Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([Sn](CCCC)(CCCC)CCCC)[CH:6]=[CH:5][N:4]=1.[C:22]([O:26][C:27](=[O:40])[N:28]([C:30]1[C:31]2[N:32]([C:36](Br)=[CH:37][N:38]=2)[CH:33]=[CH:34][N:35]=1)[CH3:29])([CH3:25])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:22]([O:26][C:27](=[O:40])[N:28]([CH3:29])[C:30]1[C:31]2[N:32]([C:36]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=3)=[CH:37][N:38]=2)[CH:33]=[CH:34][N:35]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Reactant: CN(C(=O)OC(C)(C)C)c1nccn2c(Br)cnc12
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CSc1nccc(-c2cnc3c(N(C)C(=O)OC(C)(C)C)nccn23)n1
Temperature: 25 °C

Procedure:
2-Methylsulfanyl-4-tributylstannanyl-pyrimidine (19.1 g, 46.0 mmol) was stirred in degassed toluene (achieved by bubbling nitrogen though solvent for 2 hours) (200 mL) under nitrogen, then (3-bromo-imidazo[1,2-a]pyrazin-8-yl)-methyl-carbamic acid tert-butyl ester (13.1 g, 40.0 mmol) (from Example 7 supra) was added followed by bis(triphenylphosphine)palladium (II) chloride (1.12 g, 1.60 mmol) and the reaction was heated at reflux. The reaction was cooled to room temperature and concentrated to dryness. The residue was purified by column chromatography on silica gel (petroleum ether to EtOAc, TLC Rf=0.17, 20% EtOAc in petroleum ether) and then triturated with DIPE to give methyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamic acid tert-butyl ester. (Yield 8.00 g, 54%).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:11][OH:12].C(=O)([O-])[O-].[Na+].[Na+].O>CO>[OH:12][NH:11][C:8](=[NH:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: N#CCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N=C(Cc1ccccc1)NO
Temperature: 25 °C

Procedure:
Phenyl acetonitrile (20 g, 170 mmol), hydroxylamine hydrochloride (60 g, 850 mmol) and sodium carbonate (71 g, 850 mmol) were heated under reflux in methanol (300 ml) and water (300 ml) for 5 hours. The reaction mixture was cooled to room temperature, filtered and the filtrate was evaporated and extracted with dichloromethane (3×). The combined organic solutions were washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure to give the title compound as a white solid, 15.5 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[N:5]([C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)C(OC(C)(C)C)=O.[ClH:27].CCOCC>C(Cl)Cl>[ClH:27].[CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1
Reactant: COC(=O)[C@H](CCSC)N(C(=O)OC(C)(C)C)C(=O)c1ccc(N)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1
Reaction time: 8 h

Procedure:
N-BOC-4-aminobenzoyl methionine methyl ester (3.53 g, 9.59 mmol) was placed into CH2Cl2 (30-35 ml) and to it was added 3M HCl/ Et2O (38.4 ml). After standing a white precipitate formed. After 2 hours the solution was decanted, and the crystals were collected by centrifugation. The crystals were then washed several times with fresh ether and dried overnight on the vacuum pump. Meanwhile, the filtrate was left to stand overnight to allow additional product to precipitate. The second fraction was washed with ether and dried overnight on the vacuum pump. The total yield of pure fully deprotected material was 2.87 g (93.9%) yield. mp 158-164° C.; 1H NMR (CDCl3) 2.10 (3H, s), 2.12-2.29 (1H, m), 2.52-2.71 (1H, m), 2.59 (2H, t, J=7.6 Hz), 3.75 (3H, s), 4.79 (1H, m), 7.02 (2H, d, J=8.6 Hz), 7.55 (2H, d, J=8.6 Hz); 13C NMR (CDCl3) 15.23, 31.43, 31.53, 52.91, 52.43, 124.35, 130.56, 135.31, 135.76, 168.95, 173.87; HRMS calc. for C13H18N2O3S, 282.1038, found 282.1009.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH2:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:27]1[N:32]=[C:31]([CH3:33])[N:30]=[C:29]([C:34]#[N:35])[CH:28]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH:19][C:27]3[N:32]=[C:31]([CH3:33])[N:30]=[C:29]([C:34]#[N:35])[CH:28]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: NCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Reactant: Cc1nc(Cl)cc(C#N)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C#N)cc(NCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-{(1S,2S)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanamine (29 mg, 0.10 mmol) from step 3 of this example was dissolved in DMF (0.4 mL), cesium carbonate (168 mg, 0.52 mmol) was added, stirred at room temperature for 10 minutes, then cooled down to 0° C. 6-chloro-2-methylpyrimidine-4-carbonitrile (17.5 mg, 0.114 mmol; from step 4 of this example) was added in DMF (0.1 mL) via syringe. Reaction was kept at 0° C. for 30 minutes, then warmed up to room temperature for 1 hour. Water (50 mL) was added, extracted with EtOAc (50 mL×2), second wash with Brine (20 mL). The combined organic phase was dried by magnesium sulfate, filter, concentrated and purified by column chromatography through a 40 gram RediSep Rf™ silica gel cartridge eluting with 17% acetone/hexanes to give the title compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26](I)[CH:25]=3)[C:5]2=[CH:4][CH:3]=1.C[Si]([C:36]#[CH:37])(C)C.C(N(CC)CC)C>O1CCCC1.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:36]#[CH:37])[CH:25]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cccc(I)c2)N1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#Cc1cccc(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
A solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-iodophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.56 g, 1 mmol) prepared in example 192b in anhydrous tetrahydrofuran (30 mL) was added trimethylsilyl acetylene (0.1 g, 2.0 mmol) (Aldrich), CuI (0.38 g, 2.0 mmol) (Aldrich) and triethylamine (0.2 g, 2.0 mmol) was degassed under nitrogen for 5 min, then dichlorobis(triphenylphosphine)palladium(0) (140 mg, 0.2 mmol) (Strem) was added and the reaction mixture was heated at 100° C. under nitrogen for 3 h. The reaction mixture was cooled to room temperature and filtered through a short pad of silica gel, the silica gel was washed with ethyl acetate. The filtrate was concentrated. To the residue was added methanol (10 mL) and aqueous NaOH solution (1 N, 2 mL). The mixture was stirred at room temperature for 2 h, then partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4 and concentrated. The residue was purified with chromatography (EtOAc:hexanes=2:1) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-ethynyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 0.24 g, 52%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19]>CC#N>[CH2:19]([O:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[Br:1])[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: COc1ccc(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1cc(OC)ccc1Br
Temperature: 25 °C
Yield: 111 %

Procedure:
To a solution of 4-bromo-3-hydroxyanisol (14.49, 59.3 mmol), synthesized by known methods, in CH3CN (200 ml), dry potassium carbonate (20 g) and allylbromide (8.0 ml, 92.4 mmol) was added. The reaction mixture was stirred and refluxed for 1 hour and thereafter cooled to room temperature, filtered and evaporated. The residue was dissolved in ether and extracted with water. The organic layer was separated and dried (Na2SO4). Evaporation of the solvent afforded 16.0 g (93%) of 3-allyloxy-4-bromoanisol as an oil. GC/MS (HP-5970A) m/e=244 (40) M+ and M+ -1 at m/e=242 (40), 163 (100), 149 (97), 135 (62).
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][Cl:22].O>C(#N)C>[Cl:22][CH2:21][CH2:20][CH2:19][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:2]([CH3:1])[C:3]1=[O:11]
Reactant: ClCCCBr
Reactant: CC1C(=O)Nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC1C(=O)N(CCCCl)c2ccccc21
Yield: 15.1 %

Procedure:
To a mixture of 3-methylindolin-2-one (1 g, 6.79 mmol, 1 equiv) in acetonitrile, potassium carbonate (1.877 g, 13.58 mmol, 2.5 equiv) followed by 1-bromo-3-chloropropane (2.01 ml, 20.38 mmol, 3 equiv) were added. The reaction was refluxed for 16 h. Upon cooling water was added and the mixture was extracted into ethyl acetate. The organic layer was further washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified using the Biotage flash chromatography system (SNAP 100 g cartridge, Rf=0.5, gradient—2%-20% ethyl acetate in hexanes) to afford the title compound as a yellow oil (230 mg, 15%); 1H NMR (400 MHz, DMSO-d6): δ 1.31 (d, 3H, J=7.6 Hz); 1.99-2.05 (m, 2H); 3.47-3.53 (m, 1H); 3.66 (t, 2H, J=6.4 Hz); 3.74-3.82 (m, 2H); 7.04 (d, 2H; J=7.6 Hz); 7.24-7.27 (m, 1H); 7.3-7.32 (m, 1H); MS for C12H14ClNO m/z 211.06 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10].[NH2:17][C:18]1[C:27]2[N:28]=[C:29]([CH2:34][O:35][CH2:36][CH3:37])[N:30]([CH2:31][CH2:32][CH3:33])[C:26]=2[C:25]2[CH:24]=[C:23]([OH:38])[CH:22]=[CH:21][C:20]=2[N:19]=1.CN(C=O)C>O>[CH2:36]([O:35][CH2:34][C:29]1[N:30]([CH2:31][CH2:32][CH3:33])[C:26]2[C:25]3[CH:24]=[C:23]([O:38][CH2:8][C:9]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[O:10])[CH:22]=[CH:21][C:20]=3[N:19]=[C:18]([NH2:17])[C:27]=2[N:28]=1)[CH3:37]
Reactant: CCCn1c(COCC)nc2c(N)nc3ccc(O)cc3c21
Reactant: O=C(CBr)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OCC(=O)N4CCOCC4)cc3c21
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
Cesium carbonate (1.62 g, 5.00 mmol) was added to a solution of 2-bromo-1-morpholin-4-yl-ethanone (414 mg, 1.99 mmol), 4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol (500 mg, 1.66 mmol), and anhydrous DMF (20 mL). The reaction mixture was heated at 75° C. overnight, allowed to cool, and poured into deionized water (300 mL). The resulting mixture was stirred for 30 minutes and then extracted with chloroform (3×100 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was purified by chromatography on a HORIZON HPFC system (silica cartridge, eluting with a gradient of 0-35% methanol/dichloromethane (10:90) in dichloromethane). The resulting solid was recrystallized from acetonitrile to yield 333 mg of 2-(ethoxymethyl)-8-(2-morpholin-4-yl-2-oxoethoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid, mp 196-197° C. Anal. calcd for C22H29N5O4: C, 61.81; H, 6.84; N, 16.38. Found: C, 61.72; H, 6.86; N, 16.62.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[NH:23][C:22]2=[O:35])[CH2:17][CH2:16]1.[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Cl)=[CH:39][CH:38]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[N:23]([CH2:41][C:40]3[CH:43]=[CH:44][C:37]([F:36])=[CH:38][CH:39]=3)[C:22]2=[O:35])[CH2:17][CH2:16]1
Reactant: Fc1ccc(CCl)cc1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5cc([N+](=O)[O-])ccc5n(Cc5ccc(F)cc5)c4=O)CC3)c2cc1OC
Yield: 32 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.63 mmol) of Compound 24 was used and 4-fluorobenzyl chloride was used in place of methyl iodide. As a result, 116.9 mg (yield: 32%) of Compound 9 was obtained as pale yellow crystals.
Reaction SMILES: [C:1]([C:4]1[N:8](CC2C=CC(OC)=CC=2)[C:7]([SH:18])=[N:6][N:5]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[C:1]([C:4]1[N:8]=[C:7]([SH:18])[NH:6][N:5]=1)(=[O:3])[NH2:2]
Reactant: COc1ccc(Cn2c(S)nnc2C(N)=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: NC(=O)c1n[nH]c(S)n1
Yield: 99.1 %

Procedure:
3-Carbamoyl-4-(p-methoxybenzyl)-1,2,4-triazole-5-thiol (2.0 g., 0.007 mole), trifluoroacetic acid (8 ml.) and anisole (2 ml.) were heated at 70° C. for 3.5 hours. At this point, most of the trifluoroacetic acid present was removed by means of evaporation under reduced pressure and the residue was subsequently triturated with diethyl ether. The resulting solid was then filtered, washed with diethyl ether and subsequently dired in vacuo at 50° C. to give pure 3-carbamoyl-1,2,4-triazole-5-thiol (1.0 g., 91% yield), m.p. 276°-278° C. The infrared absorption spectrum was identical to that of a reference sample prepared as described in Example XVI, Part C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:26]1([CH2:32][S:33][CH:34]([C:38](O)=[O:39])[C:35](O)=[O:36])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[OH:39][C:38]1[CH:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[O:10][C:35](=[O:36])[C:34]=1[S:33][CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)c1ccccc1C
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cc(O)c(SCc2ccccc2)c(=O)o1

Procedure:
The title compound was prepared by Method A using 2'-methylacetophenone (0.712 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). 1H NMR (400 MHz, DMSO-d6) δ2.34 (s, 3 H), 4.01 (s, 2 H), 6.32 (s, 1 H), 7.32 (m, 9H).
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7]([N+:10]([O-:12])=[O:11])=[C:6]2[NH:13]N=N[N:5]2[C:4]1=[O:16])[CH3:2].C(O)(=O)C>C1(C)C(C)=CC=CC=1>[CH2:1]([N:3]1[C:8](=[O:9])[C:7]2=[N+:10]([O-:12])[O:11][N:13]=[C:6]2[NH:5][C:4]1=[O:16])[CH3:2]
Reactant: CCn1c(=O)c([N+](=O)[O-])c2[nH]nnn2c1=O
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: CCn1c(=O)[nH]c2no[n+]([O-])c2c1=O
Yield: 77 %

Procedure:
20.0 g of 6-ethyl-8-nitrotetrazolo[1,5-c]pyrimidine-5,7(1H,6H)-dione are heated at 120° C. for 7 hours with 200 ml of glacial acetic acid in 2000 ml of xylene. A small undissolved portion is filtered off, the filtrate is concentrated in vacuo and the oily residue is made to crystallise by trituration with methylene chloride. 13.5 g (77%) of 6-ethyl-[1,2,5]oxadiazolo[3,4-d]pyrimidine-5,7(4H,6H)-dione-1-oxide are obtained.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.O[N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.N#N>O>[CH:1]1([O:6][N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: OC1CC=CC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1OC1CC=CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.3 %

Procedure:
To a solution of cyclopent-3-enol (840 mg, 10.0 mmol) in CH2CT2 (25.0 mL) was added 2-hydroxyisoindolin-1,3-dione (1.96 g, 12.0 mmol) and triphenylphosphine (3.93 g, 15.0 mmol). The resultant mixture was cooled to 0° C. and diisopropylazodicarboxylate (2.95 ml, 15.0 mmol) was slowly added drop wise under N2 atmosphere. The reaction mixture was stirred at ambient temperature for 48 h. To the reaction mixture, H2O (100 mL) was added and extracted with CH2Cl2. The organic layers washed with brine. Dried over anhydrous Na2SO4, filtered and concentrated to provide yellow oil, which was purified by flash chromatography (50% EtOAc-hexane) to yield 2-(cyclopent-3-enyloxy)isoindoline-1,3-dione (740 mg, 32%) as light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.57-2.87 (m, 4H) 5.12 (t, J=6.19 Hz, 1H) 5.75 (s, 2H) 7.74 (dd, J=5.68, 3.16 Hz, 2H) 7.79-7.87 (m, 2H). MS (ES) [M+H] calculated for C13H12NO3, 230.07. found 230.20.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[CH:20]=[CH:19][CH:18]=[CH:17][C:5]=1[C:6]([C:8]1[O:12][C:11]([C:13]([O:15]C)=[O:14])=[CH:10][CH:9]=1)=[O:7].[OH-].[Na+]>O.CO>[CH3:3][C:4]1[CH:20]=[CH:19][CH:18]=[CH:17][C:5]=1[C:6]([C:8]1[O:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=1)=[O:7]
Reactant: COC(=O)c1ccc(C(=O)c2ccccc2C)o1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccccc1C(=O)c1ccc(C(=O)O)o1
Reaction time: 1 h
Yield: 96.9 %

Procedure:
A warm solution of potassium hydroxide (28 g.) in water (60 ml.) and methanol (120 ml.) was added to a warm solution of methyl 5-(2-methylbenzoyl)-2-furoate [prepared as described in (c) above; 110 g.] in methanol (550 ml.) and the mixture was allowed to stand at ambient temperature for 1 hour. The solution was then basified by the addition of 2N aqueous sodium hydroxide solution (50 ml.) and allowed to stand at ambient temperature overnight. The alkaline solution thus obtained was evaporated to dryness and the residue was dissolved in water. The aqueous solution was magnetically stirred whilst it was made strongly acid by the addition of concentrated hydrochloric acid. The precipitate was collected and washed with water to give 5-(2-methylbenzoyl)-2-furoic acid (100.5 g.), m.p. 155°-157° C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[NH:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7].[CH:35]1([CH2:38]Br)[CH2:37][CH2:36]1>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[N:13]([CH2:38][CH:35]3[CH2:37][CH2:36]3)[CH2:12]2)[CH2:10][CH2:9]1)=[O:7]
Reactant: Cc1ccccc1N1C(=O)NCC12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Reactant: BrCC1CC1
Product: Cc1ccccc1N1C(=O)N(CC2CC2)CC12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=540.4 (M+H+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-2-one and cyclopropyl methyl bromide.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][C@@H:6]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24][C:25](=[O:45])[C@H:26]([CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:27][C:28]([O:30][CH3:31])=[O:29])[O:5][CH2:4]1.N1C=CC=CC=1.[C:52]1([S:58](Cl)(=[O:60])=[O:59])[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>C(Cl)Cl>[CH3:31][O:30][C:28]([NH:27][C@H:26]([C:25]([NH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][CH2:16][C@H:6]1[O:5][CH2:4][C@@H:3]([CH2:2][NH:1][S:58]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)(=[O:60])=[O:59])[N:8]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:7]1)=[O:45])[CH:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:29]
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CN)CO1)C(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CNS(=O)(=O)c2ccccc2)CO1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl (2R,5R)-5-(aminomethyl)-2-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}phenyl)ethyl]morpholine-4-carboxylate (1 eq.) in DCM (0.1M) were added pyridine (3 eq) and benzene sulfonyl chloride (1.3 eq). The reaction mixture was stirred for 4 hrs at room temperature, diluted with CH2Cl2 and the organic layer was washed with aqueous saturated sodium bicarbonate. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by automated silica gel flash chromatography system eluted with a gradient 10% to 100% of EtOAc/Hex to afford title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7](O)=[O:8])=[C:5]([CH3:10])[N:4]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[N:3]=1.[N:22]1([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:1][C:2]1[C:6]([C:7]([N:30]2[CH2:31][CH2:32][CH:27]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:28][CH2:29]2)=[O:8])=[C:5]([CH3:10])[N:4]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([C:18]([F:19])([F:20])[F:21])[CH:12]=2)[N:3]=1
Reactant: Cc1ccc(-n2nc(C)c(C(=O)O)c2C)cc1C(F)(F)F
Reactant: C1CCN(C2CCNCC2)C1
Product: Cc1ccc(-n2nc(C)c(C(=O)N3CCC(N4CCCC4)CC3)c2C)cc1C(F)(F)F
Yield: 77 %

Procedure:
In analogy to the procedure described in Example 18], 3,5-dimethyl-1-(4-methyl-3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid and 4-pyrrolidine-1-yl-piperidine gave the title compound in 77% yield as orange foam. MS: 435.5 (MH+).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[N:13]=[C:14]([CH2:28][CH2:29][O:30][CH3:31])[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[C:11]=2[C:10]2[CH:9]=[CH:8][C:7]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:6][C:5]=2[N:4]=1.[OH-].[NH4+]>C(O)C.O>[NH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[C:11]2[C:10]3[CH:9]=[CH:8][C:7]([O:32][CH2:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:6][C:5]=3[N:4]=[C:3]([NH2:2])[C:12]=2[N:13]=[C:14]1[CH2:28][CH2:29][O:30][CH3:31]
Reactant: COCCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COCCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CCCCN
Temperature: 70 °C

Procedure:
A solution of hydrochloric acid (9.25 mL of 2 M) in ethanol was added to tert-butyl {4-[4-amino-7-benzyloxy-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamate (2 g, 4 mmol), and the reaction was heated at 70° C. for 5 hours. The reaction was allowed to cool to ambient temperature, and nitrogen gas was bubbled through the solution overnight. The solvent was removed under reduced pressure, and the residue was triturated with diethyl ether to provide a sticky solid, which was dissolved in water and treated with concentrated ammonium hydroxide until pH 11 was achieved. The solution was extracted with dichloromethane several times, and the combined extracts were concentrated under reduced pressure to provide 1-(4-aminobutyl)-7-benzyloxy-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a dark-brown oil.