Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:12][C@H:13]2[C@@H:17]([O:18][CH2:19][CH3:20])[CH2:16][N:15]([C:21]([O:23][CH3:24])=[O:22])[CH2:14]2)=[N:5][C:6]([CH2:10][CH3:11])=[C:7]([I:9])[N:8]=1)[CH3:2].C(C1C(N[C@H]2[C@@H](OCC)CN(C(OC[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=O)C2)=NC(CC)=CN=1)C>>[CH2:1]([C:3]1[C:4]([NH:12][C@H:13]2[C@@H:17]([O:18][CH2:19][CH3:20])[CH2:16][N:15]([C:21]([O:23][CH2:24][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:22])[CH2:14]2)=[N:5][C:6]([CH2:10][CH3:11])=[C:7]([I:9])[N:8]=1)[CH3:2]
Reactant: CCO[C@H]1CN(C(=O)OC)C[C@H]1Nc1nc(CC)c(I)nc1CC
Reactant: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)cnc1CC
Product: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(I)nc1CC

Procedure:
Following the procedure for the preparation of methyl (3R,4S)-3-[(3,6-diethyl-5-iodopyrazin-2-yl)amino]-4-ethoxypyrrolidine-1-carboxylate but substituting benzyl (3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-ethoxypyrrolidine-1-carboxylate provided the title compound as an oil: 1H NMR (400 MHz, CDCl3) δ) 7.30–7.25, 5.06, 4.96, 4.53, 3.96, 3.86, 3.64–3.47, 3.35, 3.25–3.13, 2.68, 2.51, 1.20–1.12; IR (liq.) 2972, 2338 (w), 1949 (w), 1708 (s), 1554 (s), 1537 (s), 1475 (s), 1456 (s), 1447 (s), 1421 (s), 1394 (s), 1351 (s), 1165, 1126, 1097 (s) cm−1 HRMS (ESI) calcd for C22H29N4O3I+H1 25.1364. found 525.1359. Anal. Calcd for C22H29IN4O3: C, 50.39; H, 5.57; N, 10.68. Found: C, 50.48; H, 5.60; N, 10.44.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[CH:17]=O)=O)(=O)C.[NH3:19]>CCO>[CH3:16][O:15][C:12]1[CH:11]=[C:10]2[C:9](=[CH:14][CH:13]=1)[N:8]=[C:6]([CH2:5][OH:4])[N:19]=[CH:17]2
Reactant: N
Reactant: COc1ccc(NC(=O)COC(C)=O)c(C=O)c1
Solvent: CCO
Product: COc1ccc2nc(CO)ncc2c1
Temperature: 25 °C
Yield: 107.8 %

Procedure:
The solution of 2-(2-formyl-4-methoxyphenylamino)-2-oxoethyl acetate (5 g, 0.02 mol) and ammonia (6.8 g, 0.4 mol, 20 eq) in EtOH (30 mL) was reacted under a high pressure (30 psi) at 135° C. for 5 h. After cooling to room temperature, the solvent was evaporated in vacuum. The residual aqueous solution was extracted with DCM (100 mL×3). The combined extracts were dried over anhydrous Na2SO4 and evaporated to dryness in vacuum. The crude product was purified by chromatography (eluting with DCM/MeOH=100/1) to give (6-methoxyquinazolin-2-yl)methanol (4.1 g, yield: 90%) as a white solid. 1HNMR (400 MHz, DMSO-d6) δ: 9.46 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.63 (d, J=8.8, 3.2 Hz, 1H), 7.52 (d, J=2.8 Hz, 1H), 5.34 (t, J=6.4 Hz, 1H), 4.72 (d, J=6.4 Hz, 2H), 3.91 (m, 3H); ESI-MS: m/z 191.1 ([M+1]+).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:11]=1[O:12][CH:13]1[CH2:16][NH:15][CH2:14]1.[C:22](Cl)(=[O:24])[CH3:23]>O1CCCC1>[C:22]([N:15]1[CH2:14][CH:13]([O:12][C:11]2[C:17]([CH3:21])=[CH:18][CH:19]=[CH:20][C:10]=2[CH3:9])[CH2:16]1)(=[O:24])[CH3:23]
Reactant: Cc1cccc(C)c1OC1CNC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CC(Oc2c(C)cccc2C)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
Triethylamine (10.8 g, 106 mmol) was added to a stirred slurry of 3-(2,6-dimethylphenoxy)azetidine monohydrochloride (9.10 g, 42.7 mmol) in tetrahydrofuran (500 mL). After 10 minutes the reaction mixture was cooled to 0° C., and a solution of acetyl chloride (5.03 g, 64.1 mmol) in 50 mL of tetrahydrofuran was added dropwise. The reaction mixture was allowed to come to ambient temperature and was stirred overnight. The reaction mixture was then filtered and the filtrate concentrated in vacuo. The residue was chromatographed (flash, SiO2) eluting with methylene chloride/methanol (9:1) to give 9.00 g (99%) of yellow powder with a melting point of 40.0°-42.5° C.
Reaction SMILES: [C:1]([N:8]([CH3:29])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH2:24][CH3:25])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:31]1[CH:32]=[CH:33][C:34]([CH3:37])=[N:35][CH:36]=1>>[CH2:24]([O:23][C:22]1[CH:21]=[CH:20][C:19]([C:31]2[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][CH:32]=2)=[CH:18][C:17]=1[CH2:16][NH:15][CH:12]1[CH2:13][CH2:14][CH:9]([N:8]([CH3:29])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]1)[CH3:25]
Reactant: Cc1ccc(Br)cn1
Reactant: CCOc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: CCOc1ccc(-c2ccc(C)nc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 11 (812 mg, 2.0 mmol) is coupled to 5-bromo-2-methylpyridine (344 mg, 2.0 mmol) using Method A to give the title compound.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1.[C-]#N.[Na+]>O.O1CCOCC1>[CH:1]1([O:6][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Brc1cccs1
Reactant: OC1CCCC1
Agent: [C-]#N
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: c1csc(OC2CCCC2)c1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 25.3 %

Procedure:
To a mixture of cyclopentanol (51.1 ml, 0.56 mol) and dioxane (50 mL) was added sodium hydride (60% in mineral oil, 4.91 g, 0.12 mol) at 0-5° C. under argon. The mixture was heated at 80° C. until an homogenous solution was observed. 2-Bromothiophene (10 g, 5.9 mL, 0.061 mol) was added at 80° C., followed by cuprous iodide (11.7 g, 0.061 mol). The mixture was heated at 120° C. for 6 hours. After cooling to 20-25° C., sodium cyanide (30 g, 0.61 mol) in water (200 mL) was added. The mixture was vigorously stirred for 20 minutes, filtered, and extracted with hexane. The hexane extract was washed with water, dried (Na2SO4), and concentrated to dryness. Filtration through a column (silica, 100% hexane) gave 2-cyclopentyloxythiophene (2.6 g, 25.2%) as a colorless oil; 1H NMR (300 MHz, CDCl3) δ 6.7 (dd, J=5.7, 3.7 Hz, 1H), 6.54 (dd, J=5.7, 1.5 Hz, 1H), /86.18 (dd, J=3.7, 1.5 Hz, 1H), 4.66 (Sept, J=2.7 Hz, 1H), 1.5-2.0 (m, 8H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[Br:15]Br.O.[OH-].[Na+]>CO>[Br:15][C:4]1[CH:3]=[C:2]([CH3:1])[S:6][C:5]=1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12]
Reactant: BrBr
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(Br)c(NC(=O)OC(C)(C)C)s1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 75.9 %

Procedure:
To a solution of tert-butyl 5-methylthiophen-2-ylcarbamate (5.1 g, 23.91 mmol) in MeOH (478 mL) at 0° C. was added drop wise a solution of bromine (1.232 mL, 23.91 mmol) in MeOH (478 mL) during 1.5 h. The reaction mixture was then stirred at 0° C. for 0.5 h and at ambient temperature for 45 min. The reaction was poured into water (400 mL) and the solution was neutralized with 2 M NaOH (aq). MeOH was removed under reduced pressure and the cloudy aqueous phase was extracted with DCM (3×200 mL). The combined organic phases were dried over MgSO4. The solvent was removed under reduced pressure to give (5.3 g, 76%) of the title compound that was used in the next step without further purification: LC/MS (Table 1, Method a) Rt=2.48 min; m/z: 292.1 (M−H)−.
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])[CH:5]=[CH:4][C:3]1=2.Cl.[CH2:21]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([NH:37]N)[CH:32]=2)=[CH:27][CH:26]=1)[CH2:22][CH2:23][CH3:24]>>[CH2:21]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[C:33]3[C:34]([C:11]4[CH2:10][CH2:9][C:8]5[CH:7]=[C:6]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])[CH:5]=[CH:4][C:3]=5[C:2]=4[NH:37]3)=[CH:35][CH:36]=2)=[CH:27][CH:26]=1)[CH2:22][CH2:23][CH3:24]
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: CCCCc1ccc(-c2cccc(NN)c2)cc1
Agent: Cl
Product: CCCCc1ccc(-c2ccc3c4c([nH]c3c2)-c2ccc(OS(=O)(=O)C(F)(F)F)cc2CC4)cc1

Procedure:
The title material is prepared by reacting Trifluoro-methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and (4′-Butyl-biphenyl-3-yl)-hydrazine hydrochloride (example 70, step 2) in an analogous manner and similar yield to example 1, step 3 except that purification is accomplished by reverse phase UV triggered HPLC. 1H NMR (400 MHz, d6-DMSO) d 11.63 (s, 1H), 7.78 (m, 2H), 7.58 (m, 4H), 7.46 (s, 1H), 7.33 (d, J=6.7 Hz, 1H), 7.28 (m, 2H), 3.09 (m, 2H), 2.95 (m, 2H), 2.64 (m, 2H), 1.60 (m, 2H), 1.35 (m, 2H), 0.94 (m, 3H); LC/MS calculated for [M+H]+ C27H25F3NO3S: 500.5, found: 500.0.
Reaction SMILES: C(=O)([O-])O.[K+].C(OC(=O)C)(=O)C.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N+:22]([O-:24])=[O:23])=[C:18]([CH:21]=1)[CH:19]=O.[C:25]([O:33][CH2:34][CH3:35])(=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N+:22]([O-:24])=[O:23])=[C:18]([CH:19]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:25]([O:33][CH2:34][CH3:35])=[O:32])[CH:21]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(=Cc1cc(Cl)ccc1[N+](=O)[O-])C(=O)OCC
Temperature: 110 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
Potassium hydrogen carbonate (8.12 g) was added to an acetic acid anhydride (18 ml) solution of 5-chloro-2-nitrobenzaldehyde (9.99 g) and diethyl malonate (8.64 g), which was stirred at 110° C. for 2 hours. The reaction mixture was added to iced-water and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/10) to obtain the entitled compound (15.10 g). 1H-NMR δ: 1.10(3H, t), 1.36(3H, t), 4.15(2H, q), 4.44(2H, q), 7.42(1H, d), 7.52(1H, dd), 8.11(1H, s), 8.18(1H, d).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[C:9]([NH2:13])[CH:10]=[CH:11][CH:12]=2)[O:4][N:3]=1.N1C=CC=CC=1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:22]>C(#N)C>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[C:9]([NH:13][C:21](=[O:22])[O:23][C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)[CH:10]=[CH:11][CH:12]=2)[O:4][N:3]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1noc(-c2cccc(N)c2)n1
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1noc(-c2cccc(NC(=O)Oc3ccc([N+](=O)[O-])cc3)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A solution of 3-[3-methyl(1,2,4-oxadiazol-5-yl)]phenyl amine (1.00 g, 5.7 mmol, prepared in sequence by the procedures described by Lin et al., J. Org. Chem., 1979, 44, 4160 and Bellamy and Ou, Tetrahedron Letters, 1984, 25, 839) in acetonitrile (25 mL) and pyridine (0.46 mL, 0.45 g, 5.7 mmol) under argon at 0° C. was treated with p-nitrophenyl chloroformate ( 1.15 g, 5.7 mmol) and was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and an effort was made to partition the remaining oil between ethyl acetate and 10% citric acid, resulting in separation of a solid insoluble in either phase. The solid was collected, triturated with hexane and dried in vacuo to yield 1.59 g (82%) of the title compound, m.p. 217°-220° C. TLC, silica gel, EtOAc/MeOH/HOAc (20:1:.2), Rf =0.75; M.S. (M+H)+ at 341, M.W. 340. This material contained minor impurities and was used without further purification.
Reaction SMILES: [CH2:1]([C:5]1[S:20][C:8]2[N:9]=[C:10]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][N:11]3[C:12](=[O:13])[C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4].[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH2:1]([C:5]1[S:20][C:8]2[N:9]=[C:10]3[CH:17]=[CH:16][C:15]([C:18]4[NH:23][N:22]=[N:21][N:19]=4)=[CH:14][N:11]3[C:12](=[O:13])[C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1cc2c(=O)n3cc(C#N)ccc3nc2s1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1cc2c(=O)n3cc(-c4nnn[nH]4)ccc3nc2s1
Yield: 56.4 %

Procedure:
From 7 g (0.025 mol) of 2-butyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile (Example 30), 8.45 g (0.13 mol) of sodium azide and 6.95 g (0.13 mol) of ammonium chloride in 250 ml of dimethylformamide heated at 125°-128° C. under a nitrogen atmosphere, following the procedure of Example 34, there is obtained 4.6 g of 2-butyl-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-4-one; mp 281° C. (dec) after recrystallization from dimethylformamide-methanol.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:15]=O)=[N:6][N:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:8]=1)([O-:3])=[O:2].[CH3:17][N:18]([CH3:32])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]([NH2:31])[C:26]([NH2:30])=[CH:27][C:28]=1[F:29]>CO>[F:29][C:28]1[C:23]([O:22][CH2:21][CH2:20][CH2:19][N:18]([CH3:17])[CH3:32])=[CH:24][C:25]2[NH:31][C:15]([C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][N:7]([CH:9]4[CH2:14][CH2:13][CH2:12][CH2:11][O:10]4)[N:6]=3)=[N:30][C:26]=2[CH:27]=1
Reactant: O=Cc1nn(C2CCCCO2)cc1[N+](=O)[O-]
Reactant: CN(C)CCCOc1cc(N)c(N)cc1F
Solvent: CO
Product: CN(C)CCCOc1cc2[nH]c(-c3nn(C4CCCCO4)cc3[N+](=O)[O-])nc2cc1F
Temperature: 22 °C
Reaction time: 18 h
Yield: 35.2 %

Procedure:
3.4 g of 4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazole-3-carbaldehyde are added to a solution of 3.5 g of 4-(3-dimethylaminopropoxy)-5-fluorobenzene-1,2-diamine in 150 mL of methanol. The reaction medium is stirred at 22° C. for 18 hours. After evaporation, the reaction crude is purified by flash chromatography on an Intelliflash apparatus on an Analogix RS-330 cartridge. The elution is carried out in dichloromethane with 10% of methanol. 2.3 g of (3-{6-fluoro-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-3H-benzimidazol-5-yloxy}-propyl)dimethylamine are isolated. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 1.50 to 2.23 (m, 8H); 2.80 (s, 6H); 3.23 (m, 2H); 3.68 (m, 1H); 3.98 (m, 1H); 4.17 (t, J=6.0 Hz, 2H); 5.58 (dd, J=2.5 and 9.5 Hz, 1H); 7.34 (d, J=8.0 Hz, 1H); 7.49 (d, J=11.0 Hz, 1H) 9.11 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(O)C.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(N(CC)CC)C>[NH2:1][C:2]1[C:7]([NH:8][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccnc1N
Reactant: BrCc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1ncccc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2,3-diaminopyridine (45 g), ethanol (500 ml), triethylamine (42 g) and benzyl bromide (70.5 g) was stirred at room temperature for 3 days. The solvent was evaporated in vacuo and the residue partitioned between chloroform (500 ml) and water (400 ml). The organic layer was eparated, filtered through a silica gel plug and evaporated in vacuo. The residue was triturated with hot chlorobutane to yield a brown powder.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([O:17]C)=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+]>O1CCCC1.O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([OH:17])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: COC(=O)c1cc2c(s1)-c1cc(Br)ccc1OC2
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2c(s1)-c1cc(Br)ccc1OC2
Reaction time: 15 h
Yield: 93.4 %

Procedure:
To a suspension of methyl 8-bromo-4H-thieno[3,2-c]chromene-2-carboxylate 2 (2.64 g, 8.12 mmol, 1 equiv) in 4:1 tetrahydrofuran/water (80 mL) was added aqueous potassium hydroxide (24 mL, 24 mmol, 3.0 equiv, 1.0 M solution in water) at 24° C. After 15 hr, the tetrahydrofuran was removed in vacuo (<20 mm Hg). The resulting aqueous suspension was diluted with water until all the solids were dissolved. To the resulting solution was added concentrated hydrochloric acid until the solution reached pH=1. The resulting solids were collected by filtration and dried in vacuo (<1 mm Hg) to afford 3bp as a yellow solid (2.36 g, 93%). 1H NMR (500 MHz, CDCl3), δ: 13.28 (br s, 1 H), 7.64 (d, J=2.4 Hz, 1 H), 7.60 (s, 1 H), 7.40 (dd, J=8.7, 2.4 Hz, 1 H), 6.94 (d, J=8.7 Hz, 1 H), 5.30 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[CH:5]=[CH:4][C:3]=1[OH:14].Cl[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[CH:5]=[CH:4][C:3]=1[O:14][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CCl
Reactant: Oc1ccc(Cn2cccn2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(Cn2cccn2)cc1Cl
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A mixture of 5.0 g of 2-chloro-4-(1-pyrazolyl)methylphenol (produced in Reference Production Example 2), 7.6 g of ethyl chloroacetate, 13.2 g of potassium carbonate and 100 ml of anhydrous dimethylformamide was heated at 50° C. under stirring for 5 hours, and then cooled to room temperature. The reaction mixture was poured into 500 ml of water, which was extracted twice with 50 ml of ethyl acetate. The organic layers were combined, washed with water, saturated aqueous ammonium chloride solution and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude ethyl 2-chloro-4-(1-pyrazolyl)methylphenoxyacetate as an oil.
Reaction SMILES: [OH:1][C:2]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([OH:20])=[C:12]2[C:3]=1[C:4](=O)[C:5]1[CH:6]=[C:7]([C:25]([OH:27])=[O:26])[C:8]([C:22]([OH:24])=[O:23])=[CH:9][C:10]=1[C:11]2=[O:21].[CH:29]([C:32]1[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]([CH3:41])[CH3:40])[C:33]=1[NH2:34])([CH3:31])[CH3:30].ClC1C=CC=CC=1Cl>O>[CH:39]([C:35]1[CH:36]=[CH:37][CH:38]=[C:32]([CH:29]([CH3:31])[CH3:30])[C:33]=1[N:34]=[C:4]1[C:3]2[C:12](=[C:13]([OH:20])[C:14]3[C:19]([C:2]=2[OH:1])=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11](=[O:21])[C:10]2[CH:9]=[C:8]([C:22]([OH:24])=[O:23])[C:7]([C:25]([OH:27])=[O:26])=[CH:6][C:5]1=2)([CH3:41])[CH3:40]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C(O)c1cc2c(cc1C(=O)O)C(=O)c1c(c(O)c3ccccc3c1O)C2=O
Solvent: O
Solvent: Clc1ccccc1Cl
Product: CC(C)c1cccc(C(C)C)c1N=C1c2cc(C(=O)O)c(C(=O)O)cc2C(=O)c2c1c(O)c1ccccc1c2O
Reaction time: 18 h
Yield: 49.3 %

Procedure:
0.5 g (1.32 mmoles) of 6,11-Dihydroxy-naphthacene-5,12-dione-2,3-dicarboxylic acid (product of Example 8), 0.28 g (1.58 mmoles) of 2,6-diisopropylaniline, and 25 ml of o-dichlorobenzene are refluxed for 4 h with azeotropic removal of the reaction water. The mixture is filtered while hot, and the filtrate is kept at 25° for 18 h. The precipitate is washed with hot hexane and dried to give 0.35 g (51%) of red crystals, m.p. 328-330°.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=1)=[O:9])([CH3:4])[CH3:3].[H][H]>C(O)C.C1COCC1.[Pd]>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1)=[O:9])([CH3:1])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(C(=O)NCc2cccc([N+](=O)[O-])c2)cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)c1cc(C(=O)NCc2cccc(N)c2)cc(C(C)(C)C)c1O
Yield: 42.8 %

Procedure:
In a 250 ml Parr flask, 2.40 g (6.2 mmoles) of 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(3-nitrophenyl)methyl]-benzamide is dissolved in 45 ml of an absolute ethanol/THF mixture (1/2) in the presence of 10% Pd/C. The mixture is agitated under 20 PSI of hydrogen, at 30° C., for three hours. After filtration on celite, the filtrate is concentrated to dryness and the residue is purified on a silica column (eluant: heptane/ethyl acetate: 60/40). The pure fractions are collected and concentrated under reduced pressure to produce 0.94 g (45%) of a white powder. Melting point: 171-172° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][CH:23]=2)[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]1=[O:20].C(N1C=CN=C1)(N1C=CN=C1)=O.[OH:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:47]3[CH2:48][CH2:49][CH:44]([OH:43])[CH2:45][CH2:46]3)=[O:29])=[CH:24][CH:23]=2)[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]1=[O:20]
Reactant: OC1CCNCC1
Reactant: O=C(O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(N4CCCCC4)C3=O)c(Cl)c2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(N4CCCCC4)C3=O)c(Cl)c2)cc1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
Treat a solution of (R)-3′,5′-dichloro-4′-(2-oxo-1-piperidin-1-yl-pyrrolidin-3-ylmethyl)-biphenyl-4-carboxylic acid (0.102 g, 0.228 mmol) in CH2Cl2 (10 mL) with 1,1′-carbonyldiimidazole (0.074 g, 0.457 mmol) and stir for 1 hour at room temperature. Treat the reaction with 4-hydroxypiperidine (0.065 g, 0.34 mmol) and diisopropylethylamine (0.044 g, 0.34 mmol) and stir for 12 hours at room temperature. Purify the mixture on silica gel column with 100% ethyl acetate and 10% methanol in dichloromethane to afford 0.107 g (89%) of the title compound. MS (m/z): 530 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][C:8]([OH:17])=[CH:9][CH:10]=3)[C:5](=[O:18])[C:4]=2[CH:3]=1.[N:19]1([CH2:25][CH2:26][Cl:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[ClH:28].[N:29]1([CH2:35][CH2:36][Cl:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.O>[OH-].[K+].C1(C)C(C)=CC=CC=1>[OH2:1].[ClH:27].[ClH:37].[N:19]1([CH2:25][CH2:26][O:1][C:2]2[CH:15]=[CH:14][C:13]3[C:12](=[O:16])[C:11]4[C:6](=[CH:7][C:8]([O:17][CH2:36][CH2:35][N:29]5[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)=[CH:9][CH:10]=4)[C:5](=[O:18])[C:4]=3[CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[N:19]1([CH2:25][CH2:26][O:1][C:2]2[CH:15]=[CH:14][C:13]3[C:12](=[O:16])[C:11]4[C:6](=[CH:7][C:8]([O:17][CH2:36][CH2:35][N:29]5[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)=[CH:9][CH:10]=4)[C:5](=[O:18])[C:4]=3[CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[ClH:28].[ClH:27]
Reactant: O=C1c2ccc(O)cc2C(=O)c2cc(O)ccc21
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1c2ccc(OCCN3CCCCC3)cc2C(=O)c2cc(OCCN3CCCCC3)ccc21

Procedure:
With efficient stirring, 100 g (0.42 mole) of 2,7-dihydroxyanthraquinone is dissolved in 500-700 ml of about 10% potassium hydroxide solution. This solution is filtered and evaporated to dryness in a rotary evaporator. The reddish brown solid is dried in a vacuum oven at 100°C, ground to a fine powder, then redried at 100°C. To a stirred suspension of 30 g of the powdered diphenoxide, containing about 24 g (0.075 mole) of the dipotassium salt of 2,7-dihydroxyanthraquinone, in 200 ml of xylene is heated to reflux and a small amount of water collected. A solution of 2-piperidinoethyl chloride in 100 ml of xylene, prepared from 53.3 g (0.29 mole) of 2-piperidinoethyl chloride hydrochloride, is added and the resulting mixture heated to reflux for about 24 hours. The mixture is poured into about 500 ml of water, and the solid which separates at the xylene/water interface is removed by filtration, washed with hot water and dried. This major portion of the free base is recrystallized from a mixture of hot methanol and chloroform, then dissolved in chloroform and acidified to Congo Red with ethereal HCl and diluted with ether. The precipitate is suspended in boiling methanol (12-20 ml per gram) and a small volume of water is added to effect solution. This solution is filtered, reduced about 1/4 in volume, diluted with additional methanol and chilled. The recrystallized dihydrochloride is filtered and dried in a vacuum oven at 100°C to give 2,7-bis(2-piperidinoethoxy)anthraquinone dihydrochloride hemihydrate, M.P. 275°-277°C.