Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:16][CH:15]=2)[C:12](=[O:26])[C:11]2[C:6](=[N:7][C:8]([O:27]C)=[CH:9][N:10]=2)[N:5]=1)[CH3:2].Cl.N1C=CC=CC=1>CN(C)C=O>[CH2:1]([S:3][C:4]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]([F:23])([F:25])[F:24])=[CH:18][CH:19]=2)[C:12](=[O:26])[C:11]2[N:10]=[CH:9][C:8](=[O:27])[NH:7][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCSc1nc2nc(OC)cnc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCSc1nc2[nH]c(=O)cnc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 120 °C
Reaction time: 10 h
Yield: 56.3 %

Procedure:
A mixture of 2-(ethylsulfanyl)-7-methoxy-3-[4-(2,2,2-trifluoroethoxy)phenyl]pteridin-4(3H)-one (92 mg), pyridine hydrochloride (640 mg) and N,N-dimethylformamide (3 ml) was stirred at 120° C. for 10 hr, and in the same manner as in Example 6, the title compound (50 mg) was obtained as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([O:14][CH3:15])=[O:13])[N:7]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH2:6][CH2:5]2.[N:34]1([CH2:39][CH2:40]O)[CH:38]=[CH:37][N:36]=[CH:35]1.FC1C=CC(OC2C=CC(S(N3CCC4C(=CC=C(OCCCN5CCN(C)CC5)C=4)C3C(OC)=O)(=O)=O)=CC=2)=CC=1>>[N:34]1([CH2:39][CH2:40][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]([C:12]([O:14][CH3:15])=[O:13])[N:7]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)=[CH:21][CH:20]=2)(=[O:17])=[O:18])[CH2:6][CH2:5]3)[CH:38]=[CH:37][N:36]=[CH:35]1
Reactant: COC(=O)C1c2ccc(O)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(OC)cc2)cc1
Reactant: OCCn1ccnc1
Agent: COC(=O)C1c2ccc(OCCCN3CCN(C)CC3)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Product: COC(=O)C1c2ccc(OCCn3ccnc3)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(OC)cc2)cc1

Procedure:
Methyl 6-hydroxy-2-[4-(4-methoxyphenoxy)benzenesulfonyl]-1,2,3,4-tetrahydroiso-quinoline-1-carboxylate (13B) is reacted with 2-imidazol-1-ylethanol in analogy to the method described under 3C.
Reaction SMILES: [CH:1]([NH:4][C:5]([C@H:7]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:17]=[CH:16][C:15]=2[N+:29]([O-])=O)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].CC(O)=O>CO.[Zn]>[NH2:29][C:15]1[CH:16]=[CH:17][C:18]([O:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)=[CH:19][C:14]=1[NH:13][C@@H:10]1[CH2:9][CH2:8][C@H:7]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:12][CH2:11]1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OCCN3CCCCC3)ccc2[N+](=O)[O-])CC1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OCCN3CCCCC3)ccc2N)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cis-N-isopropyl-4-(2-nitro-5-(2-(piperidin-1-yl)ethoxy)phenylamino)cyclohexanecarboxamide (350 mg, 0.809 mmol) in MeOH (4.0 mL) was added AcOH (0.463 mL, 8.09 mmol) and zinc (423 mg, 6.47 mmol), and the mixture was stirred at RT for 1 hour. The mixture was filtered through a pad of Celite® brand filter aid and evaporated to afford cis-4-(2-amino-5-(2-(piperidin-1-yl)ethoxy)phenylamino)-N-isopropylcyclohexanecarboxamide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14]([OH:16])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:41][CH2:42][CH2:43][CH2:44][N:45]1[CH2:49][CH2:48][CH2:47][C:46]1=[O:50]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:10]([NH:12][C@@H:13]([C:14](=[O:16])[NH:41][CH2:42][CH2:43][CH2:44][N:45]1[CH2:49][CH2:48][CH2:47][C:46]1=[O:50])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCCN1CCCC1=O
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCCCN1CCCC1=O
Yield: 22.1 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (100 mg, 0.18 mmol) and N-(3′-aminopropyl)-2-pyrrolidinone (42 mg, 0.29 mmol) according to Method C with HPLC purification to give the title compound (26 mg). 1H-NMR (400 MHz, CD3OD) δ 1.35 (s, 9H) 1.6 (m, 2H) 2.03 (m, 2H) 2.37 (t, 2H) 2.76 (m, 1H) 2.92-3.10 (m, 5H) 3.14 (t, 2H) 3.42 (t, 2H) 4.25 (m, 1H) 4.5 (m, 1H) 4.78 (s, 2H) 7.05 (d, 1H) 7.23 (dd, 5H) 7.42 (d, 1H) 7.72 (s, 1H); HR-MS m/z 654.2880 (calc. Of monoisotopic mass for C33H42N4O10 gives 654.2901).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1.[C:30](Cl)(=[O:33])[CH2:31][CH3:32]>>[CH3:27][Si:26]([CH3:29])([CH3:28])[CH2:25][CH2:24][O:23][CH2:22][N:19]1[C:16]2=[N:17][CH:18]=[C:13]([C:12]3[C:7]([NH:6][C@@H:3]4[CH2:4][CH2:5][N:1]([C:30](=[O:33])[CH2:31][CH3:32])[CH2:2]4)=[N:8][CH:9]=[CH:10][CH:11]=3)[N:14]=[C:15]2[CH:21]=[CH:20]1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@@H]3CCNC3)cnc21
Reactant: CCC(=O)Cl
Product: CCC(=O)N1CC[C@@H](Nc2ncccc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
1-((R)-3-{3-[5-(2-Trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-ylamino}-pyrrolidin-1-yl)-propan-1-one was prepared from (R)-pyrrolidin-3-yl-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine and propionyl chloride, following the general synthetic procedures described in the above Examples.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:31][CH2:32][CH2:33][CH3:34])=[C:6]([CH:28]=[CH:29][CH:30]=1)[CH2:7][N:8]([CH3:27])[C:9](=[O:26])/[CH:10]=[CH:11]/[C:12]1[CH:25]=[N:24][C:15]2[NH:16][C:17](=[O:23])[C:18](C)(C)[NH:19][CH2:20][C:14]=2[CH:13]=1)([CH3:3])[CH3:2].[ClH:35]>C(Cl)Cl.C(OCC)C>[ClH:35].[CH:1]([C:4]1[C:5]([O:31][CH2:32][CH2:33][CH3:34])=[C:6]([CH:28]=[CH:29][CH:30]=1)[CH2:7][N:8]([CH3:27])[C:9](=[O:26])/[CH:10]=[CH:11]/[C:12]1[CH:25]=[N:24][C:15]2[NH:16][C:17](=[O:23])[CH2:18][NH:19][CH2:20][C:14]=2[CH:13]=1)([CH3:3])[CH3:2]
Reactant: CCCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CNC(C)(C)C(=O)N3)cccc1C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CNCC(=O)N3)cccc1C(C)C
Reaction time: 18 h
Yield: 91 %

Procedure:
A stirring solution of (E)-N-(3-isopropyl-2-propoxybenzyl)-3-(3,3-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)-N-methylacrylamide (0.158 g, 0.362 mmol) in CH2Cl2 (4 mL) under N2 was treated with anhydrous HCl (0.18 mL of a 2.0 M solution in diethyl ether, 0.36 mmol) After stirring for 18 h, the resulting solid was collected by filtration, washed with Et2O (100 mL) and dried to yield the title compound (0.15 g, 91%) as an off white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 11.10-11.07 (m, 1H), 10.07 (br s, 2H), 8.77-8.72 (m, 1H), 8.33-8.24 (m, 1H), 7.63-7.55 (m, 1H), 7.40-7.31 (m, 1H), 7.26-7.21 (m, 1H), 7.13-7.05 (m, 1H), 6.90-6.83 (m, 1H), 4.83-4.67 (m, 2H), 4.28-4.22 (m, 2H), 3.85-3.69 (m, 4H), 3.30-3.25 (m, 1H), 3.14-2.89 (m, 3H), 1.81-1.75 (m, 2H), 1.20-1.17 (m, 6H), 1.06-1.01 (m, 3H); MS (ESI) m/e 437 (M+H)+.
Reaction SMILES: C([O:14][C:15]([CH2:17][C:18]([NH:20][C:21]1[N:22]2[CH:25]([S:26][CH2:27][C:28]=1[C:29]1[S:33][C:32]([NH:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])=[N:31][CH:30]=1)[CH:24]([S:40][C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([Cl:48])[CH:42]=1)[C:23]2=[O:49])=[O:19])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1>C(O)=O>[C:15]([CH2:17][C:18]([NH:20][C:21]1[N:22]2[CH:25]([S:26][CH2:27][C:28]=1[C:29]1[S:33][C:32]([NH:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])=[N:31][CH:30]=1)[CH:24]([S:40][C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([Cl:48])[CH:42]=1)[C:23]2=[O:49])=[O:19])([OH:16])=[O:14]
Reactant: CN(C)CCNc1ncc(C2=C(NC(=O)CC(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(Sc4ccc(Cl)c(Cl)c4)C3SC2)s1
Solvent: COc1ccccc1
Solvent: O=CO
Product: CN(C)CCNc1ncc(C2=C(NC(=O)CC(=O)O)N3C(=O)C(Sc4ccc(Cl)c(Cl)c4)C3SC2)s1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
A mixture of 2-benzhydryloxycarbonyl-7-(3,4-dichlorophenylthio)-acetamido-3-[2-(2-dimethylamino-ethylamino)-thiazol-5-yl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2ene (1.5 g), anisole (5 cc) and formic acid (25 cc) is stirred for 30 minutes at 50° C. The mixture is concentrated to dryness under reduced pressure (0.1 mm Hg; 0.013 kPa) and the residue is then taken up in ethanol (3×50 cc) and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. The solid obtained is washed with acetone (50 cc) and then with ethyl ether (50 cc). It is dried under reduced pressure (0.1 mm Hg; 0.013 kPa), giving 2-carboxy-7-(3,4-dichloro-phenylthio)-acetamido-3-[2-(2-dimethylamino-ethylamino)-thiazol-5-yl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (1 g) in the form of a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[CH3:21][C@@H:22]1[CH2:27][C:26](=O)[CH2:25][C@H:24]([CH3:29])[O:23]1.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:26]3[CH2:25][C@H:24]([CH3:29])[O:23][C@H:22]([CH3:21])[CH2:27]3)[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: C[C@@H]1CC(=O)C[C@H](C)O1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: C[C@@H]1CC(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)C[C@H](C)O1

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and (2R,6S)-2,6-dimethyl-tetrahydro-pyran-4-one using decaborane yielded the title compound as a white solid. MS (ESI): m/z=391.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:26]=[CH:27][CH:28]=2)/[CH:11]=[CH:12]/[C:13]2[CH:25]=[CH:24][C:16]([CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C[I:32].[C:33](OCC)(=O)C>CN(C=O)C>[I-:32].[CH3:33][N+:18]1([CH2:17][C:16]2[CH:24]=[CH:25][C:13](/[CH:12]=[CH:11]/[C:10]3[CH:26]=[CH:27][CH:28]=[C:8]([O:7][CH2:6][C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:30][CH:29]=4)[CH:9]=3)=[CH:14][CH:15]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1ccc(COc2cccc(/C=C/c3ccc(CN4CCCCC4)cc3)c2)cc1
Reactant: CCOC(C)=O
Reactant: CI
Solvent: CN(C)C=O
Product: Cc1ccc(COc2cccc(/C=C/c3ccc(C[N+]4(C)CCCCC4)cc3)c2)cc1
Product: [I-]
Temperature: 25 °C
Reaction time: 66 h

Procedure:
To (E)-1-[4-[3-(4-methylbenzyloxy)styryl]benzyl]piperidine (150 mg) dissolved in DMF (3 ml) was added methyl iodide (70 μl ), and the resulting mixture was stirred at room temperature for 66 hours. The reaction mixture was mixed with ethyl acetate (100 ml) and the resulting precipitate was collected by filtration and recrystallized from ethyl acetate/methanol to obtain (E)-1-methyl-1-[4-[3-(4-methylbenzyloxy)styryl]benzyl]piperidinium iodide (compound 100) (183 mg) as colorless crystals.
Reaction SMILES: [I:1]C1N(C2C=C3C(=C(C)C=2)NC(=O)C=C3)C(C)=NC=1.[CH3:20][C:21]1[N:22]([C:26]2[CH:27]=[C:28]3[C:33](=[C:34]([CH3:36])[CH:35]=2)[NH:32][C:31](=[O:37])[CH:30]=[CH:29]3)[CH:23]=[CH:24][N:25]=1>>[I:1][C:24]1[N:25]=[C:21]([CH3:20])[N:22]([C:26]2[CH:27]=[C:28]3[C:33](=[C:34]([CH3:36])[CH:35]=2)[NH:32][C:31](=[O:37])[CH:30]=[CH:29]3)[CH:23]=1
Reactant: Cc1cc(-n2ccnc2C)cc2ccc(=O)[nH]c12
Reactant: Cc1cc(-n2c(I)cnc2C)cc2ccc(=O)[nH]c12
Product: Cc1cc(-n2cc(I)nc2C)cc2ccc(=O)[nH]c12

Procedure:
n-Butyllithium (16.42 cm3 of a 1.55M solution in n-hexane) was added dropwise to a stirred solution of 6-(4,5-di-iodo-2-methylimidazol-1-yl)-8-methyl-2-(1H)-quinolone (5.0 g) in tetrahydrofuran (100 cm3) at -30° under nitrogen. After 30 minutes saturated aqueous ammonium chloride solution (20 cm3) was added, and the mixture was warmed to room temperature. The mixture was then basified with saturated sodium carbonate solution to pH 10 (approximately) and extracted with methanol:ethyl acetate (1:19 by volume, 100 cm3) and then methanol:dichloromethane (1:19 by volume, 2×200 cm3). The combined and dried (MgSO4) organic extracts were evaporated in vacuo to give a residue which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]). Elution with methanol:dichloromethane, 1:19 by volume, followed by combination and evaporation of the appropriate fractions gave a solid which was recrystallised from methanol/ethyl acetate to afford the title compound, (0.87 g), which was shown spectroscopically to be identical to the product of Preparation 4. Also eluted were fractions which when combined and evaporated afforded a solid, (2.28 g), which was shown to be a mixture of the title compound, 6-(5-iodo-2-methylimidazol-1-yl)-8-methyl-2-(1H)-quinolone, and 6-(2-methylimidazol-1-yl)-8-methyl-2-(1H)-quinolone.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][C:11]([CH3:13])=[O:12].[OH-].[Na+].Cl>C(O)C.O>[OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:10][C:11](=[O:12])[CH3:13]
Reactant: CC(C)=O
Reactant: O=Cc1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)C=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.4 %

Procedure:
2-Hydroxybenzaldehyde (1q, 0.90 ml, 8.4 mmol) and acetone (19, 1.24 ml, 16.8 mmol) were combined in ethanol (7 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (0.5 g, 12.5 mmol) and water (2 ml) was added dropwise and the mixture stirred for 48 hr at room temperature. The mixture was neutralized with hydrochloric acid (1 N), extracted with ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was recrystallized from tetrahydrofuran/hexane to give 0.36 g (26%) of a yellow solid: mp 136-137° C. [expected mp 139-140° C.]; 1H NMR: δ 2.42 (s, 3H), 6.92 (m, 2H), 7.03 (d, 1H, J=16.5 Hz), 7.24 (dt, 1H, J=7.0, 1.4 Hz), 7.45 (d, 1H, J=7.7 Hz), 7.88 (d, 1H, J=16.3 Hz), 8.00 (s, 1H); 13C NMR: δ 26.8, 116.6, 120.5, 127.5, 129.5, 131.9, 141.0, 156.1, 156.1, 201.3.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[NH:47][CH2:48][CH2:49][CH3:50])[C:42]#[N:43]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:15])[NH:38][C:39]1[CH:40]=[C:41]([C:42]#[N:43])[CH:44]=[CH:45][C:46]=1[NH:47][CH2:48][CH2:49][CH3:50])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCNc1ccc(C#N)cc1N
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CCCNc1ccc(C#N)cc1NC(=O)CCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In chloroform (5.0 ml), 5-t-butoxycarbonylaminovaleric acid (387 mg), WSCI hydrochloride (466 mg), and HOBt (328.3 mg) were dissolved. Then, the solution was stirred at room temperature for 1 hour. A solution (3.0 ml) of 3-amino-4-propylaminobenzonitrile (283 mg) in chloroform was dropped in this solution. Then, the solution was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and then washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution, and saturated saline solution, followed by drying with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound as a colorless viscous substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[N:29]2[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]2)[CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N:13]3[CH2:14][CH2:15][N:16]([CH:32]4[CH2:31][CH2:30][N:29]([C:27]5[CH:26]=[CH:25][CH:24]=[C:23]6[C:28]=5[N:19]=[CH:20][CH:21]=[CH:22]6)[CH2:34][CH2:33]4)[CH2:17][CH2:18]3)[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: COc1cc(N2CCNCC2)c2ncccc2c1
Reactant: O=C1CCN(c2cccc3cccnc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1cc(N2CCN(C3CCN(c4cccc5cccnc45)CC3)CC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.1 %

Procedure:
To a solution of 0.247 g of 6-methoxy-8-piperazino-quinoline (Step 4) in 10 mL of dichloroethane, was added 0.226 g of 1-quinolin-8-yl-piperidin-4-one (Step 6) followed by 0.274 g of sodium triacetoxyborohydride and 0.1 mL acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2Cl2. The organic phase was washed with water and dried over magnesium sulfate. The product crystallized and filtered to give 0.200 g of the desired product. Mp.194-197° C.; MS (ES) m/z (relative intensity): 454 (M++−H, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:40]=[CH:39][C:5]([O:6][C:7]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:14]3[C:13](=[O:24])[N:12]([CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30]C4CCCCO4)[C:11](=[O:37])[N:10]([CH3:38])[C:9]=3[N:8]=2)=[CH:4][C:3]=1[C:41]([F:44])([F:43])[F:42].C(Cl)(=O)C>C(O)C>[Cl:1][C:2]1[CH:40]=[CH:39][C:5]([O:6][C:7]2[N:15]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[C:14]3[C:13](=[O:24])[N:12]([CH2:25][CH2:26][O:27][CH2:28][CH2:29][OH:30])[C:11](=[O:37])[N:10]([CH3:38])[C:9]=3[N:8]=2)=[CH:4][C:3]=1[C:41]([F:42])([F:43])[F:44]
Reactant: Cn1c(=O)n(CCOCCOC2CCCCO2)c(=O)c2c1nc(Oc1ccc(Cl)c(C(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Solvent: CC(=O)Cl
Solvent: CCO
Product: Cn1c(=O)n(CCOCCO)c(=O)c2c1nc(Oc1ccc(Cl)c(C(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of 8-(4-chloro-3-(trifluoromethyl)phenoxy)-7-(4-chlorobenzyl)-3-methyl-1-(2-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)ethyl)-1H-purine-2,6(3H,7H)-dione (100 mg, 0.15 mmol) in ethanol (5 mL) was added acetyl chloride (0.2 mL) at 0° C. The mixture was stirred at room temperature for 1 h. The mixture was partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate, filtered and concentrated to give a crude product, which was purified via preparative HPLC to give 8-(4-chloro-3-(trifluoromethyl)phenoxy)-7-(4-chlorobenzyl)-1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (37 mg, 43.1% yield) as white solid. 1H-NMR (DMSO-d6) δ 7.95(d, 1H), 7.85(d, 1H), 7.77-7.80(m, 1H), 7.44(s, 4H), 5.44(s, 2H), 4.58-4.61(m, 1H), 4.06(t, 2H), 3.59(t, 2H), 3.43-3.46(m, 4H), 3.29(s, 3). LCMS retention time 3.070 min; LCMS MH+ 573.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11](=[O:23])[C:12]([NH:15]C(=O)OC(C)(C)C)([CH3:14])[CH3:13]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:15][C:12]([CH3:14])([CH3:13])[C:11]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)=[O:23]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CCc2ccccc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)C(=O)N1CCc2ccccc2C1
Yield: 83.3 %

Procedure:
A solution of 41 (0.36 g, 1.1 mmol) in TFA (5 mL) and CH2Cl2 (5 mL) was stirred at room temperature for 40 minutes. The mixture was concentrated in vacuo and the residue was dissolved in EtOAc (50 mL). Upon sequential washings with 1 N NaOH (2×50 mL) and brine (50 mL), the organic solution was dried (Na2SO4) and concentrated to afford 42 (0.20 g, 77%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][CH:5]=1)=O.O.[C:12]([OH:16])(=O)[CH:13]=O.[OH-].[NH4+].[CH3:19][NH:20][NH2:21]>C(O)(=O)C.C(OCC)(=O)C>[I:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]2[CH:1]=[CH:13][C:12](=[O:16])[N:20]([CH3:19])[N:21]=2)=[CH:5][CH:6]=1
Reactant: O=CC(=O)O
Reactant: CNN
Reactant: CC(=O)c1ccc(I)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cn1nc(-c2ccc(I)cc2)ccc1=O
Yield: 54 %

Procedure:
The mixture of 4-iodoacetophenone (1.00 g, 4.06 mmol) and glyoxalic acid monohydrate (0.45 g, 4.9 mmol) in 20 mL acetic acid was refluxed for 18 hrs before concentrated in vacuo. The dry residue was then stirred in 15 mL water to form a slurry material. To it was added carefully with ammonium hydroxide (30%) until pH 9 as indicated by pH paper. The pH was critical for this reaction. Methylhydrazine (0.43 mL) was added, and the reaction was sent to 100° C. bath for 3 hrs before the mixture was diluted with ethyl acetate. The organic phase was washed with brine, dried, concentrated in vacuo, and purified by flash column using 5% methanol in DCM isocratically to yield 6-(4-iodophenyl)-2-methylpyridazin-3(2H)-one (680 mg, 54%). MS found for C11H91N2O (M+H)+ 313.0.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C@@H:15]([CH2:16][O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH:13]([OH:26])[CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[C:18]([O:17][CH2:16][C@@H:15]1[C@@H:11]([CH2:10][O:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][C:13](=[O:26])[CH2:14]1)(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(OC[C@H]1CC(O)C[C@@H]1COC(=O)c1ccccc1)c1ccccc1
Solvent: CO
Product: O=C1C[C@H](COC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)C1

Procedure:
(3S,4S)-3,4-di(benzoyloxymethyl)cyclopentanol (compound 9, Scheme 2). To the compound 8 obtained under a) (193 mg, 0.55 mmol) in methanol (10 ml) was added sodium borohydride (41 mg, 1.10 mmol) in successive portions. The mixture was stirred at room temperature for 30 min, and then diluted with water and diethyl ether. The organic layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and concentrated to a syrup which was purified by column chromatography on silica gel (toluen/EtOAc, 1-1) to yield title compound (189 mg, 97%; [α]D -16.4° (c 1.09, chloroform); 1H NMR (100 MHz, CDCl3) δ 1.6-2.7 (m, 7H, 2 CH, 2 CH2, OH), 4.41 (t, 4H, 2 CH2 -OBz), 7.34-7.56 and 7.97-8.09 (m, 10H, aromatic H); 13C NMR (25.05 MHz, CDCl3) δ 38.3, 39.3, 39.8, 40.0 (2 CH2 2 CH), 67.4, 68.2 (2 CH2 -OBz), 72.5 (CHOH), 128.1, 129.3, 129.8, 132.8 (aromatic C), 166.3 (C=O). Anal. Calcd for C21H22O5 (354.4): C, 71.17; H, 6.26. Found: C, 71.05; H, 6.18.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][C@H:6]([CH3:8])[CH2:5][CH2:4][C@H:3]1[C:9]([OH:11])=[O:10].N1C=CC=CC=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>ClCCl>[C:18]([O:1][C@H:2]1[CH2:7][C@H:6]([CH3:8])[CH2:5][CH2:4][C@H:3]1[C:9]([OH:11])=[O:10])(=[O:20])[CH3:19]
Reactant: C[C@@H]1CC[C@@H](C(=O)O)[C@@H](O)C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@H]1C[C@H](C)CC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.4 %

Procedure:
To a solution of (1R,2S,4R)-2-Hydroxy-4-methyl-cyclohexanecarboxylic acid (162 mg, 1.02 mmol) in dichloromethane (5 ml) was added pyridine (495 ul, 6.12 mmol) followed by acetic anhydride (385 ul, 4.08 mmol). The reaction mixture was stirred for 20 h at room temperature. Then, the solvents were removed and 10 ml of 3N HCl solution was added. This mixture was stirred for 30 minutes and then a saturated solution of NaHCO3 was slowly added until pH=9-10. This solution was then extracted with ethyl acetate (2×5 ml). The aqueous phase was then acidified with a 10% HCl solution and extracted with ethyl acetate (3×5 ml). The following ethyl acetate layers were combined, dried (Na2SO4) and concentrated to obtain 109 mg (53%) of (1R,2S,4R)-2-Acetoxy-4-methyl-cyclohexanecarboxylic acid. NMR 1H (CDCl3, 400 MHz): 5.45 ppm (s, 1H); 2.46-2.42 ppm (m, 1H); 2.02 ppm (s, 3H); 2.02-1.96 ppm (m, 1H); 1.91-1.76 ppm (m, 3H); 1.70-1.61 ppm (m, 1H); 1.16-1.08 ppm (m, 1H); 0.99-0.88 ppm (m, 1H); 0.87 ppm (d, 3H).