Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH3:18][C:19]1[C:25]2[CH:26]=[CH:27][C:28]([NH2:30])=[CH:29][C:24]=2[NH:23][C:21](=[O:22])[CH:20]=1>>[ClH:1].[CH3:18][C:19]1[C:25]2[C:24](=[CH:29][C:28]([NH:30][C:2]3[CH:7]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=4)[N:5]=[CH:4][N:3]=3)=[CH:27][CH:26]=2)[N:23]=[C:21]([OH:22])[CH:20]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: Cc1cc(=O)[nH]c2cc(N)ccc12
Product: Cc1cc(O)nc2cc(Nc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)ccc12
Product: Cl

Procedure:
Analogous to the procedure used to prepare Example 5(b), 4-chloro-6-(4-trifluoromethylphenyl)pyrimidine, Example 5(a), (150 mg, 0.58 mmol) and carbostyril 124 (50 mg, 0.29 mmol, Aldrich) afforded, after recrystallization from MeOH, the title product as bright-yellow crystals. MP: 373° C. (with decomposition). MS (ESI, pos. ion) m/z: 397 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:22]=[CH:21][C:8](/[CH:9]=[N:10]/[C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][O:14][C:15]3=[O:20])=[CH:7][CH:6]=1)[CH3:3].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1.[O-:35][CH2:36][CH3:37].[Na+].CO>C(OCC)(=O)CC>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH:9]2[CH:29]([C:28]3[CH:31]=[CH:32][C:25]([C:24]([F:34])([F:33])[F:23])=[CH:26][CH:27]=3)[C:13](=[O:14])[C:12]3[C:16]([C:15]([O:35][CH2:36][CH3:37])=[O:20])=[CH:17][CH:18]=[CH:19][C:11]=3[NH:10]2)=[CH:21][CH:22]=1)[CH3:1]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CN(C)Cc1ccc(/C=N/c2cccc3c2COC3=O)cc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC(=O)CC
Solvent: CO
Product: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(C(F)(F)F)cc1)C(c1ccc(CN(C)C)cc1)N2
Temperature: 0 °C
Reaction time: 4 h
Yield: 16 %

Procedure:
A mixture of (E)-4-(4-((dimethylamino)methyl)benzylideneamino)isobenzofuran-1(3H)-one (541 mg, 1.84 mmol) and 4-(trifluoromethyl)benzaldehyde (320 mg, 1.84 mmol) in anhydrous ethyl propionate (25 mL) was cooled to 0° C. Then sodium ethoxide in methanol solution (sodium (127 mg, 5.51 mmol) in anhydrous ethanol (10 mL)) was added dropwise and the mixture was stirred at 25° C. for 4 hr. The resulting mixture was quenched with water (5 mL), and then evaporated the solvents off under reduced pressure. The residue was extracted with ethyl acetate (100 mL×3) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated to give crude product, which was purified by column chromatography (silica gel, dichloromethane to dichloromethane/methanol=30:1) to give the title compound (150 mg, yield 16%) as a yellow solid. LC-MS (ESI) m/z: 497 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-]>BrC1C=CC(OC)=CC=1.C1COCC1.CCOCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH3:1])=[CH:10][CH:11]=2)=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccccc1)c1ccc(OCc2ccccc2)cc1
Agent: COc1ccc(Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C(=Cc2ccccc2)c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 159.6 %

Procedure:
To the Grignard reagent prepared from 1.52 g (63 mg-atom) Mg turnings and 13.45 g (9 mL, 72 mmol) 4-bromoanisole (initiated with one I2 crystal and one drop EtBr2) in 25 mL THF was added 3 g (9.9 mmol) of Benzyl 4-benzyloxyphenyl ketone, prepared in Example 3. The reaction mixture was stirred at reflux for 48 h and then treated with 10 mL aqueous NH4Cl. After cooling to room temperature, the slurry was filtered, the filter cake washed with 50 mL THF, and the filtrates concentrated to give an orange oil. The oil was chromatographed over 60 g flash SiO2 (petroleum ether followed by Me2CO). The Me2CO fractions were combined, concentrated, dissolved in 100 mL 1:1 95% EtOH-2N H2SO4, and refluxed with stirring for 8 h. The solvents were removed to give a brown gum, which was dissolved in 100 mL Et2O, washed with saturated aqueous NaHCO3 (100 mL), brine (100 mL), and H2O (100 mL). The organic layer was dried (MgSO4), filtered, and concentrated to give a brown oil. The oil was purified on 60 g flash SiO2 (9:1 petroleum ether-CH2Cl2) to give 3.1 g of 1-(4-Benzyloxyphenyl)-1-(4-methoxyphenyl)-2-phenylethene (80%) as a clear oil. NMR δ7.41 (brs, 5H, O-benzyl C6H5), 7.3 to 6.75 (m, 9H, substituted rings' ArH and C=CH), 7.11 (s, 5H,=C--C6H5), 5.05 (s, 2H, OCH2Ph), 3.79 (s, 3H, OCH3).
Reaction SMILES: C1(OC)C=CC=CC=1.C(OC([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH2:25][C@@H:26]2[CH2:31][N:30]3[CH2:32][C:33]([C:36]4[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=4)=[CH:34][CH2:35][C@@H:29]3[CH2:28][N:27]2[C:42](=[O:57])[C:43]2[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:46]=[C:45]([C:53]([F:56])([F:55])[F:54])[CH:44]=2)=[CH:17]1)=O)(C)(C)C.C(OC(N1C2C(=CC=CC=2)C(C[C@@H]2CN3C=C(C4C=CN=CC=4)CC[C@@H]3CN2C(=O)C2C=C(C(F)(F)F)C=C(C(F)(F)F)C=2)=C1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:56][C:53]([F:54])([F:55])[C:45]1[CH:44]=[C:43]([C:42]([N:27]2[C@H:26]([CH2:25][C:18]3[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:16][CH:17]=3)[CH2:31][N:30]3[CH:32]=[C:33]([C:36]4[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=4)[CH2:34][CH2:35][C@@H:29]3[CH2:28]2)=[O:57])[CH:48]=[C:47]([C:49]([F:50])([F:51])[F:52])[CH:46]=1
Reactant: CC(C)(C)OC(=O)n1cc(C[C@@H]2CN3CC(c4ccncc4)=CC[C@@H]3CN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc21
Agent: CC(C)(C)OC(=O)n1cc(C[C@@H]2CN3C=C(c4ccncc4)CC[C@@H]3CN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@H]2CCC(c3ccncc3)=CN2C[C@H]1Cc1c[nH]c2ccccc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To mixture of anisole (35 mg), (3R,9aR)-3-[2-(3,5-bis(trifluoromethyl)-benzoyl)-7-pyridin-4-yl-1,3,4,6,9,9a-hexahydro-2H-pyrido[1,2-a]pyrazin-3-ylmethyl]-indole-1-carboxylic acid tert-butyl ester and (3R,9aR)-3-[2-(3,5-bis(trifluoromethyl)-benzoyl)-7-pyridin-4-yl-1,3,4,8,9,9a-hexahydro-2H-pyrido[1,2-a]pyrazin-3-ylmethyl]-indole-1-carboxylic acid tert-butyl ester (0.20 g) in dichloromethane (2 ml) was added trifluoroacetic acid, at 0° C. After 1.5 h at room temperature the mixture was diluted with dichloromethane, quenched with ice, and carefully basified with ammonium hydroxide. The layers were separated, the organic layer dried filtered and concentrated in vacuo. The residue was dissolved in methanol and heated at 50° C. for 1 h, then cooled to room temperature and concentrated in vacuo. The residual solid was stirred with hexanes overnight and then collected by filtration to afford (3R,9aR)-(3,5-bis(trifluoromethyl)phenyl)-[3-(1H-indol-3-ylmethyl)-7-pyridin-4-yl-1,3,4,8,9,9a-hexahydro-pyrido[1,2-a]pyrazin-2-yl]-methanone (compound 1) (70 mg). Rf 0.51 (SiO2, CH2Cl2/MeOH/NH4OH 93:7:0.5).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:44])[CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:27]3[C:26]4[C@@H:25]([CH2:28][C@@H:29]([NH:33][C:34](=O)[O:35]CC5C=CC=CC=5)[C:30](=[O:32])[NH2:31])[CH2:24][CH2:23][C:22]=4[S:21][C:20]=3[N:19]=[CH:18][N:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.C(OCC)(=O)C>[O:35]=[C:34]1[NH:33][C@H:29]([CH2:28][C@H:25]2[CH2:24][CH2:23][C:22]3[S:21][C:20]4[N:19]=[CH:18][N:17]=[C:16]([O:15][CH:12]5[CH2:11][CH2:10][CH:9]([N:8]([CH3:44])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:14][CH2:13]5)[C:27]=4[C:26]2=3)[C:30](=[O:32])[NH:31]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@@H](NC(=O)OCc2ccccc2)C(N)=O)CC4)CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H]2NC(=O)NC2=O)CC4)CC1
Temperature: 70 °C
Reaction time: 4 h
Yield: 77.6 %

Procedure:
To a solution of benzyl N-[(1R)-2-[(3R)-12-[(4-[[(tert-butoxy)carbonyl](methyl)amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]-1-carbamoylethyl]carbamate (80 mg, 0.15 mmol, 1.00 equiv) in 20 mL of THF was added TBAF hydrate (134 mg, 0.51 mmol, 4.00 equiv) at room temperature. The resulting solution was stirred for 4 h at 70° C. under nitrogen. After cooling down to room temperature, the resulting solution was diluted with 50 mL of ethyl acetate and washed with H2O and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10) to yield 60 mg (94%) of tert-butyl N-(4-[[(3R)-3-[[(4R)-2,5-dioxoimidazolidin-4-yl]methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate as a white solid.
Reaction SMILES: C(O)C.Cl.[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7][CH:6]=1>O=[Pt]=O.O1CCCC1>[NH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: Oc1ccc2cccnc2c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: Oc1ccc2c(c1)NCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
PtO2 (528 mg, 2.33 mmol) was added to a dry flask. Ethanol (70 mL), tetrahydrofuran (70 mL), and hydrogen chloride (7.6 mL, 2N) were added after the flask was flushed with argon. Quinolin-7-ol (1000 mg, 6.89 mmol) was added into the flask under argon atmosphere. The solution was degassed and flashed with argon. Hydrogen gas was introduced to the flask by a balloon. The mixture was stirred at H2 atmosphere at room temperature overnight. The mixture was filtered and the filtrate was concentrated. The resulting residue was purified by MPLC (biotage) to afford 730 mg (71%) of the title compound. 1H-NMR (CDCl3) δ 6.77 (d, J=7.6 Hz, 1H), 6.10 (dd, J=8.0 Hz, 2.8 Hz, 1H), 5.95 (d, J=2.4 Hz, 1H), 3.24 (t, J=5.9 Hz, 2H), 2.66 (t, J=5.9 Hz, 2H), 2.44 (m, 2H); Rf=0.74, 50% ethyl acetate-hexane.
Reaction SMILES: CO[C:3]1[C:4](=[O:21])[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](OC)[CH:14]=2)[CH2:6][CH2:7][C:8]=1[C:9](=O)[CH2:10][CH3:11].Cl.[CH:23]1([NH:28][NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24]1.[CH3:30][O-:31].[Na+]>C(O)C>[CH:23]1([N:28]2[C:3]3[C:4](=[O:21])[N:5]([C:13]4[CH:14]=[CH:15][C:16]([O:31][CH3:30])=[CH:17][CH:18]=4)[CH2:6][CH2:7][C:8]=3[C:9]([CH2:10][CH3:11])=[N:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C[O-]
Reactant: CCC(=O)C1=C(OC)C(=O)N(c2cccc(OC)c2)CC1
Reactant: NNC1CCCC1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCc1nn(C2CCCC2)c2c1CCN(c1ccc(OC)cc1)C2=O
Reaction time: 16 h

Procedure:
A stirred mixture of 3-methoxy-1-(3-methoxyphenyl)-2-oxo-4-propionyl-1,2,5,6-tetrahydro-pyridine (0.49 grams, 1.7 mmole), cyclopentylhydrazine hydrochloride (0.40 grams) and sodium methoxide (46 mg, 0.85 mmole) in anhydrous ethanol was heated to reflux. After 16 hours, the mixture was concentrated under reduced pressure and chromatographed on a silica gel column using 1:4 ethyl acetate/hexane as eluent to give a white solid. Recrystallization from ether gave white needles. M.P. 64.65° C.; MS m/z [M+] 340.2025; HRMS [M+] 340.2046.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[N:4][N:3]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)[CH2:24][CH2:23]1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6]([C:5]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[N:4][N:3]=[C:2]2[NH:21][CH:22]2[CH2:23][CH2:24][N:25]([CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=3)[CH2:26][CH2:27]2)=[CH:7][CH:8]=1
Reactant: COc1ccc2c(-c3ccc(C)cc3)nnc(Cl)c2c1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Product: COc1ccc2c(-c3ccc(C)cc3)nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-7-methoxy-4-(4-methylphenyl)phthalazine with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[OH:10])[CH:5]=[O:6].[OH-].[K+].I[CH2:15][CH3:16]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[O:10][CH2:15][CH3:16])[CH:5]=[O:6]
Reactant: O=Cc1cc(F)c(O)c(Cl)c1
Reactant: CCI
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1c(F)cc(C=O)cc1Cl
Yield: 98 %

Procedure:
3-Chloro-5-fluoro-4-hydroxybenzaldehyde (1.0 gram, 5.7 mmol) in THF (40 mL) was heated at reflux for 17 hrs with KOH (534 mg, 9.5 mmol, 1.7 eq) in water (5 mL) and iodoethane (1 mL, 2.2 eq). The reaction was then transferred to a separatory funnel with water and extracted with methylene chloride (thrice, 150 mL each). The combined organic layers were washed with 10% aqueous HCl (40 mL), dried (MgSO4), and concentrated to a viscous orange liquid to yield 1.13 g of 3-chloro-4-ethoxy-5-fluorobenzaldehyde (98%). 1H-NMR (500 MHz, CDCl3): 9.84 (d, J=1.9 Hz, 1H), 7.71 (t, J=1.6 Hz, 1H), 7.53 (dd, J=1.9, 10.7 Hz, 1H), 4.37-4.32 (m, 2H), 1.47-1.40 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.O[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]cc(I)c12
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(I)c3c(Cl)ncnc32)CC1
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
A solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (6.48 g, 21.78 mmol) in tetrahydrofuran (200 mL) at 0° C. under a nitrogen atmosphere was treated with tert-butyl 4-hydroxy-1-piperidinecarboxylate (13.147 g, 65.33 mmol) and triphenylphosphine (11.43 g, 43.56 mmol) and stirred for 30 minutes. Diethylazodicarboxyate (7.61 g, 43.56 mmol) was added drop-wise over 15 minutes to the reaction solution. The ice bath was removed after 15 minutes, and the reaction mixture was allowed to stir over night. The solvent was evaporated under reduced pressure, and then the yellow gummy solid dissolved in dichloromethane. The solid precipitated was filtered and discarded. The filtrate was evaporated under reduced pressure. Recrystallization from ethyl acetate/heptane yielded 4.82 g (47%) of tert-butyl 4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate. 1H NMR (DMSO-d6, 400 MHz) 8.64(s, 1H), 8.20 (s, 1H), 4.89-4.84(m, 1H), 4.13-4.10 (m, 2H), 3.00-2.80(br s, 2H), 2.01-1.88 (m, 4H), 1.43(s, 9H). Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 m, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 7.825 minutes.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[N:15]([C:39]2[CH:44]=[CH:43][C:42]([S:45][CH3:46])=[CH:41][CH:40]=2)[C:16](=[O:38])[C:17]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:26][CH:25]=2)=[C:18]([CH2:20][CH2:21][CH3:22])[N:19]=1>O.C(OCC)(=O)C>[CH3:13][C:14]1[N:15]([C:39]2[CH:44]=[CH:43][C:42]([S:45][CH3:46])=[CH:41][CH:40]=2)[C:16](=[O:38])[C:17]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:3][C:4](=[O:7])[O:5][N:37]=3)=[CH:28][CH:29]=2)=[C:18]([CH2:20][CH2:21][CH3:22])[N:19]=1
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)n(-c2ccc(SC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(SC)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
A mixture of hydroxylammonium chloride (0.35 g), sodium hydrogen carbonate (0.51 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C. for 30 min, 4′-({2-methyl-1-[4-(methylthio)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.24 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (3 mL). N,N′-carbonyldiimidazole (0.10 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.091 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.17 g, 64%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[NH:14][N:13]=2)[C:5]2[CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[NH:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([OH:24])=[O:23].[OH-].[Na+].C(N(CC)C(C)C)(C)C>O1CCOCC1>[CH:17]([C:15]1[NH:14][N:13]=[C:12]([NH:11][C:4]2[C:5]3[CH2:10][CH2:9][CH2:8][C:6]=3[N:7]=[C:2]([N:20]3[CH2:27][CH2:26][CH2:25][CH:21]3[C:22]([OH:24])=[O:23])[N:3]=2)[CH:16]=1)([CH3:19])[CH3:18]
Reactant: CC(C)c1cc(Nc2nc(Cl)nc3c2CCC3)n[nH]1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cc(Nc2nc(N3CCCC3C(=O)O)nc3c2CCC3)n[nH]1
Temperature: 100 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
To a suspension of 2-chloro-N-(5-isopropyl-1H-pyrazol-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine, Compound (iii) (5 g, 18 mmol) in dioxane (60 mL) was added L-proline (3.11 g, 27 mmol) followed by 5N NaOH (5.4 mL, 27 mmol) and N,N-diisopropylethyl amine (2.32 g, 18 mmol). The reaction mixture was allowed to stir at 100° C. for 16 h. The solvent was removed under reduced pressure and the residue was acidified with 1 N HCl solution to pH 4. The product was suspended in water (10 mL), filtered, washed with ether and dried to afford 1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylic acid (5 g, 78% yield).
Reaction SMILES: [C:1]([CH:4]([NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)(=O)[CH3:2].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Br:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH2:5][C:4]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[O:15][C:1]=2[CH3:2])[CH:7]=1
Reactant: CC(=O)C(Cc1cccc(Br)c1)NC(=O)c1ccc(C)cc1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-c2nc(Cc3cccc(Br)c3)c(C)o2)cc1
Yield: 86.2 %

Procedure:
1-[2-Acetyl-2-(p-toluoylamino)ethyl]-3-bromobenzene (13.26 g) was dissolved in 260 ml of toluene, and 6.8 ml of phosphorus oxychloride was added and heated to reflux for 3 hours. The reaction solution was cooled, poured into ice-cold water and extracted with ethyl acetate. The resulting solution was washed with aqueous solution of saturated sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=4:1) to provide 10.86 g of the objective compound as yellowish crystals. M.p. 74–75° C.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:20][C:21]([CH3:44])([CH3:43])[C:22](=[O:42])[O:23][CH2:24][O:25][P:26]([CH2:38][C:39](O)=[O:40])([CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:27]>CN(C)C=O>[CH3:20][C:21]([CH3:44])([CH3:43])[C:22](=[O:42])[O:23][CH2:24][O:25][P:26]([CH2:38][C:39]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:40])([CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:27]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)(C)C(=O)OCOP(=O)(CCCCc1ccccc1)CC(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCOP(=O)(CCCCc1ccccc1)CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
L-Phenylalanine (1.65 g, 10 mmol), triethylamine (2.8 ml, 20 mmol) and [[(2,2-dimethyl-1-oxopropoxy)methoxy]-(4-phenylbutyl)phosphinyl]acetic acid, N-hydroxy succinimide ester (4.67 g, 10 mmol) are dissolved in 50 ml of dry dimethylformamide and stirred overnight under argon at room temperature. The reaction mixture is partitioned between dichloromethane and 5% KHSO4, and the organic layer is washed with water and brine and then dried and evaporated to yield the desired product.
Reaction SMILES: [Cl:1]Cl.[CH:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1>>[Cl:1][C:10]1[C:9]2[C:8](=[O:18])[C:7]3[C:16](=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:15](=[O:17])[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Reactant: ClCl
Product: O=C1c2ccccc2C(=O)c2c(Cl)cccc21
Yield: 99 %

Procedure:
1,400 g of a 93% pure 1-chloroanthraquinone, produced from anthraquinone-1-sulphonic acid by exchanging the sulpho group by chlorine according to Fischer (Ullmann's Encyklopaedie der technischen Chemie (Ullmann's Encyclopaedia of Industrial Chemistry), 4th Edition, Volume 7, Example 1, page 589 (1973)) and contaminated with 0.5% of anthraquinone, 2.0% of 1,6- and 1,7-dichloroanthraquinone, 2.5% of 1,5- and 1,8-dichloroanthraquinone and 2.0% of other compounds, are employed in the flask of the test installation (according to Example 1). At an absolute pressure at the top of 20 mm Hg and a reflux ratio R/T= 4/1, highly pure 1-chloroanthraquinone (>99% pure) is obtained:
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=O)[CH2:8]1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[N:23][NH:22][C:19]([NH2:21])=[NH:20])[CH2:8]1
Reactant: N=C(N)NN
Reactant: Cc1ccnc2c1C(=O)CC(c1sccc1Cl)C2
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1sccc1Cl)C2
Yield: 115 %

Procedure:
A mixture of 7-(3-chloro-2-thienyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.3 g), aminoguanidine hydrochloride (0.14 g), concentrated hydrochloric acid (0.27 ml), water (0.27 ml) and ethanol (30 ml) was refluxed for 6 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added water. The mixture was washed with ethyl acetate, and to the mixture was added sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethanol. To the solution was added a solution of 4N hydrochloric acid-ethyl acetate (0.4 ml), and the mixture was concentrated under reduced pressure. The resulting crystals were recrystallized from ethanol-water to give 7-(3-chloro-2-thienyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 74) (0.23 g) as colorless crystals.