Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([CH:6]([N:14]2[CH2:19][CH2:18][CH:17]3[S:20][C:21](=[O:23])[CH:22]=[C:16]3[CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].[C:26](Cl)(=[O:35])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(OCC)(=O)C>CN(C)C=O>[CH:1]1([C:4]([CH:6]([N:14]2[CH2:19][CH2:18][C:17]3[S:20][C:21]([O:23][C:26](=[O:35])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:22][C:16]=3[CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])=[O:5])[CH2:2][CH2:3]1
Reactant: O=C1C=C2CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S1
Reactant: CCCCCCCCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCC(=O)Oc1cc2c(s1)CCN(C(C(=O)C1CC1)c1ccccc1F)C2
Reaction time: 0.5 h
Yield: 40 %

Procedure:
1.0 g (3.0 mmole) of 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine (prepared as described in Example 20) was dissolved in 15 ml of dimethylformamide, and then 0.18 g (4.5 mmole) of a 60% w/w dispersion of sodium hydride in mineral oil and 0.82 ml (4.5 mmole) of nonanoyl chloride were added, in that order, to the resulting mixture, whilst ice-cooling. The resulting reaction mixture was then stirred at the same temperature for 30 minutes, after which it was stirred at room temperature for a further 5 hours. 300 ml of ethyl acetate were then added to the mixture, which was then washed with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography, using a 100:2 by volume mixture of toluene and ethyl acetate as the eluent, to give a yellow oil. The oil was crystallized from petroleum ether to obtain the title compound as white crystals, melting at 45°-48° C., in a yield of 40%.
Reaction SMILES: [CH2:1]([N:8]([CH3:17])[C:9]1[CH:10]=[C:11]([NH2:16])[CH:12]=[CH:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21](SC)[N:20]=1>CO>[CH2:1]([N:8]([CH3:17])[C:9]1[CH:10]=[C:11]([NH:16][C:21]2[N:20]=[C:19]([OH:18])[CH:24]=[CH:23][N:22]=2)[CH:12]=[CH:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(N)cc1N(C)Cc1ccccc1
Reactant: CSc1nccc(O)n1
Solvent: CO
Product: Cc1ccc(Nc2nccc(O)n2)cc1N(C)Cc1ccccc1
Temperature: 160 °C
Yield: 29.2 %

Procedure:
An intimate mixture of N3-benzyl-N3,4-dimethyl-benzene-1,3-diamine (158 mg, 0.7 mmol) and 4-hydroxy-2-methylthio-pyrimidine (109 mg, 0.77 mmol) is heated in an oil bath of 160° C. After 3 h the melt is cooled to room temperature and treated with MeOH. The remaining solid is collected by filtration, washed with MeOH, and dried, giving 65.5 mg (29%) of N3-benzyl-N1-(4-hydroxy-pyrimidin-2-yl)-N3,4-dimethyl-benzene-1,3-diamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([O:20]CC3C=CC=CC=3)=[CH:18][N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:19]([OH:20])=[CH:18][N:17]=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncncc2OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ncncc2O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a stirred solution of 4-(5-benzyloxypyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.540 g, 1.46 mmol) in MeOH (20 mL) under N2 was cautiously added 10% Pd on carbon (40 mg). The reaction vessel was evacuated under vacuum and then put under an atmosphere of hydrogen using a balloon. The mixture was stirred for 2 hours at room temperature. At this time the hydrogen gas was evacuated and the catalyst was removed by filtration. The filtrate was concentrated. The residue was purified by flash chromatography (1:1 hexanes/EtOAc) to give 4-(5-Hydroxypyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.390 g, 95%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.18 (s, 1H), 7.75 (s, 1H), 3.93 (m, 4H), 3.54 (m, 4H), 1.41 (s, 9H). LCMS (APCI+) m/z 281 [M+H]+; Rt=2.01 minutes.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:8]=1[Cl:34])[CH3:6])=[O:4].[O:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]1>>[Cl:34][C:8]1[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][C:42](=[O:43])[CH2:41][N:38]1[CH2:39][CH2:40][O:35][CH2:36][CH2:37]1
Reactant: O=C(O)CN1CCOCC1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Product: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CN4CCOCC4)c3Cl)cccc2n1Cc1ccccn1

Procedure:
2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide and 2-morpholinoacetic acid were combined to give 14 as previously described. LCMS (+ESI) 627 (M+). 1H-NMR (CDCl3, δ): 8.58 (dd, J=0.8, 4.8 Hz, 1H), 7.88 (bt, 1H), 7.58 (td, J=1.6, 8.0 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.19 (m, 1H), 7.03 (t, J=8.0 Hz, 1H), 6.92 (d, J=7.6 Hz, 1H), 6.83 (d, J=7.6 Hz, 1H), 6.81 (d, J=7.6 Hz, 1H), 5.67 (d, J=3.2 Hz, 2H), 5.28 (s, 2H), 4.21 (s, 3H), 3.87 (dd, J=5.2, 17.6 Hz, 1H), 3.77 (m, 4H), 3.54 (dd, J=4.4, 17.6 Hz, 1H), 3.25 (s, 3H), 2.55 (m, 4H). Calcd. for C30H32Cl2N6O5: C, 57.42; H, 5.14; N, 13.39. Found: C, 57.23; H, 5.22; N, 13.23.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[CH:9]=1)(C)(C)C.[ClH:18]>O1CCOCC1>[ClH:18].[S:12]1[C:8]([NH2:7])=[CH:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]1=2
Reactant: CC(C)(C)OC(=O)Nc1cc2ccccc2s1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cc2ccccc2s1
Temperature: 25 °C
Yield: 83 %

Procedure:
Compound 1-B (1.45 g, 5.81 mmol) was added to a solution of HCl in dioxane (4 N, 20 mL), and the mixture was stirred at rt until all the starting material was consumed. The mixture was diluted with diethyl ether, the product collected by filtration, and washed with diethyl ether, to afford compound 1-C as an off-white solid (0.89 g, 83%). 1H-NMR (DMSO-d6): δ 6.43 (s, 1H), 6.8-7.2 (br s, 3H) superimposed on 7.05 (m, 1H) and 7.20 (m, 1H), 7.45 (d, 1H), 7.66 (d, 1H); MS: m/z 150.1 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])[CH3:2].[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl>CO>[CH2:11]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[O:3][CH2:1][CH3:2])[CH:13]1[O:15][CH2:14]1
Reactant: CCOc1ccccc1N
Reactant: ClCC1CO1
Solvent: CO
Product: CCOc1ccccc1NCC1CO1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-ethoxyaniline (54.8 g.), methanol (300 ml.) and epichlorhydrin (18.6 g.) is stirred at 25°C. for 24 hours. The methanol and unreacted 2-ethoxyaniline are removed by vacuum distillation and the residue is dissolved in methanol (300 ml.) and sodium hydroxide (8.0 g.) added. The mixture is stirred at 25°C. for 3 hours, filtered and the filtrate evaporated under reduced pressure to give N-glycidyl-2-ethoxyaniline which is then dissolved in methanol (69 ml.). This solution is added to a stirred suspension of 2-aminoethyl hydrogen sulphate (97.0 g.) in a mixture of methanol (69 ml.), water (16.5 ml.) and sodium hydroxide solution (17 N; 35.0 ml.). The mixture is stirred at 25°C. for 16 hours.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].[ClH:5].NC(N)=N.C[O-].[Na+].[NH:13]([CH:20]=[C:21]([CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([O:35][CH3:36])=[CH:27][CH:26]=1)[C:22]#N)C1C=CC=CC=1>C(O)C.COCCO>[ClH:5].[NH2:3][C:2]1[N:4]=[C:20]([NH2:13])[C:21]([CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([O:35][CH3:36])=[CH:27][CH:26]=2)=[CH:22][N:1]=1
Reactant: N=C(N)N
Reactant: COc1ccc(CC(C#N)=CNc2ccccc2)c2ccccc12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: COCCO
Product: COc1ccc(Cc2cnc(N)nc2N)c2ccccc12

Procedure:
To 65 mL of ethanolic guanidine solution prepared from 3.42 g (35.8 mmol) of guanidine hydrochloride and 2.00 g (37.0 mmol) of sodium methoxide was added 9.00 g (28.6 mmol) of 3-anilino-2-(4-methoxy--naphthylmethyl)acrylonitrile. The solution was heated under reflux for 1.5 hr, and then 60 mL of 2-methoxyethanol was added. The internal temperature was allowed to gradually increase to 108° by distillation of the ethanol, after which it was heated at this temperature for 2.5 hr. The hot mixture was filtered, and the precipitate (7.04 g, 87% of crude product) recrystallized from 30% ethanol in the presence of hydrochloric acid, to give the title compound; mp 312°-314° dec. Anal. Calcd for C16H16N4O.HCl: C, 60.66; H, 5.41; N, 17.69; Cl, 11.19. Found: C, 60.67; H, 5.45; N, 17.70; Cl, 11.19.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24]([N:26]1[CH2:31][C@H:30]([O:32][CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:29][CH2:28][C@@H:27]1[CH:42]=[O:43])=[O:25])([CH3:22])([CH3:21])[CH3:20].[F:44][C:45]1[CH:50]=[C:49]([CH2:51][CH2:52][N+:53]([O-:55])=[O:54])[CH:48]=[C:47]([F:56])[CH:46]=1>O1CCCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][C@H:30]([O:32][CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:29][CH2:28][C@@H:27]1[CH:42]([OH:43])[CH:52]([N+:53]([O-:55])=[O:54])[CH2:51][C:49]1[CH:50]=[C:45]([F:44])[CH:46]=[C:47]([F:56])[CH:48]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCOCc2ccccc2)CC[C@@H]1C=O
Reactant: O=[N+]([O-])CCc1cc(F)cc(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](OCOCc2ccccc2)CC[C@@H]1C(O)C(Cc1cc(F)cc(F)c1)[N+](=O)[O-]
Reaction time: 8 h

Procedure:
Add tetrabutylammonium fluoride (12.0 mL, 11.9 mmol, 1.0 M in tetrahydro-furan) to (2R, 5R)-5-Benzyloxymethoxy-2-formyl-piperidine-1-carboxylic acid 1-tert-butyl ester (8.0 g, 23.90 mmol) and 1,3-difluoro-5-(2-nitro-ethyl)-benzene (4.92 g, 26.30 mmol) in 150 mL tetrahydrofuran at room temperature, stir overnight and concentrate. Subject to silica gel chromatography, eluting with 100% hexane to 90:10 hexane: ethyl acetate) to provide the desired compound as a mixture of 3 isomers (8.0 g, 62% overall yield).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].Br[CH2:10][CH2:11][CH2:12][CH:13]1[S:17][C:16]2[C:18]([CH3:28])=[C:19]([O:24][CH2:25][O:26][CH3:27])[C:20]([CH3:23])=[C:21]([CH3:22])[C:15]=2[O:14]1>CS(C)=O>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][CH2:10][CH2:11][CH2:12][CH:13]1[S:17][C:16]2[C:18]([CH3:28])=[C:19]([O:24][CH2:25][O:26][CH3:27])[C:20]([CH3:23])=[C:21]([CH3:22])[C:15]=2[O:14]1
Reactant: COCOc1c(C)c(C)c2c(c1C)SC(CCCBr)O2
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COCOc1c(C)c(C)c2c(c1C)SC(CCCOCCN(C)C)O2
Temperature: 50 °C

Procedure:
740 mg of 2-dimethylaminoethanol were dissolved in 10 ml of dimethyl sulfoxide, and 220 mg of a 50% w/w oily suspension of sodium hydride was added to the resulting solution; the reaction mixture was then heated at 50° C. for 1 hour, after which it was cooled down with ice, and a solution of 1.68 g of 2-(3-bromopropyl)-5-methoxymethoxy-4,6,7-trimethyl-1,3-benzoxathiole (prepared as described in Example 87) in 5 ml of dimethyl sulfoxide was added dropwise, while stirring. The reaction product was then subjected to the same reaction process, extraction and separation procedures as described in (a) above, to give the title compound with the same Rf value and mass spectrum as those of the product obtained in (a).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Cl:11])[C:3]=1[N:12]1[CH:29]=[C:15]2[C:16]([NH:21][C:22]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=3)=[N:17][CH:18]=[C:19]([F:20])[C:14]2=[N:13]1.C1COCC1.O.[Cl-].[NH4+]>C(O)C.[Fe]>[NH2:8][C:6]1[CH:5]=[C:4]([Cl:11])[C:3]([N:12]2[CH:29]=[C:15]3[C:16]([NH:21][C:22]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=4)=[N:17][CH:18]=[C:19]([F:20])[C:14]3=[N:13]2)=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cc([N+](=O)[O-])cc4Cl)cc23)ncn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cc(N)cc4Cl)cc23)ncn1
Temperature: 70 °C
Yield: 74.2 %

Procedure:
[2-(2,6-Dichloro-4-nitrophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)-amine (173 mg, 0.40 mmol) was dissolved in ethanol (10 mL) and THF (4.0 mL) and water (1.0 mL) were added, followed by iron powder (325 mesh, 112 mg, 2.0 mmol) and ammonium chloride (86 mg, 1.6 mmol). The reaction mixture was heated at 70° C. for 4 hours. More iron powder (112 mg) and ammonium chloride (100 mg) were added and the mixture was heated at 70° C. for another 5 hours. The resultant mixture was cooled and filtered through Celite®. The filtrate was concentrated under reduced pressure and the residue was triturated with water. The solid obtained was dried under reduced pressure and purified by silica gel flash chromatography (0-5% methanol in DCM) to afford the title compound as an off-white solid (120 mg, 74% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.62 (s, 1H), 9.13 (d, J=2.6 Hz, 1H), 8.71 (d, J=1.2 Hz, 1H), 8.42 (s, 1H), 7.96 (d, J=3.5 Hz, 1H), 6.83 (s, 2H), 6.30 (s, 2H), 2.46 (s, 3H). LCMS (Method B): RT=3.00 min, m/z: 404 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][C:10](=[O:12])[CH:9]=[CH:8][O:7]1)=[O:5])[CH3:2].[H][H]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][C:10](=[O:12])[CH2:9][CH2:8][O:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC(=O)C=CO1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CC(=O)CCO1
Yield: 33.1 %

Procedure:
A mixture of 4-oxo-3,4-dihydro-2H-pyran-2-carboxylic acid ethyl ester (8.0 g, 46.0 mmol) and Pd/C (10%, 0.20 g) in EtOAc (70 mL) was shaken in a Parr bottle with hydrogen at 50 psi overnight and filtered through a pad of Celite. The filtrate was concentrated and the residue was distilled to give 2.62 g (33%) of yellowish oil: 1H NMR (CDCl3) δ 1.29 (t, 3H), 2.40 (d, 1H), 2.58-2.75 (m 3H), 3.79 (tt, 1H), 4.23 (q, 2H), 4.28 (m 1H), 4.40 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:15]=[C:16](O)[C:17]4[S:22][CH2:21][CH2:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:16]1[C:17]2[S:22][CH2:21][CH2:20][C:18]=2[N:19]=[C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)[N:15]=1
Reactant: Oc1ccc(N2CCN(c3nc(O)c4c(n3)CCS4)CC2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Oc1ccc(N2CCN(c3nc(Cl)c4c(n3)CCS4)CC2)cc1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
1.11 g (3.36 mmol) of 2-[4-(4-hydroxyphenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidin-4-ol (II) is placed in 5 mL of phosphorus oxychloride, then stirred for 4 hours at 120° C. Excess phosphorus oxychloride is then distilled off and the residue is combined with water. The iii precipitate formed is suction filtered, washed with plenty of water, and dried. 1.18 g of product III is obtained as a brown powder.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:18]C)[C:10](=[O:20])[C:9]=2[CH:8]=[CH:7][CH:6]=1)(C)C.B(Cl)(Cl)Cl>C(Cl)Cl>[OH:18][C:15]1[C:16]2[C:17]3[C:9](=[CH:8][CH:7]=[CH:6][C:5]=3[O:4][CH3:1])[C:10](=[O:20])[C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: COc1cccc2c1-c1c(OC(C)C)cccc1C2=O
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COc1cccc2c1-c1c(O)cccc1C2=O
Temperature: 0 °C

Procedure:
Prepare a solution of 4-isopropoxy-5-methoxy-fluoren-9-one (0.78 g, 2.9 mmole) in methylene chloride (15 mL) and stir at 0° C. under an argon atmosphere. Dropwise add 9 mL (9.0 mmole) of boron trichloride (1.0 M in methylene chloride and stir the mixture for 1 hour, observing the color change to dark. Quench the reaction with 20 mL water, observing a mild exothermic reaction and an orange precipitate. Filter and wash the solid twice with 100 mL methylene chloride. Separate the organic layer from the filtrate and wash with brine. Dry over magnesium sulfate, filter and remove the solvent. Recrystalize the solid from chloroform/hexane (20:80; Rf =0.2) to give the title compound. Yield; 0.55 g, 84%.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[C:5]([Cl:10])=[C:4]([Cl:11])[C:3]=1[Cl:12].C([Li])CCC.[F:18][C:19]([F:31])([O:23][C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[C:20](F)=[O:21].C(OCCOCC)(=O)C>C(OCC)C>[F:18][C:19]([C:20]([C:2]1[C:3]([Cl:12])=[C:4]([Cl:11])[C:5]([Cl:10])=[C:6]([Cl:9])[C:7]=1[Cl:8])=[O:21])([F:31])[O:23][C:24]([F:29])([F:30])[C:25]([F:26])([F:28])[F:27]
Reactant: O=C(F)C(F)(F)OC(F)(F)C(F)(F)F
Reactant: Clc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: [Li]CCCC
Solvent: CCOCCOC(C)=O
Solvent: CCOCC
Product: O=C(c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)C(F)(F)OC(F)(F)C(F)(F)F
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Hexachlorobenzene (35 g) was slurried in 160 ml of anhydrous ethyl ether at −40° C. A 2.5 M hexanes solution of n-butyllithium (54.1 mL) was added, and the reaction was stirred for 30 minutes at −40° C. Perfluoro-2-ethoxyacetylfluoride (40 g, 72% pure, prepared from 2-ethoxyethyl acetate by the method described in Example 1 of U.S. Pat. No. 5,326,919, incorporated herein by reference) was added to the −40° C. reaction mixture which was then allowed to warm slowly to room temperature. The reaction mixture was quenched with 200 mL of cold 5% aqueous HCl. The aqueous mixture was extracted with ethyl ether and the extracts were dried over MgSO4 and rotary evaporated to give pentachlorophenyl perfluoroethoxymethyl ketone (49% crude yield). Vacuum distillation (105-109° C., 240 Pa) using a 15 cm Vigreux column gave 19.7 g of a colorless liquid which slowly crystallized on standing.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([CH3:21])[CH3:20])[CH:13]=2)=[N:5][C:4]([NH2:22])=[N:3]1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25].CN(C)C=O>O>[CH3:20][N:19]([CH2:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([NH:22][C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:5]=1)[CH3:21]
Reactant: CN(C)Cc1cccc(OCCCNc2nc(N)nn2C)c1
Reactant: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Nc1nc(NCCCOc2cccc(CN(C)C)c2)n(C)n1
Reaction time: 12 h
Yield: 84.9 %

Procedure:
A mixture of 1-methyl-N5 -[3-[3-[(dimethylamino) methyl]phenoxy]propyl]-1H-1,2,4-triazole-3,5-diamine (2.0 g), ethyl chloroformate (0.72 g) and dimethylformamide (30 ml) was stirred at 25° for 12 h. The suspension was diluted with water (100 ml) and extracted with ethyl acetate. The organic extracts were evaporated to leave the title compound as a pale yellow oil (2.1 g). TLC silica, methanol/0.88 amonia 80:1, Rf 0.61. NMR (D2O 2.52 t (1H); 2.8-3 m (3H); 5.42 s (2H); 5.6-6 m (6H); 6.48 t (2H); 6.5 s (3H); 7.09 s (6H); 7.88 m (2H); 8.67 t (3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:29]4[CH2:32][C:31]5(OCC[O:33]5)[CH2:30]4)[C:17]4[CH2:22][CH2:21][CH:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:37][CH3:38])[CH:6]=1.O>CC(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:29]4[CH2:30][C:31](=[O:33])[CH2:32]4)[C:17]4[CH2:22][CH2:21][CH:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:37][CH3:38])[CH:6]=1
Reactant: COc1cc(Nc2nc3c(c(N4CC5(C4)OCCO5)n2)CCC3c2ccccc2)ccc1-n1cnc(Cl)c1
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(Nc2nc3c(c(N4CC(=O)C4)n2)CCC3c2ccccc2)ccc1-n1cnc(Cl)c1
Temperature: 50 °C
Yield: 20.1 %

Procedure:
The mixture of N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-phenyl-4-(5,8-dioxa-2-azaspiro[3.4]octan-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (Example 184) (12 mg, 0.023 mmol) in Acetone (161 μL)/Water (32.3 μL)/HClO4, 70% (32.3 μL) was heated at 50° C. overnight. The crude product was purified by Prep-HPLC to get 1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)azetidin-3-one (2.5 mg, 4.62 μmol, 20.5% yield). LC-MS (M+H)+=487.2 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.57 (s, 1H) 7.42 (t, J=7.63 Hz, 3H) 7.26-7.38 (m, 3H) 7.12-7.26 (m, 2H) 7.00-7.12 (m, 1H) 5.23 (br. s., 4H) 4.43 (br. s., 1H) 3.68-3.79 (m, 3H) 3.10-3.27 (m, 1H) 2.93-3.08 (m, 1H) 2.71-2.84 (m, 1H) 2.37 (br. s., 1H).
Reaction SMILES: ClC(OCC)=O.C([O:10][CH2:11][C:12]([OH:14])=O)(=O)C.C(N(CC)CC)C.[NH:22]([C:24]1[N:25]=[N:26][C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:28]([CH3:30])[N:29]=1)[NH2:23]>C(Cl)Cl.C(Cl)(Cl)Cl>[OH:10][CH2:11][C:12]([NH:23][NH:22][C:24]1[N:25]=[N:26][C:27]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[C:28]([CH3:30])[N:29]=1)=[O:14]
Reactant: Cc1nc(NN)nnc1-c1ccccc1
Reactant: CC(=O)OCC(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1nc(NNC(=O)CO)nnc1-c1ccccc1
Reaction time: 0.17 h
Yield: 71.5 %

Procedure:
A solution of ethyl chloroformate (1.628 g) in methylene chloride (6 ml) was added dropwise to a stirred solution of acetoxyacetic acid (1.77 g) and triethylamine (1.515 g) in methylene chloride (30 ml) under ice cooling in 3 minutes, and the stirring was continued for 10 minutes under ice cooling. To the mixture was added quickly a solution of 3-hydrazino-5-methyl-6-phenyl-1,2,4-triazine (2.01 g) in chloroform (28 ml) with stirring under ice cooling, and then the stirring was continued for 20 minutes. The solution was washed with water, dried over sodium sulfate, and concentrated. The resultant residue was dissolved in methanol (50 ml), and a solution of sodium hydroxide (0.8 g) in water (10 ml) was added thereto under ice cooling. After stirring for 0.5 hours, the solution was evaporated under reduced pressure and the residue was dissolved in water. To the solution was added dry ice and then the solution was concentrated under reduced pressure. The resultant precipitates were collected by filtration, washed with cold water and dried. On the other hand, the filtrate was salted out and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated to give a solid residue. The residue was combined with the substance obtained above, and recrystallized from a mixture of ethyl acetate and ethanol to give colorless crystals of 3-(2-hydroxyacetylhydrazino)-5-methyl-6-phenyl-1,2,4-triazine (1.852 g).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH2:17][CH2:18][CH2:19][OH:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.[OH-].[Na+]>ClCCl.O>[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:20][CH2:19][CH2:18][CH2:17][C:9]1[N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1
Reactant: BrCCCCCBr
Reactant: OCCCc1nc2ccccc2n1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: BrCCCCCOCCCc1nc2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 20.9 %

Procedure:
A mixture of 1-(phenylmethyl)-2-benzimidazolepropanol (3.0 g), 1,5-dibromopentane (7.77 g), TAB (0.5 g) and 40% sodium hydroxide (5 ml) in dichloromethane (10 ml) was stirred at room temperature for 6 h under nitrogen. The mixture was diluted with water (100 ml) and extracted with dichloromethane (2×30 ml). The dried extracts were evaporated in vacuo to give an oil. Purification by FCC eluting with hexane-ether (10:0→0:10) gave the title compound as a colourless oil (0.98 g).