =-48.6° (C=1, dioxane).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4]O.C(N(S(F)(F)[F:17])CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4][F:17]
Reactant: CCN(CC)S(F)(F)F
Reactant: OCc1cc(Cl)ccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FCc1cc(Cl)ccc1Br
Temperature: 25 °C
Yield: 65.6 %

Procedure:
To a suspension of 2-bromo-5-chlorobenzyl alcohol (2.0 g, 9.0 mmol, Fluorochem) in anhydrous DCM (30 mL) was added (diethylamino)sulfur trifluoride (1.30 mL, 10 mmol), at about −75° C. After complete addition the mixture was allowed to warm slowly to rt, over about 1 h. Then saturated aqueous sodium bicarbonate (8 mL) was added and the mixture was partitioned between DCM (20 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted twice with DCM (20 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, DCM/hexanes 1:1) to give 1-bromo-4-chloro-2-(fluoromethyl)benzene (1.31 g, 5.9 mmol, 65%) as a pale yellow oil: 1H-NMR (CDCl3, Bruker 400 MHz) δ 5.42 (2 H, d, J=47.0 Hz) 7.19 (1 H, dd, J=8.8, 2.5 Hz) 7.41 (1 H, d, J=2.5 Hz) 7.48 (1 H, d, J=8.8 Hz).
Reaction SMILES: [CH:1]1[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[N+:17]([O-])([OH:19])=[O:18]>C(O)(=O)C.O>[N+:17]([C:8]1[C:7]2[C:16]3=[C:15]4[C:4](=[CH:5][CH:6]=2)[CH:3]=[CH:2][CH:1]=[C:14]4[CH:13]=[CH:12][C:11]3=[CH:10][CH:9]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: c1cc2ccc3cccc4ccc(c1)c2c34
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2ccc3cccc4ccc1c2c34

Procedure:
A solution was prepared by dissolving 101 g of pyrene in 800 ml of glacial acetic acid. While heating this solution at 50° C. in water bath with stirring, a mixed solution of 42 ml of nitric acid (D=1.4) and 50 ml of glacial acetic acid was slowly added thereto dropwise. At the end of 30 minutes, the reacted mixture was filtered with suction. The precipitate was washed with a small quantity of glacial acetic acid and then thoroughly washed with water to obtain 115 g of yellow crystals (melting point: 150° C.). By recrystallizing these crystals in glacial acetic acid, crystals having a melting point in the range of 153°~154° C. were obtained. The result of elemental analysis of this product was as shown in the following table:
Reaction SMILES: CN(C)CCCOC1C=CC(C2SC(NC3C=CC=CC=3)=NC=2)=CC=1.[S:26]1[CH:30]=[CH:29][C:28]([C:31]2[S:35][C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=3)=[N:33][CH:32]=2)=[CH:27]1.Cl.Cl[CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>>[N:48]1([CH2:47][CH2:46][O:43][C:40]2[CH:41]=[CH:42][C:37]([NH:36][C:34]3[S:35][C:31]([C:28]4[CH:29]=[CH:30][S:26][CH:27]=4)=[CH:32][N:33]=3)=[CH:38][CH:39]=2)[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1
Reactant: ClCCN1CCOCC1
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Agent: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Agent: Cl
Product: c1cc(-c2cnc(Nc3ccc(OCCN4CCOCC4)cc3)s2)cs1

Procedure:
The title compound is prepared as described in Example 8 for {5-[4-(3-dimethylamino-propoxy)-phenyl]-thiazol-2-yl}-phenyl-amine but starting from 4-(5-thiophen-3-yl-thiazol-2-yl-amino)-phenol (Example 12) and using (2-chloroethyl)-morpholine hydrochloride. MPLC (CH3CN/H2O/TFA) purification affords the title compound: ES-MS: 388.0 [M+H]+; single peak at tR=2.80 min (System 2).
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].C([Li])CCC.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[N:19]2[CH2:22][CH:21]([C:23]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=3)=[O:24])[CH2:20]2)=[CH:14][CH:13]=1.[NH4+].[Cl-]>C1COCC1.CCOCC>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:33]2[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=2)[N:19]2[CH2:22][CH:21]([C:23]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=3)([OH:24])[C:2]([CH3:4])([CH3:3])[C:1]#[N:5])[CH2:20]2)=[CH:14][CH:13]=1
Reactant: CC(C)C#N
Reactant: O=C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C#N)C(O)(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reaction time: 0.83 h

Procedure:
To a solution of 84 uL (0.928 mmol) of isobutyronitrile in 2 mL of THF was added a solution of 370 uL (0.928 mmol) of butyllithium (2.5M solution in hexanes), followed by stirring for 50 minutes at −55° C. to −40° C. Then a solution of 334 mg (0.773 mmol) of {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)methanone (as in Preparation 6) in THF was added at −78° C. and the solution was stirred for 5 h at −60° C. to −50° C. A solution of 2 mL of saturated NH4Cl was added to quench the reaction and the reaction mixture was poured into 30 mL of ether and washed with 5 mL of aq NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate=4:1 to afford the title compound. 1NMR(CDCl3) δ 1.24 (s, 3H), 1.34 (S, 3H), 2.58 (br, 1H), 3.12 (br, 1H), 3.40 (br, 2H), 3.60 (br, 1H), 4.26 (m, 1h) 4.43 (s, 1H), 6.76 (m, 1H), 7.06 (m, 2H), 7.25-7.34 (m, 8H); Mass Spectrum: m/e=501 (M+1 35Cl, 38Cl) and 503 (M+1 35Cl, 37Cl).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH:14]=C)[C:7]([O:9][CH3:10])=[O:8])[CH2:2][CH3:3].[O:16]=[O+][O-].CSC>CO.C(Cl)Cl>[CH:14]([C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[CH2:1][CH2:2][CH3:3])=[O:16]
Reactant: O=[O+][O-]
Reactant: C=Cc1ccc(C(=O)OC)cc1CCC
Solvent: CSC
Solvent: CO
Solvent: ClCCl
Product: CCCc1cc(C(=O)OC)ccc1C=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 59 %

Procedure:
To a magnetically stirred solution of 2.796 g (14.0 mmol) of the product of Step B dissolved in a mixture of 15 mL methanol and 5 mL methylene chloride was introduced a slow stream of ozone at -78° C. After 15 minutes a persistent blue color of excess ozone was observed and the flow of ozone was stopped. Excess methylsulfide (2 mL) was added via syringe, the reaction mixture was allowed to warm to room temperature, and stirring was continued for 12 hours. The reaction mixture was then concentrated on a rotary evaporator and then purified on a silica gel flash chromatography column eluted with 5% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded 1.677 g (59%) of the title compound as a clear oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C@H:7]1[C@@H:12]2[C:13]([CH2:16][OH:17])=[CH:14][CH2:15][C@@H:11]2[C:10]([C:18]([O:20][CH3:21])=[O:19])=[CH:9][O:8]1)[CH3:5])[CH3:2].[H-].[Na+].[CH3:24]I>CN(C)C=O>[CH2:1]([O:3][CH:4]([O:6][C@H:7]1[C@@H:12]2[C:13]([CH2:16][O:17][CH3:24])=[CH:14][CH2:15][C@@H:11]2[C:10]([C:18]([O:20][CH3:21])=[O:19])=[CH:9][O:8]1)[CH3:5])[CH3:2]
Reactant: CI
Reactant: CCOC(C)O[C@@H]1OC=C(C(=O)OC)[C@H]2CC=C(CO)[C@@H]12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(C)O[C@@H]1OC=C(C(=O)OC)[C@H]2CC=C(COC)[C@@H]12
Temperature: 25 °C
Yield: 81.7 %

Procedure:
Methyl (1S, 4aS, 7aS)-1-[1-(ethoxy)ethoxy]-7-(hydroxymethyl)-1, 4a, 5, 7a-tetrahydrocyclopenta[c]-pyran-4-carboxylate (2.0 g, 0.0067 mol) obtained in Example 16 was dissolved in 30 mι of dimethylformamide, and 540 mg (0.013 mol) of sodium hydride (in 60% oil) was added while the reaction mixture was being cooled by ice and stirred. After the reaction mixture was stirred at the same temperature for 30 minutes, 1.9 g (0.013 mol) of methyl iodide was added dropwise. After the temperature was raised up to the room temperature and the reaction mixture was stirred for 2 hours, the reaction mixture was extracted by adding 50 mι of 2N hydrochloric acid solution and 200 mι of ethyl acetate. The organic layer was washed with water (100 mι×2), saturated sodium bicarbonate solution (100 mι) and saturated sodium thiosulfate (100 mι), it was dried by adding magnesium sulfate and was then filtered, and thereafter concentrated under a reduced pressure. The residual matter was purified by chromatography using silica gel, and the solvent of the fraction obtained from hexane:ether=7:3 eluent was distilled off. A colorless oily substance was thus obtained, i.e., methyl (1S, 4aS, 7aS)-1-[1-(ethoxy)ethoxy]-7-(methoxymethyl)-1, 4a, 5, 7a-tetrahydrocyclopenta[c]pyran-4-carboxylate (1.71 g, yield=81.8%). This methyl (1S, 4aS, 7aS)-1-[1-(ethoxy)ethoxy]-7-(methoxymethyl)-1, 4a, 5, 7a-tetrahydrocyclopenta[ c]pyran-4-carboxylate had the following physicochemical properties:
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([C:10](=[S:13])[NH:11][N:12]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C[O-].[Na+]>CO.O>[F:1][C:2]1[C:3]2[N:12]([NH:11][C:10](=[S:13])[N:4]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(F)c2n[nH]c(=S)n12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ncc(F)c2nc(=S)[nH]n12
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A mixture of 10.01 g (0.050 mol) of 8-fluoro-5-methoxy-1,2,4-triazolo[4,3-c]pyrimidine-3(2H)-thione in 8.6 g of methanol was prepared and cooled with an ice water bath. Sodium methoxide in methanol (32.4 g of 25 percent, 0.15 mol) was added under nitrogen with stirring and cooling. After 2.5 hours, 25.6 mL of ice cold 6.25N aqueous hydrochloric acid was added with stirring to the thick slurry obtained. The resulting mixture was diluted with a little water and the solids were recovered by vacuum filtration and dried under reduced pressure to obtain 8.26 g (83 percent of theory) of the title compound as a colorless powder. The compound melts at 155°-160° C. and then resolidifies and does not remelt up to 230° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:9][CH2:10][N:11]1[CH2:30][CH2:29][C:14]2([NH:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=3)[C:15]2=[O:28])[CH2:13][CH2:12]1)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O.[OH-].[Na+]>>[NH2:7][C@H:8]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][C:14]2([NH:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=3)[C:15]2=[O:28])[CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCN1CCC2(CC1)NC(=O)N(Cc1ccc(Br)cc1)C2=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CCN1CCC2(CC1)NC(=O)N(Cc1ccc(Br)cc1)C2=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.9 %

Procedure:
To 116 mg (0.2 mmol) of {3-[3-(4-bromobenzyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-yl]-1-(S)-phenylpropyl}-carbamic acid tert-butyl ester were added 2 mL of a solution DCM/TFA 20%. The reaction mixture was agitated one hour at room temperature before neutralizing with 1.8 mL of a 10% aqueous solution of sodium hydroxide. Then the solution was extracted with DCM, dried over sodium sulfate, filtered and evaporated in vacuo yielding Compound 5 as a white solid (97 mg, 100%).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][CH:19](O)[CH3:20])[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:29]1[C:30]([CH:38]([CH3:40])[CH3:39])=[CH:31][C:32]2[N:33]([N:35]=[CH:36][N:37]=2)[N:34]=1.[O:41]1CCCC1>>[C:22]1([CH:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:41][C:29]3[C:30]([CH:38]([CH3:40])[CH3:39])=[CH:31][C:32]4[N:33]([N:35]=[CH:36][N:37]=4)[N:34]=3)[CH2:14][CH2:15]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)c1cc2ncnn2nc1Cl
Reactant: CC(O)OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)c1cc2ncnn2nc1OCCOCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C

Procedure:
160 mg of 60% sodium hydride in oil was suspended in 20 ml of tetrahydrofuran; 1.20 g of [2-[4-(diphenylmethyl)-1-piperazinyl]ethoxy]ethanol was added, followed by heating and refluxing for 1 hour. After cooling, 610 mg of 6-chloro-7-isopropyl[1,2,4]triazolo[1,5-b]pyridazine was added, followed by heating and refluxing for 1 hour. After cooling, ice water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol (10:1). The desired fraction was collected; the crystal precipitated was collected by filtration, washed with ethyl ether and dried to yield 790 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][C:15](=[CH2:18])[CH:16]=[O:17].[NH4+].[Cl-]>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:16]([OH:17])[C:15]([CH3:18])=[CH2:14])=[CH:3][CH:4]=1
Reactant: C=C(C)C=O
Reactant: Brc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C(C)C(O)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of 1,4-dibromobenzene 1 (42.4 mmol, 10 g) in THF (60 mL) was added butyl lithium(42.4 mmol, 2.5 M in hexane). The mixture was stirred at −78° C. for 1 h. 2-methylpropenal (42.4 mmol, 2.97 g) was added. The mixture was stirred at −78° C. for 1 h. NH4Cl was added. The mixture was extracted with EtOAc. The organic extract was washed with brine, dried and concentrated to an oil. Chromatography (5-15% EtOAc/hexane) gave the desired alcohol.