Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[N:25][CH:26]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.[CH2:50]([N:57]1[CH2:61][C@H:60]([C:62]2[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=2)[C@@H:59]([C@H:69](O)[CH3:70])[CH2:58]1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C1COCC1>[CH2:50]([N:57]1[CH2:61][C@H:60]([C:62]2[CH:63]=[CH:64][C:65]([F:68])=[CH:66][CH:67]=2)[C@@H:59]([C@@H:69]([O:27][C:24]2[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][N:25]=2)[CH3:70])[CH2:58]1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: Oc1ccc(Cl)cn1
Reactant: C[C@@H](O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)cc1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)cc1
Temperature: 25 °C
Yield: 73 %

Procedure:
To a suspension of PPh3 (PPh3 polymer bound, 3 mmol PPh3/g resin) (0.36 g, 1.1 mmol) in THF (40 mL) at 0° C. were added 5-chloro-pyridin-2-ol (97 mg, 0.75 mmol) and then DBAD (0.18 g, 0.80 mmol). After 5 minutes was added (R)-1-[(3R,4S)-1-benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethanol (0.15 g, 0.50 mmol). The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc/aq.NaOH 1M, followed by column chromatography (SiO2, EtOAc/H, 1:3) yielded 0.15 g (73%) of the title compound as a colorless oil. ES-MS m/e: 411.2 (M+H+).
Reaction SMILES: [CH:1]1([NH:7][CH:8](O)[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:23]([Cl:25])=[O:24].C(OCC)(=[O:35])C>>[CH3:9][CH2:8][N:7]([C:21]1[C:20]([O:19][CH3:18])=[C:28]([O:29][CH3:30])[C:27]([O:31][CH3:32])=[CH:26][C:22]=1[C:23]([O-:35])=[O:24])[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:25]
Reactant: CCOC(C)=O
Reactant: CC(O)NC1CCCCC1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: CCN(CC)CC
Product: CCN(c1c(C(=O)[O-])cc(OC)c(OC)c1OC)C1CCCCC1
Product: Cl

Procedure:
2.86 g. of cyclohexylamino ethanol and 2.02 g. of triethyl amine are dissolved in 30 ml. of anhydrous ethyl acetate. A solution of 4.6 g. of 3,4,5-trimethoxybenzoyl-chloride and 20 ml. of anhydrous ethyl acetate are added under stirring and boiling. The reaction mixture is refluxed for 2 hours, whereafter it is cooled and the precipitate is filtered off by suction and washed with ethyl acetate. The ethyl acetate solution is saturated with gaseous hydrochloric acid. The mixture is refluxed for an hour. On cooling white crystals precipitate. Thus N-2-ethyl-cyclohexylamino-3,4,5-trimethoxy-benzoate-hyrochloride is obtained. M.p.: 209° - 210° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:24])[N:11]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=[N:13]2)=[CH:8][C:7]=1[O:25][CH3:26].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:26][O:25][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:31]1[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]1)[N:13]=[CH:12][N:11]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]2=[O:24]
Reactant: CN1CCNCC1
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCCl
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCN1CCN(C)CC1
Yield: 92 %

Procedure:
A solution of 7-(3-chloropropoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (3 g, 7.84 mmol) in 1-methylpiperazine (30 ml) was heated at 100° C. for 1 hour. After cooling, the mixture was partitioned between saturated ammonium chloride and methylene chloride. The organic layer was washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5 followed by 90/10). The volatiles were removed by evaporation to give 6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (3.24 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH:9]([CH2:11][OH:12])[O:10][C:6]=2[C:5]([N+:13]([O-:15])=[O:14])=[CH:4][C:3]=1[CH3:16].[CH3:17]CCCCC>O1CCCC1>[Cl:1][C:2]1[C:7]2[CH2:8][CH:9]([CH2:11][O:12][CH3:17])[O:10][C:6]=2[C:5]([N+:13]([O-:15])=[O:14])=[CH:4][C:3]=1[CH3:16]
Reactant: Cc1cc([N+](=O)[O-])c2c(c1Cl)CC(CO)O2
Reactant: CCCCCC
Solvent: C1CCOC1
Product: COCC1Cc2c(Cl)c(C)cc([N+](=O)[O-])c2O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of the 7C in 200 ml of tetrahydrofuran (THF) was added slowly drop-by-drop to a stirred mixture of 5.7 g of freshly hexane-washed sodium hydride in 100 ml of THF, under nitrogen, at 25°-28° C. After gas ceased to envolve, 42.6 g of methyl iodide was added drop-by-drop over 5 minutes. The mixture was stirred for 18 hours at room temperature, mixed with ice water, and the resulting mixture was extracted with methylene chloride. The extract was washed with cold water, dried (MgSO4) and the solvent was evaporated. The residue was chromatographed over silica gel, using a 1:24 mixture of THF and hexane as eluent. The first fraction that was collected was recrystallized from ether to give 4-chloro-2,3-dihydro-2-(methoxymethyl)-5-methyl-7-nitrobenzofuran (7D), as a tan solid, m.p.: 117°-119° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.O>C(Cl)Cl>[C:8]1([CH2:7][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: c1c[nH]cn1
Reactant: ClCc1cccc2ccccc12
Solvent: O
Solvent: ClCCl
Product: c1ccc2c(Cn3ccnc3)cccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
A mixture of imidazole (15.4 g) and 1-chloromethyl-naphthalene (14.9 ml, 0.1 mol) in 200 ml of methylene chloride was stirred at room temperature overnight. The mixture was stirred with 200 ml of water, the layers were separated, the organic layer was washed with water (2×200 ml), the resulting solids were removed by filtration and then the organic layer was stirred with 30 ml of conc. HCl and 200 ml of water. The methylene chloride layer was discarded, and the aqueous layer was extracted with 100 ml of ether. The above aqueous layer was basified with 3N NaOH solution, extracted with methylene chloride, and the organic layer was dried over magnesium sulfate. The above organic solution was concentrated in vacuo to afford 13.58 g of 1-(1-naphthylmethyl)imidazole.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][C@@H:13]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=4[CH3:30])[CH2:19][CH2:18]3)=[O:16])[NH:12][C:11]2=[O:31])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].C([O-])([O-])=O.[Na+].[Na+]>CC(C)=O.C(OCC)(=O)C>[C:1]1([S:7]([N:10]2[CH2:14][C@@H:13]([C:15]([N:17]3[CH2:18][CH2:19][N:20]([C:23]4[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=4[CH3:30])[CH2:21][CH2:22]3)=[O:16])[N:12]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:11]2=[O:31])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(S(=O)(=O)c4ccccc4)C(=O)N3)CC2)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(S(=O)(=O)c4ccccc4)C(=O)N3Cc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-1-benzenesulfonyl-4-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-imidazolidin-2-one (40 mg) in acetone (5 mL) was treated with benzyl bromide (0.02 mL) and potassium carbonate (25 mg). The reaction mixture was stirred at ambient temperature overnight, additional benzyl bromide (0.03 mL) and potassium carbonate (37 mg) were added, and the mixture was heated to 70° C. for 5 h. After cooling to room temperature, ethyl acetate and a diluted aqueous solution of Na2CO3 were added. The phases were separated and the inorganic one was extracted with ethyl acetate. The combined organic phases were washed with brine, dried (Na2SO4) and evaporated. Purification by column chromatography (SiO2, n-heptane/ethyl acetate 3:1 to 1:1) yielded (S)-1-benzenesulfonyl-3-benzyl-4-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-imidazolidin-2-one (41 mg) as a white solid. MS: 533.3 ([M+H]+)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][N:29]=3)[C:23]([O:25]C)=[O:24])=[CH:18][N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CC(O)=O.CCOC(C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][N:29]=3)[C:23]([OH:25])=[O:24])=[CH:18][N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccnc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)c1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccnc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)c1
Yield: 21.1 %

Procedure:
The title compound was prepared from methyl 2-(2-(7-phenylheptanoyl)oxazol-5-yl)isonicotinate (12 mg, 0.025 mmol) following General Procedure E. Preparative thin layer chromatography (2% AcOH/EtOAc) yielded the title compound as a white solid (2 mg, 17%): 1H NMR (CDCl3, 600 MHz) 8.85 (d, 1H, J=4.2 Hz), 8.42 (s, 1H), 7.93-7.90 (m, 2H), 7.26-7.30 (m, 2H), 7.17-7.16 (m, 3H), 3.12 (t, 2H, J=7.5 Hz), 2.61 (t, 2H, J=7.6 Hz), 1.79 (quint, 2H, J=7.4 Hz), 1.65 (quint, 2H, J=7.5 Hz), 1.44-1.40 (m, 4H); MALDI-FTMS m/z 377.1523 (M−H−, C22H21N2O4, requires 377.1507).
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N:18]1CCC[N:22]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]=12.C(#[N:31])C>>[N:18]1([O:1][C:2]2[C:3]3[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=2[N:22]=[N:31]1
Reactant: CC#N
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(C)(C)OC(=O)N1Cc2ncnc(O)c2C1
Product: CC(C)(C)OC(=O)N1Cc2ncnc(On3nnc4ccccc43)c2C1
Reaction time: 1.5 h

Procedure:
tert-Butyl 4-hydroxy-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (300 mg, 1.264 mmol) and (1H-benzo[d][1,2,3]triazol-1-yloxy)tris(dimethylamino)-0phosphonium hexafluorophosphate(V) (671 mg, 1.517 mmol) were stirred in acetonitrile (10 mL). To the slurry was added 2,3,4,6,7,8,9,10-octahydropyrimido-[1,2-a]azepine (289 mg, 1.897 mmol). The reaction mixture was stirred 1.5 hours. The solvents were removed in vacuo to afford tert-butyl 4-(1H-benzo[d][1,2,3]triazol-1-yloxy)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate which was carried on to the next step without further purification.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:49][CH:50]1[C@H:54]2[C@H:55](OC3CCCCO3)[N:56](C(OC(C)(C)C)=O)[C:57]3[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:58]=3[C:59](=[O:60])[N:53]2[CH2:52][CH2:51]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]1[C@H:22]2[C@H:23](OC3CCCCO3)[N:24](C(OC(C)(C)C)=O)[C:25]3[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:26]=3[C:27](=[O:28])[N:21]2[CH2:20][CH2:19]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:16]([O:17][CH:18]1[C@@H:22]2[CH:23]=[N:24][C:25]3[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:26]=3[C:27](=[O:28])[N:21]2[CH2:20][CH2:19]1)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:49][CH:50]1[C@@H:54]2[CH:55]=[N:56][C:57]3[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:58]=3[C:59](=[O:60])[N:53]2[CH2:52][CH2:51]1
Reactant: COc1ccc2c(c1)N(C(=O)OC(C)(C)C)[C@@H](OC1CCCCO1)[C@@H]1C(OCCCCCCCCCOC3CCN4C(=O)c5ccc(OC)cc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)CCN1C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)N=C[C@H]1C(OCCCCCCCCCOC3CCN4C(=O)c5ccc(OC)cc5N=C[C@@H]34)CCN1C2=O
Reaction time: 1 h
Yield: 83.3 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 8g (170 mg, 0.18 mmol) at 0° C. This was then stirred for 1 hr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 9g (93 mg, 0.15 mmol, 88%) as a solid: [α]20D=+547° (c=0.13, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.31-1.53 (m, 10H, 14-H, 14′-H, 15-H, 15′-H, 16-H), 1.83-1.94 (m, 4H, 13-H, 13′-H), 2.00-2.12 (m, 4H, 2-H, 2′-H), 2.27-2.38 (m, 4H, 1-H, 1′-H), 3.54-3.64 (m, 2H, 3-H, 3′-H), 3.69-3.78 (m, 2H, 11a-H, 11a′-H), 3.79-3.87 (m, 2H, 3-H, 3′-H), 3.92 (s, 6H, 7-OMe, 7′-OMe), 4.01-4.19 (m, 4H, 12-H, 12′-H), 6.81 (s, 2H, 9-H, 9′-H), 7.52 (s, 2H, 6-H, 6′-H), 7.67 (d, 2H, J=4, 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 24.1, 25.9, 29.0, 29.3, 29.4, 29.6, 46.6, 53.7, 56.0, 69.1, 109.6, 112.5, 120.2, 140.5, 147.1, 151.6, 162.2, 164.6; IR (neat): 3325, 2933, 1600, 1507, 1448, 1388, 1261, 1217, 1092, 1024 cm−1; MS (FAB) m/z (relative intensity) 617 (M+., 100), 635 (10), 785 (6).
Reaction SMILES: [CH:1]([C@:4]1([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2].[CH3:28][CH:29]1[C:34](=O)[CH2:33][CH2:32][O:31][CH2:30]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:1]([C@:4]1([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:34]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[CH3:28])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC1COCCC1=O
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)cyclopentanamine (80 mg, 0.2 mmol), 3-methyltetrahydro-4H-pyran-4-one (71 mg, 0.62 mmol) and triethylamine (0.12 mL, 0.83 mmol) in dichloromethane (10 mL) was added sodium triacetoxyborohydride (130 mg, 0.62 mmol). After being stirred at room temperature overnight, the solution was diluted with dichloromethane. The resulting solution was washed with NaHCO3 and brine, dried over MgSO4 and concentrated. The residue was purified on silica gel to give the desired product which was further separated by chiral HPLC affording four isomers. MS calculated for C26H38F3N3O2: (M+H) 482; found 482.2 for four isomers.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:34][CH2:33][C@:7]2([O:11][CH2:10][C@H:9]([C:12]3[CH:17]=[C:16]([C:18]4[C:19]([CH3:30])=[N:20][N:21](C(OC(C)(C)C)=O)[CH:22]=4)[CH:15]=[CH:14][C:13]=3[O:31][CH3:32])[CH2:8]2)[C@@H:6]1[C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)=[O:4].FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3]([C@H:5]1[CH2:34][CH2:33][C@:7]2([O:11][CH2:10][C@H:9]([C:12]3[CH:17]=[C:16]([C:18]4[C:19]([CH3:30])=[N:20][NH:21][CH:22]=4)[CH:15]=[CH:14][C:13]=3[O:31][CH3:32])[CH2:8]2)[C@@H:6]1[C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@@]2(C[C@@H](c3cc(-c4cn(C(=O)OC(C)(C)C)nc4C)ccc3OC)CO2)[C@@H]1c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)[C@H]1CC[C@@]2(C[C@@H](c3cc(-c4c[nH]nc4C)ccc3OC)CO2)[C@@H]1c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
A solution of (3S,5R,6S,7S)-6-(4-fluorophenyl)-3-(2-methoxy-5-(1-(tert-butoxycarbonyl)-3-methylpyrazol-4-yl)phenyl)-1-oxaspiro[4.4]nonane-7-carboxylic acid methyl ester (12 mg, 0.021 mmol) in 2.0 mL of dichloromethane was stirred at 0° C. and 2.0 mL of trifluoroacetic acid was added. After the solution had been stirred at 0° C. for 1.5 h, toluene (5 mL) was added and the solvent was evaporated at reduced pressure. The residue was purified by flash column chormatogrpahy on 1 g of silica gel, eluting with 25% ethyl acetate in dichloromethane to give 8 mg of colorless film (80% yield). 1H NMR (400 MHz, CDCl3): δ 7.60 (bs, 1H), 7.29 (dd, 2H, J=9, 6 Hz), 7.22 (dd, 1H, J=8, 2 Hz), 6.91 (d, 1H, J=8 Hz), 6.89 (t,,2H, J=9 Hz), 6.86 (d, 1H, J=2 Hz), 6.21 (t, 1H, J=2 Hz), 4.77 (dd, 1H, J=12, 2 Hz), 4.10 (dd, 1H, J=12, 2 Hz), 3.85 (s, 3H), 3.59 (s, 3H), 3.47 (dt, 1H, J=11, 8 Hz), 3.22 (d, 1H, J=11 Hz), 2.43-2.22 (m, 2H), 2.40 (s, 3H), 2.15-1.94 (m, 2H). Mass spectrum (NH3CI): m/e=436 M+1.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.N1C=CC=C[CH:17]=1.C(O[C:30]1[CH:39]=[C:38]2[C:33]([C:34](=[S:40])[NH:35][CH:36]=[N:37]2)=[CH:32][CH:31]=1)C1C=CC=CC=1.Cl>C(Cl)Cl>[CH3:17][S:40][C:34]1[C:33]2[C:38](=[CH:39][C:30]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])=[CH:31][CH:32]=2)[N:37]=[CH:36][N:35]=1
Reactant: S=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Reactant: c1ccncc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Product: CSc1ncnc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Yield: 47.3 %

Procedure:
Trifluoromethane sulfonic anhydride (0.96 ml, 5.73 mmol) and pyridine (0.46 ml, 5.73 mmol) were added to a solution of 7-benzyloxy-3,4-dihydroquinazolin-4-thione (1.0 g, 5.21 mmol) in methylene chloride (20 ml) at 0° C. for 1.5 hour. Hydrochloric acid (0.5 N) was then added to the mixture which was extracted with ethyl acetate. The organic phase was washed brine, dried over magnesium sulphate and the solvents were removed in vacuo. Purification by flash chromatography on silica gel, eluting with isohexane/ethyl acetate (1:4) yielded 4-(methylthio)-7-(trifluoromethanesulphonyloxy)quinazoline (800 mg, 50% yield):
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[O:14][CH3:15].CN(C=O)C.[N-:28]=[N+:29]=[N-:30].[Na+]>>[N:28]([CH2:3][C:4]1[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[O:14][CH3:15])=[N+:29]=[N-:30]
Reactant: COc1cccc2cc(CCl)c(-c3cccc(F)c3)nc12
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2cc(CN=[N+]=[N-])c(-c3cccc(F)c3)nc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 3-(chloromethyl)-2-(3-fluorophenyl)-8-methoxyquinoline hydrochloride (0.9601 g, 2.839 mmol) in DMF (14.19 mL, 2.839 mmol) was added sodium azide (0.3691 g, 5.678 mmol) at room temperature and the mixture was stirred at room temperature After 1 h, the mixture was partitioned between EtOAc (100 mL) and H2O (100 mL). The organic layer was washed with brine (100 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 3-(azidomethyl)-2-(3-fluorophenyl)-8-methoxyquinoline as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.48 (1 H, s), 7.54-7.62 (3 H, m), 7.43-7.49 (2 H, m), 7.32-7.39 (1 H, m), 7.21-7.28 (1 H, m), 4.68 (2 H, s), 3.97 (3 H, s); LC-MS (ESI) m/z 309.1 [M+H]+. The yellow solid was carried on crude without purification for the next step.
Reaction SMILES: [CH2:1]([O:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:9]([O-])=[CH:8][C:7]=2[N:6]=[CH:5]1)[CH3:2].ClC(Cl)(Cl)C([N:22]=C=O)=O.CO>ClCCl>[CH2:1]([O:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:22])[C:7]=2[N:6]=[CH:5]1)[CH3:2]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CCOn1cnc2c[n+]([O-])c3ccccc3c21
Solvent: CO
Solvent: ClCCl
Product: CCOn1cnc2c(N)nc3ccccc3c21
Temperature: 0 °C
Yield: 22.5 %

Procedure:
A solution of 1-ethoxy-5-oxido-1H-imidazo[4,5-c]quinoline (2.4 g, 10.5 mmol) in dichloromethane (75 mL) was cooled to 0° C., and trichloroacetyl isocyanate (1.9 mL, 16 mmol) was added. The reaction was stirred for ten minutes at 0° C. and then stirred overnight at room temperature. Methanol (15 mL) was added, and the mixture was stirred for 15 minutes and concentrated under reduced pressure. The residue was dissolved in methanol (15 mL), and sodium methoxide (0.5 mL of a 25% w/w solution in methanol) was added. The mixture was stirred at room temperature for three hours and concentrated under reduced pressure. The residue was stirred with methanol (15 mL) and water (15 mL), and a solid formed. The solid was collected by filtration, recrystallized from methanol/water, and purified by column chromatography on silica gel (eluting with 5% methanol in dichloromethane containing 2 mL of aqueous ammonium hydroxide per liter of eluent). The resulting solid was recrystallized from methanol/water and dried overnight under vacuum to provide 0.54 g of 1-ethoxy-1H-imidazo[4,5-c]quinolin-4-amine as brown crystals, mp 179-181° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6]>C(Cl)Cl.CCOCC>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: OCc1cccc(I)c1
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1cccc(I)c1

Procedure:
Commercially available 3-iodobenzyl alcohol (5.32 mL, 41.9 mmol) was dissolved in 200 mL CH2Cl2. Upon completion, the reaction was diluted with 250 mL Et2O. The product was recovered as off-white crystals (8.1 g, 83.4%) mp: 48.0–55.0° C. TLC: Rf0.54 (3:1 hexanes/EtOAc). IR (neat): 3058, 2824, 2728, 1698, 1586, 1566. 1H-NMR (400 MHz, CDCl3): δ 9.93 (s, 1H, C1-H), 8.22 (t, 1H, J=1.6, C3-H), 7.96 (dt, 1H, J=7.7, 1.4, C5-H), 7.85 (dt, 1H, J=7.7, 1.3, C7-H), 7.29 (t, 1H, J=7.7, C6-H). 13C-NMR (125 MHz, CDCl3): δ 190.6, 143.1, 138.4, 138.0, 130.7, 128.8, 94.6. EI-MS m/z (rel int): 232 (M+, 100), 231 ([M−H]+, 25), 203 ([M−CHO]+, 14), 104 ([M−HI]+, 38).
Reaction SMILES: [C:1]([C:8]1[C:14]([OH:15])=[C:13]([C:16](C(C)C)=[CH2:17])[C:12]([OH:21])=[CH:11][C:9]=1[OH:10])(=[O:7])[CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5].F[C:23](F)(F)[C:24]([OH:26])=O.[CH:29]1C=CC=CC=1>>[OH:21][C:12]1[CH:11]=[C:9]([OH:10])[C:8]([C:1](=[O:7])[CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5])=[C:14]2[C:13]=1[CH2:16][CH2:17][C:24]([CH3:23])([CH3:29])[O:26]2.[OH:15][C:14]1[C:8]([C:1](=[O:7])[CH2:2][CH2:3][CH:4]([CH3:5])[CH3:6])=[C:9]([OH:10])[CH:11]=[C:12]2[C:13]=1[CH2:16][CH2:17][C:24]([CH3:23])([CH3:29])[O:26]2
Reactant: C=C(c1c(O)cc(O)c(C(=O)CCC(C)C)c1O)C(C)C
Reactant: O=C(O)C(F)(F)F
Reactant: c1ccccc1
Product: CC(C)CCC(=O)c1c(O)cc(O)c2c1OC(C)(C)CC2
Product: CC(C)CCC(=O)c1c(O)cc2c(c1O)CCC(C)(C)O2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2-Isocaproyl-4-(3-methylbuten-2-yl)phloroglucinol (7 (2 g) was suspended in benzene (25 ml). Trifluoro acetic acid (1.5 ml) was added and the mixture was stirred for 6 hours at room temperature. The resulting solution was stripped to dryness under vacuum. The residue was chromatographed, preferably on silica gel (open column chromatography, preparative HPLC or preparative TLC) using preferably mixtures of benzene and ethyl acetate or petroleum ether and ethyl acetate for eluation. Two chromanes, namely 5,7-dihydroxy-2,2-dimethyl-8-isocaproyl chroman (31 and 5,7 -dihydroxy-2,2-dimethyl-6-isocaproyl chroman (33, were obtained in a ratio of about 3 to 2. These chromanes were both recrystallized from petroleum ether to give light straw coloured crystals.