Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:25][C:14]3=[N:15][CH:16]=[CH:17][C:18]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[C:13]3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([C:28]1[NH:29][C:30]([CH3:35])=[C:31]([CH:33]=O)[N:32]=1)[CH3:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:25][C:14]3=[N:15][CH:16]=[CH:17][C:18]([N:19]4[CH2:20][CH2:21][N:22]([CH2:35][C:30]5[N:29]=[C:28]([CH2:26][CH3:27])[NH:32][C:31]=5[CH3:33])[CH2:23][CH2:24]4)=[C:13]3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCc1nc(C=O)c(C)[nH]1
Reactant: CC(C)(C)c1ccc(-c2nc3c(N4CCNCC4)ccnc3[nH]2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCc1nc(CN2CCN(c3ccnc4[nH]c(-c5ccc(C(C)(C)C)cc5)nc34)CC2)c(C)[nH]1
Reaction time: 18 h
Yield: 33.3 %

Procedure:
2-(4-tert-Butyl-phenyl)-7-piperazin-1-yl imidazo[4,5-b]pyridine (7) (50 mg, 0.15 mmol) and 2-ethyl-5-methyl-1H-imidazole-4-carbaldehyde (21 mg, 0.15 mmol) were dissolved in NMP (4 ml) with sodium triacetoxyborohydride (64 mg, 0.30 mmol). The reaction mixture was allowed to stir for 18 hours under nitrogen. It was judged complete by MS, and purified by HPLC Method E to yield the title product 8 (23 mg (33%), 0.05 mmol). 1H NMR (DMSO-d6): δ 8.09 (d, J=8.3 Hz, 3H), 7.59 (d, J=8.3 Hz, 2H), 6.80 (s, 1H), 3.80-4.00 (m, 8H), 2.84 (q, J=7.7 Hz, 2H), 2.25 (s, 3H), 1.31 (m, 12H). The product 8 was determined to be 96% pure by analytical HPLC. MS (ESI-POS): [M+H]+=458; MS(ESI-NEG):[M−H]−=456.
Reaction SMILES: O=O.[CH3:3][C:4](=[CH:6][CH2:7][CH2:8]/[C:9](=[CH:11]/[CH2:12][OH:13])/[CH3:10])[CH3:5].C(OCC)(=O)C>O>[CH3:3][C:4](=[CH:6][CH2:7][CH2:8][C@H:9]([CH2:11][CH2:12][OH:13])[CH3:10])[CH3:5]
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: O=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)=CCC[C@@H](C)CCO
Temperature: 20 °C
Reaction time: 68 h
Yield: 86.4 %

Procedure:
A 185 ml autoclave was charged in a glove box (O2 content<1 ppm) with 8.8 g geraniol VIII [(E)-3,7-dimethyl-2,6-octadien-1-ol], 75.2 mg ((S)-MeO-BIPHEP-TS-Na)Ru(OCOCF3)2, 31 ml ethyl acetate and 8 ml water. The hydrogenation was effected under vigorous stirring at 20 ° C. and 60 bar. After 68 hours the conversion amounted to 96%. The organic phase was separated and evaporated at 45 ° C./17 mbar. The residue consisted 92% (R)-Citronellol (A) and 4% by-product B. For purification the clear residue was destilled at 60° C./0.2 mbar. There were obtained 7.7 g (R)-Citronellol (A) [(R)-3,7-dimethyl-6-octen-1-ol] as a colourless oil; e.e. 97%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:5]=[C:6]([Cl:23])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N:12]1C(=O)C2=CC=CC=C2C1=O.O.NN.Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:5]=[C:6]([Cl:23])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH2:12]
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Yield: 71 %

Procedure:
A reaction vessel was charged with 4.67 g of crude 3,5-dichloro-4-(3-phthalimidopropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene, 0.55 g of hydrazine monohydrate and 200 ml of ethanol. After heating under reflux for 2 hours, the reaction mixture was made weak acidic by the addition of concentrated hydrochloric acid, and then further heated under reflux for 1 hours. The deposited solid was collected by filtration, and the filtrate was concentrated. Water was poured into the concentrated, and the mixture was extracted twice with 150 ml of chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography which afforded 2.4 of 3,5-dichloro-4-(3-aminopropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (71% yield), nD23.5 1.5672.
Reaction SMILES: [F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[CH:6][C:7]([C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:9]=2)[N:4]=1.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:11]1[C:10]2[C:5](=[CH:6][C:7]([C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:9]=2)[N:4]=[C:3]([C:2]([F:25])([F:1])[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc2c(O)nc(C(F)(F)c3ccc(F)cc3)nc2c1
Product: COC(=O)c1ccc2c(Cl)nc(C(F)(F)c3ccc(F)cc3)nc2c1
Yield: 86 %

Procedure:
A mixture of methyl 2-(difluoro(4-fluorophenyl)methyl)-4-hydroxyquinazoline-7-carboxylate (1.1 g, 3.2 mmol) and phosphorus oxychloride (15 mL) was heated at reflux overnight. The mixture was concentrated under reduced pressure, and then toluene (20 mL) was added and evaporated under reduced pressure (2×). The residue in DCM was filtered through a pad of silica gel eluting with DCM. The filtrate was concentrated under reduced pressure to afford methyl 4-chloro-2-(difluoro(4-fluorophenyl)methyl)quinazoline-7-carboxylate (1 g, 86%). 1H NMR (300 MHz, DMSO-d6) δ 3.98 (s, 3H), 7.37 (t, 2H), 7.75 (t, 2H), 8.39 (d, 1H), 8.49 (s, 1H), 8.64 (d, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:23]I>CN(C=O)C.CCOC(C)=O>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)[CH3:23])=[CH:7][CH:8]=1
Reactant: CSc1ccc(Nc2nc(C)nc3ccccc23)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ccc(N(C)c2nc(C)nc3ccccc23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
To a solution of (4-methylthio-phenyl)-(2-methyl-quinazolin-4-yl)-amine (263 mg, 0.94 mmol) in DMF (4 ml) at 0° C. was added sodium hydride (56.4 mg, 1.40 mmol, 60% oil dispersion) and followed by methyl iodide (0.09 ml, 1.40 mmol). The mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature and stirred for another 2 h. The reaction mixture was diluted with EtOAc (15 ml), washed with saturated NaHCO3 aq., brine, dried over Na2SO4, filtered and concentrated by vacuum. The residue was purified by chromatography on silica gel with acetate and hexane (1:2 to 1:1) as eluent, yielding 120 mg of title compound (40.7%). 1H NMR (CDCl3): 7.76 (d, J=9.0 Hz, 1H), 7.54 (t, J=7.5 Hz, 1H), 7.24-7.19 (m, 2H), 7.10-6.97 (m, 4H), 3.59 (s, 3H), 2.74 (s, 3H), 2.48 (s, 3H)
Reaction SMILES: I.CS[C:4](=[N:18][CH3:19])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH3:20][O:21][CH2:22][CH2:23][NH2:24].C(O)C.[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH3:19][NH:18][C:4]([NH:24][CH2:23][CH2:22][O:21][CH3:20])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CN=C(Nc1ccccc1N1CCOCC1)SC
Reactant: COCCN
Agent: I
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CO
Product: CNC(=Nc1ccccc1N1CCOCC1)NCCOC

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-3-methyl-2-thiopseudourea hydroiodide (3.9 g prepared as described in Example 210), 2-methoxyethylamine (0.82 g) and ethanol (25 ml) was stored at ambient temperature for three months to yield an oil which was dissolved in methanol and treated with fumaric acid to give 1-methyl-2-(2-morpholinophenyl)-3-(2-methoxyethyl)guanidine monofumarate (m.p. 158°-160° C.) which was recrystallised rom a 1:2 mixture of methanol and ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:15])[S:10][C:11]=1[CH3:12]
Reactant: N[C@@H](Cc1ccc(F)cc1)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1sc(C(=O)N[C@@H](Cc2ccc(F)cc2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (276 mg, 1.08 mmol) [Prepared according to the procedure of Example 158], 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (317 mg, 0.95 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (612 mg, 1.31 mmol) in Chloroform (14 mL). DIEA (940 μL, 5.38 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (319 mg, 0.50 mmol, 71%): LC-MS (ES) m/z=537 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:7]([O:14]COC)=[C:6]([O:18][CH3:19])[CH:5]=1.Cl>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:7]([OH:14])=[C:6]([O:18][CH3:19])[CH:5]=1
Reactant: COCOc1c(OC)cc(C(=O)OC)cc1C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC)c(O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
To a solution of 3-methoxy-4-methoxymethoxy-5-trifluoromethylbenzoic acid methyl ester (453 mg) in THF (4 mL) was added 6N-hydrochloric acid (4 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1 to 3:1, v/v) to give the title compound (186 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:51])[NH:4][C@@H:5]([CH:48]([CH3:50])[CH3:49])[C:6]([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@H:9]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[C:23]3[CH2:25][O:26][C:27]4[CH:47]=[C:46]5[C:30]([CH:31]=[CH:32][C:33]6[N:37]=[C:36]([C@@H:38]7[CH2:42][C@H:41]([CH2:43][O:44][CH3:45])[CH2:40][NH:39]7)[NH:35][C:34]=65)=[CH:29][C:28]=4[C:22]3=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:7].[CH3:52][O:53][C:54]([NH:56][CH:57]([CH:61]([CH3:63])[CH3:62])[C:58](O)=[O:59])=[O:55].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:51])[NH:4][C@@H:5]([CH:48]([CH3:50])[CH3:49])[C:6]([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@H:9]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[C:23]3[CH2:25][O:26][C:27]4[CH:47]=[C:46]5[C:30]([CH:31]=[CH:32][C:33]6[N:37]=[C:36]([C@@H:38]7[CH2:42][C@H:41]([CH2:43][O:44][CH3:45])[CH2:40][N:39]7[C:58](=[O:59])[C@@H:57]([NH:56][C:54]([O:53][CH3:52])=[O:55])[CH:61]([CH3:63])[CH3:62])[NH:35][C:34]=65)=[CH:29][C:28]=4[C:22]3=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:7]
Reactant: COC(=O)NC(C(=O)O)C(C)C
Reactant: COC[C@@H]1CN[C@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(-c3cnc([C@@H]4C[C@H](C)CN4C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]3)ccc2-5)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(-c3cnc([C@@H]4C[C@H](C)CN4C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]3)ccc2-5)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl{(2S)-1-[(2S,4S)-2-(5-{2-[(2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (57 mg, 0.08 mmol), 2-methoxycarbonylamino-3-methylbutyric acid (19 mg, 0.1 mmol), HATU (303 mg, 0.79 mmol) in DMF (1 mL) was added diisopropylethylamine (43 μL, 0.24 mmol). After stirring for 2 hours at room temperature, the reaction was diluted with ethyl acetate, washed with 5% NaHCO3 solution, water and brine, dried (Na2SO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 43% ACN/H2O+0.1% TFA). The product fractions were lyophilized to give methyl{(2S)-1-[(2S,4S)-2-(5-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methyl butanoyl}-4-methoxymethylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate. (13 mg, 19%). MS (ESI) m/z 850 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:12]3[CH2:14][CH2:15][CH2:16][CH2:17][C:11]=3[O:10][C:9]=2[C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:7][C:6]=1[Cl:22])(=[O:3])[CH3:2]>[Pd]>[C:1]([NH:4][C:5]1[C:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10][C:9]=2[C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:7][C:6]=1[Cl:22])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)c2c3c(oc12)CCCC3
Agent: [Pd]
Product: COC(=O)c1cc(Cl)c(NC(C)=O)c2c1oc1ccccc12
Temperature: 230 °C

Procedure:
A mixture of 1 g methyl 1-acetylamino-2-chloro-6,7,8,9-tetrahydrodibenzofuran-4-carboxylate and 0.5 g of 5% palladium-charcoal is heated under nitrogen at 230° C. for 5 hours. The cooled residue is extracted with toluene and the solvent evaporated to dryness. The residue is crystallized from ethyl acetate/hexane to give methyl 1-acetylamino-2-chloro-dibenzofuran-4-carboxylate.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Cl)=[CH:10][CH:9]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CN(C=O)C.C(OCC)(=O)C>[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][N:19]2[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Potassium carbonate (1.45 g, 10.47 mmol) and 4-chlorobenzyl chloride (1.82 g, 8.86 mmol) were added to a solution of tert-butyl piperazine-1-carboxylate (1.5 g, 8.05 mmol) in DMF (10 ml), and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) to afford tert-butyl 4-(4-chlorobenzyl)piperazine-1-carboxylate (2.50 g, quantitative) as a colorless oil.
Reaction SMILES: CO[CH:3](OC)[C:4](=[N:7][OH:8])[C:5]#[N:6].[OH:11][CH2:12][CH2:13][NH:14][NH2:15].[ClH:16]>CO>[ClH:16].[NH2:6][C:5]1[N:14]([CH2:13][CH2:12][OH:11])[N:15]=[CH:3][C:4]=1[N:7]=[O:8]
Reactant: NNCCO
Reactant: COC(OC)C(C#N)=NO
Agent: Cl
Solvent: CO
Product: Nc1c(N=O)cnn1CCO
Temperature: 67 °C
Yield: 94 %

Procedure:
To a flask having an inner volume of 25 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged 1.47 g (10.0 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile with a purity of 98.1% by weight synthesized in the same manner as in Example 1, 0.84 g (10.5 mmol) of 2-hydroxyethylhydrazine with a purity of 95% by weight, 10 ml of methanol and 1.5 ml (18.0 mmol) of conc. hydrochloric acid, and the mixture was reacted under reflux (67° C.) for 1.5 hours. After completion of the reaction, when the reaction mixture was analyzed by high performance liquid chromatography (absolute calibration curve method), it was found that 1.81 g of 5-amino-1-(2-hydroxyethyl)-4-nitrosopyrazole hydrochloride (Reaction yield: 93.8%) had been formed.
Reaction SMILES: [Si]([O:18][C:19]1[CH:59]=[CH:58][C:22]([O:23][CH2:24][C@@H:25]([OH:57])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:56]=[CH:55][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=4[C:51]([F:54])([F:53])[F:52])=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[F:53][C:51]([F:52])([F:54])[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[CH2:44][NH:43][C:41]([N:38]1[CH2:39][CH2:40][CH:35]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:57])[CH2:24][O:23][C:22]3[CH:21]=[CH:20][C:19]([OH:18])=[CH:59][CH:58]=3)=[CH:56][CH:55]=2)[CH2:36][CH2:37]1)=[O:42]
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCc4ccccc4C(F)(F)F)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(NCc1ccccc1C(F)(F)F)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 58.3 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)anilino]-N-[2-(trifluoromethyl)benzyl]-1-piperidinecarboxamide (0.211 g, 0.24 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.085 g, 0.14 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]([CH:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[CH2:14][N:13]([C:24](Cl)=[O:25])[CH2:12]2)[CH3:10])=[N:6][CH:7]=1.CCN(CC)CC.[CH3:34][N:35]([CH3:44])[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]([CH:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[CH2:14][N:13]([C:24]([N:41]3[CH2:42][CH2:43][N:38]([CH2:37][CH2:36][N:35]([CH3:44])[CH3:34])[CH2:39][CH2:40]3)=[O:25])[CH2:12]2)[CH3:10])=[N:6][CH:7]=1
Reactant: CC(Oc1ccc(Cl)cn1)C1CN(C(=O)Cl)CC1c1ccc(Cl)c(Cl)c1
Reactant: CN(C)CCN1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(Cl)cn1)C1CN(C(=O)N2CCN(CCN(C)C)CC2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 35 %

Procedure:
To a stirred solution of (3SR,4RS)-3-[(RS)-1-(5-chloro-pyridin-2-yloxy)-ethyl]-4-(3,4-dichloro-phenyl)-pyrrolidine-1-carbonyl chloride (80 mg, 0.18 mmol) in CH2Cl2 (2 mL) were added Et3N (0.03 mL, 0.15 mmol) and dimethyl-(2-piperazin-1-yl-ethyl)-amine (0.035 mL) (commercially available). Stirring was continued overnight, and the reaction mixture was concentrated under vacuo and directly purified by flash chromatography (SiO2, CH2Cl2/MeOH/NH3, 9/4/1) to yield 36 mg (35%) the title compound as light yellow oil. ES-MS m/e: 553.8 (M+H+).
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[Cl:7][CH2:8][C:9](Cl)=[O:10].Cl.[Cl-].[Na+]>[OH-].[Na+]>[Cl:7][CH2:8][C:9]([N:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2])=[O:10]
Reactant: O=C(Cl)CCl
Reactant: CNCC(=O)O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: CN(CC(=O)O)C(=O)CCl
Temperature: -5 °C

Procedure:
Sarcosine (32.38 g, 363 mmol) was dissolved in 90 mL 4N aqueous sodium hydroxide, and cooled in an ice-salt bath to -5° C. The mixture was stirred vigorously and treated simultaneously with chloroacetyl chloride (32 mL, 402 mmol) and 110 mL 4N aqueous sodium hydroxide dropwise over 20 minutes. After warming to ambient temperature and stirring for 34 hours, the solution was carefully acidified to pH 2 (concentrated hydrochloric acid), saturated with sodium chloride, and extracted with ethyl acetate (2×400 mL). The extracts were combined, dried over anhydrous magnesium sulfate and evaporated to afford N-chloroacetylsarcosine as an oil, sufficiently pure for the next step (39.34 g, 238 mmol, 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[OH:21][NH2:22].C([O-])(=O)C.[Na+].C(OCC)(=O)C.CCCCCC>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[N:22][OH:21])[CH:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: NO
Reactant: CCCC(CCC)C(=O)c1ccc(OC)c(OC)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCCC(CCC)C(=NO)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
To a stirred solution of 3′,4′-dimethoxy-2-propylvalerophenone (2.64 grams, 10 mmol) in a mixture of ethanol (45 milliliters) and water (10 milliliters) was added hydroxyamine hydrochloride (1.11 grams, 16 mmol) and sodium acetate (1.64 grams, 20 mmol) in water (10 milliliters). The solution was refluxed for 1 week. Reaction progress was monitored by TLC (30%, ethyl acetate/hexane, UV) and had reached an equilibrium after 1 week. The reaction was allowed to cool to ambient temperature and the ethanol was removed in vacuo to afford an oil/aqueous mixture which was extracted with methylene chloride, dried over magnesium sulfate and concentrated in vacuo to afford 2.93 grams of crude product as a yellow oil. The crude product was purified by flash chromatography (silica gel, 30%, ethyl acetate/hexane) to afford 1.28 grams (46%) of product as a yellow oil. 1H NMR (CDCl3) δ7.10-6.75(m, 3H), 3.78-3.96(m, 6H), 3.49-3.31(m, 0.5H), 2.65-2.50 (m, 0.5H), 1.91-1.19(m, 8H), 1.01-0.81(m, 6H). 13C NMR (CDCl3) δ162.5, 161.5, 149.5, 149.0, 148.6, 129.4, 125.9, 120.2, 111.2, 110.6, 110.5, 55.9, 55.8, 45.1, 38.9, 34.8, 21.3, 20.5, 14.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:6][C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([N+:14]([O-])=O)=[C:9]([N:17]1[CH:21]=[C:20]([CH2:22][OH:23])[N:19]=[CH:18]1)[CH:8]=2)[CH3:2].CN(C)C=O>C(O)C.[Pd]>[NH2:14][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[N:17]1[CH:21]=[C:20]([CH2:22][OH:23])[N:19]=[CH:18]1)[N:6]=[C:5]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:4]([O:3][CH2:1][CH3:2])=[N:13]2
Reactant: CCOC(=O)c1nc2cc(-n3cnc(CO)c3)c([N+](=O)[O-])cc2nc1OCC
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1nc2cc(-n3cnc(CO)c3)c(N)cc2nc1OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl 3-ethoxy-7-(4-(hydroxymethyl)imidazole-1-yl)-6-nitroquinoxaline-2-carboxylate&Asteriskpseud;A (2.00 g, 5.16 mmol) in ethanol (200 ml) was added 10% palladium on carbon (200 mg), and the mixture was stirred for 4 hours at room temperature under hydrogen atmosphere (4 atm, 392 KPa). After completion of reaction, N,N-dimethylformamide was added to the reaction mixture to dissolve the precipitated crystals and then catalyst was filtered off using celite. By distilling off solvent, 1.89 g of title compound were obtained as yellow powder. The yield was quantitative.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.CO[CH:13](OC)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[CH:15]=1>>[N:20]1([C:16]2[CH:15]=[C:14]([CH:13]3[C:3]4[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=4[NH:1][C:2]4[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]3=4)[CH:19]=[CH:18][CH:17]=2)[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: COC(OC)c1cccc(-n2ccnc2)c1
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1cccc(-n2ccnc2)c1

Procedure:
Reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 3-(1-imidazolyl)-benzaldehyde dimethyl acetal in an analogous manner to that described in Example 1 gave 3,4,6,7,9,10-hexahydro-9-[3-(1-imidazolyl)-phenyl]-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from methanol/water gave a yellow crystalline solid of melting point 286-288° C.