Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)[CH:5]=[C:4]([C:29]2[C:34]([O:35]CC3C=CC(OC)=CC=3)=[CH:33][CH:32]=[CH:31][C:30]=2[O:45][CH2:46][CH:47]2[CH2:49][CH2:48]2)[N:3]=1.[ClH:50]>O1CCOCC1.C(OCC)(=O)C>[ClH:50].[NH2:1][C:2]1[N:3]=[C:4]([C:29]2[C:30]([O:45][CH2:46][CH:47]3[CH2:49][CH2:48]3)=[CH:31][CH:32]=[CH:33][C:34]=2[OH:35])[CH:5]=[C:6]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[C:7]=1[CH2:8][S:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c(CSc3ccccc3)c(N)n2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1nc(-c2c(O)cccc2OCC2CC2)cc(C2CCCNC2)c1CSc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of tert-butyl 3-{2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-3-[(phenylsulfanyl)methyl]-4-pyridinyl}-1-piperidinecarboxylate in 1,4-dioxane (2 mL) was added 4 N HCl in dioxane (2 mL). The mixture was stirred at room temperature overnight, and diluted with ethyl acetate. The resulting precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give 2-[6-amino-5-[(phenylsulfanyl)methyl]-4-(3-piperidinyl)-2-pyridinyl]-3-(cyclopropylmethoxy)phenol hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)=[C:6](Cl)[N:5]2[N:14]=[CH:15][N:16]=[C:4]2[N:3]=1.[CH:17]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[C:7]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)=[C:6]([NH:22][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:5]2[N:14]=[CH:15][N:16]=[C:4]2[N:3]=1
Reactant: NC1CCCC1
Reactant: Clc1nc2ncnn2c(Cl)c1-c1ccsc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Clc1nc2ncnn2c(NC2CCCC2)c1-c1ccsc1
Yield: 70.4 %

Procedure:
5,7-Dichloro-6-thien-3-yl-1,2,4-triazolo[1,5-a]pyrimidine (0.54 g, 0.002 mol) was dissolved in tetrahydrofuran (20 ml). A mixture of cyclopentylamine (0.2 g, 0.002 mol), tetrahydrofuran (2 ml) and triethylamine (0.25 g, 0.002 mol) was then added with stirring and the stirring continued for a further hour after the addition was complete. The solvent was then distilled off in vacuo and the residue treated with ethyl acetate and water (50 ml each). The organic phase was separated, dried with sodium sulphate, filtered and the solvent removed in vacuo. The residue was purified by chromatography on silica gel using 8:2 ethyl acetate: petroleum ether (300 ml) as eluant to give 0.45 g 5-chloro-6-thien-3yl-7-cyclopentylamino-1,2,4-triazolo[1,5-a]-pyrimidine as colourless crystals, m.pt. 78° C. Yield: 71% of theoretical.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].Cl.[CH3:16][O:17][C:18](=[O:24])[C@@H:19]([CH:21]([CH3:23])[CH3:22])[NH2:20].CO.C(N(CC)CC)C>>[CH3:22][CH:21]([CH3:23])[C@@H:19]([N:20]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:9]1=[O:14])[C:18]([O:17][CH3:16])=[O:24]
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: COC(=O)[C@H](N)C(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)[C@@H](C(C)C)n1ccc2c([N+](=O)[O-])cccc2c1=O

Procedure:
5-Nitro-isochromen-1-one (5 g, 0.03 mol) and D-Valine methyl ester hydrochloride (5 g, 0.03 mol) were refluxed in methanol (40 mL, 1 mol) with triethylamine (5 g, 0.05 mol) for 2 hours. The volatiles were removed via rotovapor, and the residue was purified via flash column chromatography (40 g silica gel, 0-30% EtOAc/Hexane) and gave a brown oil. MS m/z 305.2 (M+H)+.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[NH2:6][C:7]1[O:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.S(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[NH2:6][C:7]1[O:8][C:9]2[CH:15]=[C:14]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:13]=[CH:12][C:10]=2[N:11]=1
Reactant: Nc1nc2ccccc2o1
Reactant: O=S(=O)(O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: Nc1nc2ccc(S(=O)(=O)Cl)cc2o1
Temperature: 80 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
7.5 ml of chlorosulfonic acid was stirred at room temperature under an inert atmosphere (nitrogen). 5 g of 2-aminobenzoxazol (7-2) was added in small portions. The temperature was kept between 30-60° C. during the addition of 7-2. The mixture was heated to 80° C. for 2 hours. 5.3 g of thionyl chloride was added drop wise, keeping the temperature at 65° C. The mixture was stirred during 2 hours. After cooling to 0° C. 0.10 ml of ethyl acetate and 10 ml of a solution of sodium carbonate (1N) were added. The organic layer was separated from the water layer and this latter was extracted with ethyl acetate. The combined organic layers were dried over calcium chloride, yielding 7.8 g (90%) of 2-amino-6-chlorosulfonylbenzoxazole (7-3).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].C[O-].[Na+].Cl[CH2:10][C:11]1[N:15]=[C:14]([CH3:16])[O:13][N:12]=1>CO>[CH3:16][C:14]1[O:13][N:12]=[C:11]([CH2:10][S:5][CH2:4][CH2:3][NH2:2])[N:15]=1
Reactant: NCCS
Reactant: Cc1nc(CCl)no1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1nc(CSCCN)no1
Reaction time: 1.17 h
Yield: 121.9 %

Procedure:
Cysteamine hydrochloride (3.03 g; 26.7 mmoles) was added in several portions over a period of 10 minutes to a stirred solution of sodium methylate (2.89 g; 53.4 mmoles) in 50 ml of methanol at 0°. After stirring for 70 minutes at 0°, a solution of 3-chloromethyl-5-methyl-1,2,4-oxadiazole (3.54 g; 26.7 mmoles) in 15 ml of methanol was added dropwise over a period of 15 minutes, and the reaction mixture was allowed to stir at ambient temperature for 16 hours. The mixture was filtered, evaporated and redissolved in isopropyl alcohol, then filtered and evaporated under reduced pressure to give the title compound (5.64 g) as a yellow oil. The NMR spectrum (60 MHz) in CDCl3 gave the following resonances δ: 3.77 (s, 2H); 2.77 (m, 4H); 2.63 (s, 3H).
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:30][CH3:31])=[CH:12][CH:13]=[C:14]2[C:19]=1[O:18][C:17](=[O:20])[CH:16]=[C:15]2[NH:21][C:22]1[C:27]([Cl:28])=[CH:26][N:25]=[CH:24][C:23]=1[Cl:29]>>[Cl:29][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([Cl:28])[C:22]=1[NH:21][C:15]1[C:14]2[C:19](=[C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][NH:2][CH3:1])[C:11]([O:30][CH3:31])=[CH:12][CH:13]=2)[O:18][C:17](=[O:20])[CH:16]=1
Reactant: CN
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr
Product: CNCCCCCOc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc12

Procedure:
The title compound was prepared from methylamine and 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 28) following the procedure outlined in Example 27. 1H NMR (400 MHz, DMSO-d6): δ 8.44 (br s, 2H), 8.33 (s, 2H), 7.78 (d, 1H), 6.92 (d, 1H), 3.94 (t, 2H), 3.85 (s, 1H), 3.84 (s, 3H), 2.93 (t, 2H), 2.53 (s, 3H), 1.82-1.56 (m, 6H); MS (ESI): 452.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14](O)=[O:15])[CH:11]=[CH:10][C:9]=2[O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:4][CH:3]=1.[CH3:23][CH:24]([C:26]1[O:30][N:29]=[C:28]([CH2:31][NH2:32])[CH:27]=1)[CH3:25]>>[CH:24]([C:26]1[O:30][N:29]=[C:28]([CH2:31][NH:32][C:14]([C:12]2[CH:11]=[CH:10][C:9]([O:17][CH2:18][C:19]([F:20])([F:22])[F:21])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:13]=2)=[O:15])[CH:27]=1)([CH3:25])[CH3:23]
Reactant: O=C(O)c1ccc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1
Reactant: CC(C)c1cc(CN)no1
Product: CC(C)c1cc(CNC(=O)c2ccc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 41, using 6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example AF) and 5-(1-methylethyl)-3-isoxazolemethanamine (CAN 154016-49-6) as starting materials; LC-MS (UV peak area/ESI) 97.1%, 454.6 (M+H)+.
Reaction SMILES: [CH3:1][NH2:2].C[O:4][C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.C(OCC)(=O)C>CO>[CH3:1][NH:2][C:5](=[O:4])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1
Reactant: CN
Reactant: COC(=O)Cc1ccc(O)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CNC(=O)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Monomethylamine (22.43 kg, 722.15 mol, 6 eq.) was added over a 7-hour period to a solution of methyl-4-hydroxyphenylacetate (20.0 kg, 120.35 mol, 1.0 eq.) in methanol (31.7 gal) and stirred overnight at room temperature. Methanol was then displaced under vacuum with ethyl acetate. The resulting slurry (ca. 20 gal) was stirred at +10° C. for 1 hour, then filtered and dried under vacuum at 45° C. to yield of the title compound(18.68 kg, 94% of theory). mp 124-125° C. NMR (300 MHz, d6-DMSO): δ=9.26 (s, 1H), 8.00-7.65 (br s, 1H), 7.21-6.90 (m, 2H), 6.86-6.55 (m, 2H), 3.26 (s, 2H), 2.75-2.45 (m, 3H).
Reaction SMILES: C([O:4][C:5]1[N:6]=[C:7]([CH2:35][NH:36]C(=O)C)[C:8]2[C:13]([C:14]=1[CH2:15][C:16]1[C:17]([NH:28][CH2:29][CH3:30])=[N:18][C:19]3[C:24]([CH:25]=1)=[CH:23][C:22]([O:26][CH3:27])=[CH:21][CH:20]=3)=[CH:12][C:11]([O:31][CH3:32])=[C:10]([O:33][CH3:34])[CH:9]=2)(=O)C.CC(N(C(C)C)CC1C=CC=CC=1)C.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.[CH3:72][S:73](Cl)(=[O:75])=[O:74]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:72][S:73]([O:4][C:5]1[N:6]=[C:7]([CH2:35][NH:36][S:73]([CH3:72])(=[O:75])=[O:74])[C:8]2[C:13]([C:14]=1[CH2:15][C:16]1[C:17]([NH:28][CH2:29][CH3:30])=[N:18][C:19]3[C:24]([CH:25]=1)=[CH:23][C:22]([O:26][CH3:27])=[CH:21][CH:20]=3)=[CH:12][C:11]([O:31][CH3:32])=[C:10]([O:33][CH3:34])[CH:9]=2)(=[O:75])=[O:74]
Reactant: CCNc1nc2ccc(OC)cc2cc1Cc1c(OC(C)=O)nc(CNC(C)=O)c2cc(OC)c(OC)cc12
Reactant: CS(=O)(=O)Cl
Agent: C=Cc1ccc(C=C)cc1
Agent: CC(C)N(Cc1ccccc1)C(C)C
Agent: CN(C)c1ccncc1
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: CCNc1nc2ccc(OC)cc2cc1Cc1c(OS(C)(=O)=O)nc(CNS(C)(=O)=O)c2cc(OC)c(OC)cc12
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
The other portion of the residue CCH 42006-2 (see preparation of compound 56) was transferred in a 5 mL microwave vial equipped with a magnetic stirrer before addition of diisopropylaminomethyl-polystyrene resin (3 mmol/g, 86 mg, 258 μmol), DMAP (2 mg, 16 μmol) and methanesulfonyl chloride (25 μL, 323 μmol) and the reaction mixture was stirred for 20 min at 100° C. under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2 (30 mL), filtered through cotton wool, then washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 0:100) gave 4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-(methylsulfonamidomethyl)isoquinolin-3-yl methanesulfonate as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:30][O:31][C:32](=[O:35])[CH2:33]Cl.CCOC(C)=O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[O:14][CH2:33][C:32]([O:31][CH3:30])=[O:35])=[CH:4][C:3]=1[C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: Nc1ncc(-c2cccc(O)c2)cc1-c1nc2ccccc2s1
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc(-c2cnc(N)c(-c3nc4ccccc4s3)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-[6-amino-5-(1,3-benzothiazol-2-yl)pyridin-3-yl]phenol (80 mg, 0.20 mmol), potassium carbonate (100 mg, 0.700 mmol) and chloroacetic acid methyl ester (33 mg, 0.30 mmol) in DMF was left to stir at rt overnight. To the mixture was added EtOAc (10 mL), which was left to stir at rt for 10 min. Then, the mixture was washed with NaHCO3 aq. soln. (2×). The combined organic extracts were treated with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. Purification via silica gel chromatography (5% MeOH in DCM) afforded the title compound as a yellow solid. MS (ES+): m/z=392.02 (100) [MH+]. HPLC: tR=3.63 min (ZQ3, polar—5 min).
Reaction SMILES: [N:1]1([C:11](Cl)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:14]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[N:37]([C:38]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:36]=[N:35][N:34]=2)=[CH:23][CH:22]=1)[CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)C(C)C)(C)C>>[CH2:14]([N:19]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[N:37]([C:38]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:36]=[N:35][N:34]=2)=[CH:25][CH:26]=1)[C:11]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:12])[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(Cl)N1CCCc2ccccc21
Reactant: CCCCCNCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCN(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)C(=O)N1CCCc2ccccc21
Yield: 27 %

Procedure:
Following the procedure of Example 7, Step B, 1,2,3,4-tetrahydroquinoline-1-carbonyl chloride (from Step A) was reacted with 1.2 equivalents of N-pentyl-N-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]amine (from Step D) in the presence of N,N-diisopropylethylamine. Flash chromatography of the crude product on silica gel (elution with 4:1 and then 3:1 hexane-EtOAc) gave two major products. (Concentration of fractions containing the pure second product afforded a 27% yield of the title compound as a stiff foam, homogeneous by TLC in 3:1 hexane-EtOAc; FAB-MS m/e 723 (M+1)+. The 1H NMR spectrum indicated the presence of two isomeric forms.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:7]=1.[Cl:17][C:18]1[CH:31]=[CH:30][C:29]2[CH:28]3[CH2:32][C:21]([CH2:33][N:34]4[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][CH2:35]4)([C:22]4[C:27]3=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:20]=2[CH:19]=1>>[Si:10]([O:9][CH2:8][C:6]1[CH:7]=[C:2]([C:37]2([OH:40])[CH2:38][CH2:39][N:34]([CH2:33][C:21]34[CH2:32][CH:28]([C:29]5[CH:30]=[CH:31][C:18]([Cl:17])=[CH:19][C:20]=53)[C:27]3[C:22]4=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:35][CH2:36]2)[CH:3]=[N:4][CH:5]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Reactant: CC(C)(C)[Si](C)(C)OCc1cncc(Br)c1
Product: CC(C)(C)[Si](C)(C)OCc1cncc(C2(O)CCN(CC34CC(c5ccccc53)c3ccc(Cl)cc34)CC2)c1
Yield: 51 %

Procedure:
Using a procedure similar to that described in example 1 except employing 3-bromo-5-(tert-butyldimethylsilyl)oxymethylpyridine (described in example 69b) and 1-(2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 1m), the title compound was formed in 51% yield as an oil. TLC analysis (Rf 0.20, 25% ethyl acetate in hexane). MS (CI, CH4) m/z 561 (M+1,100), 563 (40), 589 (M+29,20), 545 (26), 429 (26)
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]([NH2:7])=[NH:6].[C:8]1(=O)[CH2:12][CH2:11][CH2:10][C:9]1=O.[NH4+].[OH-]>O.C(O)C.Cl>[NH2:6][C:5]1[NH:7][C:9]2=[CH:10][CH:11]=[CH:12][C:8]2=[N:3][CH:4]=1
Reactant: N=C(N)CN
Reactant: O=C1CCCC1=O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cnc2cccc-2[nH]1

Procedure:
A solution of aminoacetamidine dihydrochloride (Mengelberg, M. Chem. Ber. 89, 1185 (1956)) (2.4 g, 0.01 mol, 1 equiv.) in H2O (~10 mL) was added dropwise to a cold (0° C.) stirring solution of 1,2-cyclopentanedione (1.0 g, 0.01 mol) in ethanol (8-10 mL). After allowing the reaction mixture to come to room temperature, concentrated NH4OH (aq.) was added slowly until the pH was 8-9. Small amounts of concentrated NH4OH were added as needed in order to maintain a pH of 8-9. When the 1,2-cycopentanedione was no longer visible on TLC (30% EtOAc/hexanes) the reaction mixture was diluted with 5% HCl, washed (3×) with CH2Cl2 and the organic portions discarded. The aqueous portion was made basic with 6N NaOH (aq.), extracted (4×) with CH2Cl2 and the combined extracts dried over sodium sulfate. Concentration of the solution under reduced pressure gave 2-amino-cyclopent[b]pyrazine as a greenish-yellow solid.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.[CH2:13]([C:17]1([C:21](OC)=[O:22])[CH2:20][CH2:19][CH2:18]1)[CH2:14][CH2:15][CH3:16]>C1COCC1>[CH2:13]([C:17]1([C:21](=[O:22])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[CH2:20][CH2:19][CH2:18]1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCC1(C(=O)OC)CCC1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC1(C(=O)CP(=O)(OC)OC)CCC1
Reaction time: 0.25 h

Procedure:
To a solution of dimethyl methylphosphonate (1.46 g, 11.8 mmol) in anhydrous THF (25 mL) at −78° C. was added n-BuLi (7.4 mL, 1.6 M, 11.8 mmol) dropwise under Ar. The reaction was stirred for 15 minutes. A solution of methyl 1-butylcyclobutanecarboxylate (1.00 g, 5.87 mmol) in THF (5 mL) was added dropwise. The reaction mixture was stirred for 30 minutes at −78° C., after which it was allowed to warn to room temperature. The reaction was quenched with 5% HCl, extracted with CH2Cl2 (3×30 mL), the combined organic phase was washed with brine, dried (MgSO4). After concentration, flash chromatography (silica gel, 1:1 ethylacetate:hexanes), the title compound was obtained as a colorless oil. 1HNMR (CDCl3) δ 0.85˜0.89 (m, 3H), 1.05˜1.15 (m, 2H), 1.22˜1.35 (m, 2H), 1.65˜1.95 (m, 6H), 2.35˜2.50 (m, 2H), 3.00 (s, 1H0, 3.06 (s, 1H), 3.78 (s, 3H), 3.82 (s, 3H). MS (m/z) 285 (M+Na)
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[C:12]([CH:17]=[CH:18][C:19](=[O:21])[CH3:20])=[C:11]([CH3:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[Si:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:15])([CH3:16])[C:12]2([CH:17]=[CH:18][C:19](=[O:21])[CH3:20])[O:31][C:11]2([CH3:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)C=CC1=C(C)CC(O[Si](C)(C)C(C)(C)C)CC1(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)C=CC12OC1(C)CC(O[Si](C)(C)C(C)(C)C)CC2(C)C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
To 20 ml of an anhydrous chloroform solution containing 1.0 g of 4-[4-(t-butyldimethylsilyl)oxy-2,6,6-trimethylcyclohex-1-enyl]but-3-en-2-one was added 616 mg of m-chloroperbenzoic acid under ice-cooling, followed by stirring at the same temperature for 8 hours. After completion of the reaction, the reaction mixture was washed several times with a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was washed with a saturated aqueous solution of sodium chloride and then, with water, and dried over anhydrous magnesium sulfate. The solvent, etc. were removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 644 mg (yield: 70%) of 4-[4-(t-butyldimethylsilyl)oxy-1,2-epoxy-2,6,6-trimethylcyclohexyl]but-3-en-2-one.
Reaction SMILES: O=[C:2]1[NH:8][C:7]2[S:9][CH:10]=[CH:11][C:6]=2[CH2:5][N:4]2[CH:12]=[CH:13][CH:14]=[C:3]12.[B].CSC>>[S:9]1[C:7]2[NH:8][CH2:2][C:3]3[N:4]([CH:12]=[CH:13][CH:14]=3)[CH2:5][C:6]=2[CH:11]=[CH:10]1
Reactant: O=C1Nc2sccc2Cn2cccc21
Agent: [B]
Solvent: CSC
Product: c1cc2n(c1)Cc1ccsc1NC2

Procedure:
The synthesis of 9,10-dihydro-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepin-9-one ##STR143## is reported by F. Povazunec, B. Decroix and J. Morel, J. Het. Chem. 29, 1507(1992) and is reduced to give the tricyclic heterocycle 9,10-dihydro-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepine. ##STR144## The tricyclic 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine ring system is reported by L. Cecchi and G. Filacchioni, J. Het. Chem., 20, 871(1983); ##STR145## The synthesis of 9-oxo-9,10-dihydro-4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepine is reported by A. Daich and B. Decroix, Bull. Soc. Chim. Fr 12, 360(1992); ##STR146## and is reduced with boron-dimethylsulfide to give 9,10-dihydro-4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepine. ##STR147## Also reported by A. Daich and B. Decroix is 5-oxo-4,5-dihydropyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine ##STR148## which is also reduced to give 4,10-dihydro-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine ##STR149## Reported by B. Decroix and J. Morel, J. Het. Chem., 28, 81(1991) are pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine; ##STR150## and pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepine. Reduction by hydrogen-Pd/c or chemical reduction with reagents such as sodium cyanoborohydride and acetic acid gives the dihydro tricyclic heterocycles ##STR151## The synthesis of the tricyclic 1,5-benzodiazepine ring system, 6,7-dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepine, has been reported by F. Chimenti, S. Vomero, R. Giuliano and M. Artico, IL Farmaco, Ed. Sc., 32, 339(1977). Annelated 1,5-benzodiazepines containing five membered rings have been reviewed by A. Chimirri, R. Gitto, S. Grasso, A. M. Monforte, G. Romeo and M. Zappala, Heterocycles, 36, No. 3, 604(1993), and the ring system 6,7-dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepine is described. ##STR152##
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][CH2:20][CH2:21][CH2:22][S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9](Cl)[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4].C(C1[N:35](CCCCSC2C=CC=CC=2)C2C3C=CC=CC=3N=C(SC3C=CC=CC=3)C=2N=1)CCC.N.C>CO.C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]([CH2:19][CH2:20][CH2:21][CH2:22][S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:35])[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(Cl)nc3ccccc3c2n1CCCCSc1ccccc1
Reactant: CCCCc1nc2c(Sc3ccccc3)nc3ccccc3c2n1CCCCSc1ccccc1
Agent: N
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCSc1ccccc1
Temperature: 150 °C
Reaction time: 5 h

Procedure:
A 3:1 mixture of 2-butyl-4-chloro-1-[4-(phenylthio)butyl]-1H-imidazo[4,5-c]quinoline to 2-butyl-4-(phenylthio)-1-[4-(phenylthio)butyl]-1H-imidazo[4,5-c]quinoline (1.38 g) and a solution of 7% ammonia in methanol (30 mL) were combined in a bomb and heated to 150° C. The reaction was judged to be complete after 5 hours. The volatiles were removed under reduced pressure and the resulting residue was stirred in water and made basic (pH 10) with solid sodium carbonate. The aqueous mixture was extracted with chloroform (3×). The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a yellow crystalline solid. The solid (0.8 g) was dissolved in ethyl acetate (50 mL) and brought to reflux. Activated charcoal (0.4 g) was added; the resulting mixture was heated at reflux for 5 minutes and then the charcoal was removed by filtration through fluted paper to provide a colorless solution. The solution was concentrated under reduced pressure to give a solid that was recrystallized from ethyl acetate and hexanes to provide 2-butyl-1-[4-(phenylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine (0.51 g, 1.25 mmol) as white needles, m.p. 118-120° C.