Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:19]=[CH:18][C:8]2[CH:9]=[N:10][C:11]3[C:16]([C:7]=2[CH:6]=1)=[C:15]([OH:17])[CH:14]=[CH:13][CH:12]=3)(=[O:3])[CH3:2].[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:1]([NH:4][C:5]1[CH:19]=[CH:18][C:8]2[CH:9]=[N:10][C:11]3[C:16]([C:7]=2[CH:6]=1)=[C:15]([O:17][C:20](=[O:22])[CH3:21])[CH:14]=[CH:13][CH:12]=3)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2cnc3cccc(O)c3c2c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2cnc3cccc(OC(C)=O)c3c2c1

Procedure:
Alternatively, the corresponding 9-acetamido-1-hydroxybenzo[c]quinoline is obtained when the residue obtained upon hydrogenation is acetylated with acetic anhydride by the procedure of Example 7. When a molar excess of acetic anhydride is employed, the corresponding 9-acetamido-1-acetoxybenzo[c]quinoline is obtained.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])C=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].[Cl-].[CH3:23][NH3+:24].C(O)(=O)C>C(OCC)(=O)C>[CH3:23][N:24]1[C:12](=[O:20])[CH2:13][CH2:14][C@@:15]2([CH3:16])[C:10]1=[CH:9][CH2:8][C@@H:7]1[C@@H:17]2[CH2:18][CH2:19][C@@:2]2([CH3:1])[C@H:6]1[CH2:5][CH2:4][C:3]2=[O:21]
Reactant: C[NH3+]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN1C(=O)CC[C@@]2(C)C1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Androst-4-ene-3,17-dione is oxidized into 5-oxo-4-nor-3,5-seco-androstane-5,17-dione as in Example 16A (seco-acid). The seco-acid (9.000 g, 31.423 mmol) is slurried with methylammonium chloride (19.5000 g, 288.80 mmol) into acetic acid (75 mL) and heated to reflux under an inert atmosphere. After 3 days, the reaction mixture is allowed to cool to room temperature and diluted with ethyl acetate (EtOAc, 500 mL). The organic solution is washed with water (3×200 mL), saturated aqueous NaHCO3 (2×200 mL) and brine (200 mL), then dried over magnesium sulfate (MgSO4), filtered, concentrated and purified by flash chromatography (1:1:2 EtOAc/CH2Cl2) to afford 4-methyl-4-aza-androst-5-ene-3,17-dione (aza-dione).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].O>N1C=CC=CC=1>[C:15]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C(=O)c1ccc(OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7.25 g of ethyl 2-(4-hydroxyphenyl)-2-oxoacetate was dissolved in 15 ml of pyridine, followed by adding 4 ml of acetic anhydride and then stirring at room temperature for 1 hour. The resulting reaction solution was poured into water, and extracted with diethyl ether. The resulting organic layer was washed with water, and then concentrated to dryness. Thereafter, the residue was dissolved in benzene, and then concentrated to obtain 8.3 g of the title compound in an oily form.
Reaction SMILES: NCCSCCC1N=CNC=1.[N+](C=C(SC)SC)([O-])=O.[N+:21]([CH:24]=[C:25](SC)[NH:26][CH2:27][CH2:28][S:29][CH2:30][CH2:31][C:32]1[N:33]=[CH:34][NH:35][CH:36]=1)([O-:23])=[O:22].[NH2:39][CH2:40][CH2:41][S:42][CH2:43][C:44]1[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][N:45]=1>>[N+:21]([CH:24]=[C:25]([NH:39][CH2:40][CH2:41][S:42][CH2:43][C:44]1[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][N:45]=1)[NH:26][CH2:27][CH2:28][S:29][CH2:30][CH2:31][C:32]1[N:33]=[CH:34][NH:35][CH:36]=1)([O-:23])=[O:22]
Reactant: CSC(=C[N+](=O)[O-])NCCSCCc1c[nH]cn1
Reactant: NCCSCc1ncccc1Cl
Agent: CSC(=C[N+](=O)[O-])SC
Agent: NCCSCCc1c[nH]cn1
Product: O=[N+]([O-])C=C(NCCSCCc1c[nH]cn1)NCCSCc1ncccc1Cl

Procedure:
4-[2-(2-Aminoethylthio)ethyl]imidazole (from the dihydrobromide (4.0 g) is reacted with 1-nitro-2,2-bis-methylthioethylene (2.0 g) by the procedure of Example 8(i) and the resultant 1-nitro-2-methylthio-2-[2-(2-(4-imidazolyl)ethylthio)ethylamino]ethylene is treated with 2-[(2-aminoethyl)thiomethyl]-3chloropyridine by the procedure of Example 1(a)(ii) to yield the title compound.
Reaction SMILES: [CH2:1]([C:3](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]>[Pd].C(OCC)(=O)C>[CH2:1]([CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][CH:22]=2)[CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccc(OC)c(OCCc2ccc(C(F)(F)F)cc2)c1)CC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC)Cc1ccc(OC)c(OCCc2ccc(C(F)(F)F)cc2)c1
Reaction time: 6 h
Yield: 95.1 %

Procedure:
Ethyl 2-ethyl-3-[4-methoxy-3-[2-[4-(trifluoromethyl)phenyl]ethoxy]phenyl]acrylate (840 mg, 1.99 mmol), 5% palladium on carbon (100 mg) and ethyl acetate (50 mL) were mixed, and hydrogenation was carried out for 6 hours at room temperature. The catalyst was removed by filtration, and then the filtrate was concentrated to afford 803 mg (95%) of the title compound as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C:7]([CH2:18][S:19][CH2:20][CH2:21]O)([CH2:13][S:14][CH2:15][CH2:16]O)[CH2:8][S:9][CH2:10][CH2:11]O)([CH3:4])([CH3:3])[CH3:2].[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.ClCCl>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:23])[C:7]([CH2:18][S:19][CH2:20][CH2:21][S:30]([C:27]1[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=1)(=[O:32])=[O:31])([CH2:13][S:14][CH2:15][CH2:16][S:30]([C:27]1[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=1)(=[O:32])=[O:31])[CH2:8][S:9][CH2:10][CH2:11][S:30]([C:27]1[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=1)(=[O:32])=[O:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)C(CSCCO)(CSCCO)CSCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)CCSCC(CSCCS(=O)(=O)c2ccc(C)cc2)(CSCCS(=O)(=O)c2ccc(C)cc2)C(=O)OC(C)(C)C)cc1
Reaction time: 15 h

Procedure:
A solution of t-butyl-tris[(2-hydroxyethyl)thiomethyl]acetate (11.2 g, 0.029 mol) in 50 mL of pyridine is cooled to 0° C. and p-toluenesulfonyl chloride (18.3 g, 0.096 mol) is added in portions over 1 hr. The mixture is kept at 0° C. for 15 hrs. Then dichloromethane (200 mL) is added and the solution is washed four times with 100 mL of 10% hydrochloric acid, once with 100 mL of saturated sodium bicarbonate and once with 100 mL of water. The organic layer is dried over anhydrous sodium sulfate and evaporated to give t-butyl-tris[(2-tosylethyl)-thiomethyl]acetate.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C@H:7]1[C@@H:12]2[C@@H:13]([CH3:16])[CH2:14][CH2:15][C@@H:11]2[C:10]([CH3:17])=[CH:9][O:8]1)[CH3:5])[CH3:2].[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH2:1]([O:3][CH:4]([O:6][C@H:7]1[C@@H:12]2[C@@H:13]([CH3:16])[CH2:14][CH2:15][C@H:11]2[C@@H:10]([CH3:17])[CH2:9][O:8]1)[CH3:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(C)O[C@@H]1OC=C(C)[C@H]2CC[C@H](C)[C@@H]12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(C)O[C@@H]1OC[C@H](C)[C@@H]2CC[C@H](C)[C@@H]12
Yield: 69.4 %

Procedure:
28.0 g of (1S, 4aS, 7S, 7aR)-1-[1-(ethoxy)ethoxy]-1, 4a, 5, 6, 7, 7a-hexahydro-4, 7-dimethylcyclopenta[c]pyran was dissolved in 500 mι of ethyl acetate, and after 90 mg of 10% palladium carbon was added, the reaction mixture was stirred at room temperature for 48 hours in a hydrogen gas atmosphere of 1 atm. The catalyst was filtered by celite, and the solvent was distilled off under a reduced pressure. There was thus obtained a colorless oily substance, (1S, 4R, 4aS, 7S, 7aR)-1-[1-(ethoxy)ethoxy]-1, 3, 4, 4a, 5, 6, 7, 7a-octahydro-4, 7-dimethylcyclopenta[c]pyran. 28.0 g of this (1S, 4R, 4aS, 7S, 7aR)-1-[1-(ethoxy)ethoxy]-1, 3, 4, 4a, 5, 6, 7, 7a-octahydro-4, 7-dimethylcyclopenta[c]pyran was dissolved in 400 mι of tetrahydrofuran without purification, and after 50 mι of 2N hydrochloric acid solution wad added, the reaction mixture was stirred for 12 hours while being cooled by ice. 300 mι of saturated sodium hydrogen carbonate solution was added to the reaction mixture, extraction was made with ethyl acetate (500 mι×3). The joined organic layer was dried by magnesium sulfate, and after filtration, the solvent was distilled off under a reduced pressure. The residue was purified by column chromatography using 200 g of silica gel, and 13.5 g of a colorless oily substance (yield=69.4%) was obtained from the hexane:ether=1:1 eluent. Since various spectral data of this colorless oily substance were in agreement with the data described in the reference ("Tetrahedron Lett.", 5325, 1968), it was determined as (4R, 4aR, 7S, 7aR)-1, 3, 4, 4a, 5, 6, 7, 7a-octahydro-4, 7-dimethylcyclopenta[c]pyran-1-ol.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]([OH:14])[CH2:10][C:11]([OH:13])=[O:12])[C:2]([NH2:4])=[NH:3].Cl.[C:16](O)(=[O:18])[CH3:17]>>[NH:1]([CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]([O:14][C:16](=[O:18])[CH3:17])[CH2:10][C:11]([OH:13])=[O:12])[C:2]([NH2:4])=[NH:3]
Reactant: CC(=O)O
Reactant: N=C(N)NCCCC[C@H](O)CC(=O)O
Agent: Cl
Product: CC(=O)O[C@@H](CCCCNC(=N)N)CC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.55 g (14.8 mmols) of 7-guanidino-3(S)-hydroxyheptanoic acid was dissolved in 100 ml of glacial acetic acid, and hydrogen chloride gas was introduced to saturation at a temperature lower than room temperature. The reaction mixture was stirred for 2 hours at room temperature, and concentrated under reduced pressure. The above procedure was carried out two more times, and the residue was sufficiently dried to obtain the desired product in a quantitative yield.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]3[C:20]4[C:15](=[CH:16][C:17]([N:21]([CH3:31])[C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-])=O)[CH:23]=5)=[CH:18][CH:19]=4)[N:14](COCC[Si](C)(C)C)[N:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.O1C2C=CC(C=CC3C4C(=CC(N(C)C5C=CC=C([N+]([O-])=O)C=5)=CC=4)NN=3)=CC=2OC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]3[C:20]4[C:15](=[CH:16][C:17]([N:21]([CH3:31])[C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=5)=[CH:18][CH:19]=4)[NH:14][N:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN(c1cccc([N+](=O)[O-])c1)c1ccc2c(C=Cc3ccc4c(c3)OCO4)nn(COCC[Si](C)(C)C)c2c1
Agent: CN(c1cccc([N+](=O)[O-])c1)c1ccc2c(C=Cc3ccc4c(c3)OCO4)n[nH]c2c1
Product: CN(c1cccc(N)c1)c1ccc2c(C=Cc3ccc4c(c3)OCO4)n[nH]c2c1

Procedure:
{3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-methyl-(3-nitro-phenyl)-amine was converted to [3-(2-Benzo[1,3]dioxol-5-yl-vinyl)-1H-indazol-6-yl]-methyl-(3-nitro-phenyl)-amine as described in Example 11. LCMS (ESI) [M+H]/z Calc'd 415, found 415. Anal. Calc'd: C, 66.66; H, 4.38; N, 13.52. Found: C, 66.56; H, 4.48; N, 13.35.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C(O)(C(F)(F)F)=O.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41](=[O:46])[CH2:42][C:43](=O)[CH3:44]>>[CH3:44]/[C:43](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[CH:42]/[C:41](=[O:46])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=1
Reactant: CC(=O)CC(=O)c1ccccn1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: C/C(=C/C(=O)c1ccccn1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 441 mg (0.92 mmol) of Intermediate 45 (as the TFA salt) and 150 mg (0.92 mmol) of Intermediate 35 to yield 240 mg of Example 34: TLC (DCM/MeOH, 4/1): Rf=0.46; 1H NMR (DMSO-d6, 400 MHz) δ11.49 (d, 1H, J=9.2), 8.52 (d, 1H, J=4.8), 7.90 (m, 4H), 7.47 (m, 4H), 7.11 (d, 2H, J=8.4), 6.80 (d, 2H, J=8.4), 6.13 (s, 1H), 4.12 (m, 3H), 3.16 (m, 2H), 2.87 (t, 2H, J=6.4), 2.77 (dd, 1H, J=13.6, 9.2), 2.34 (s, 3H), 1.71 (s, 3H); low resolution MS (ES−)m/e 510.1 (M-H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].C(=O)([O-])O.[Na+].[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19]Br)[CH3:16]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:19][CH:18]([O:21][CH2:22][CH3:23])[O:17][CH2:15][CH3:16])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: CCOC(CBr)OCC
Reactant: Cc1ccc(N)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(CNc1ccc(C)c(Cl)c1)OCC
Yield: 26.2 %

Procedure:
3-Chloro-4-methylaniline (10.26 g, 72.5 mmol), sodium hydrogen carbonate (9.1 g, 108 mmol) and bromoacetaldehyde diethyl acetal (13.1 ml, 87.1 mmol) were stirred at reflux under Ar in ethanol (150 ml) for 6 days. The mixture was then evaporated to dryness, partitioned between ether and water, and separated. The organic portion was washed with brine, dried (Na2SO4) and evaporated to a black oil. Bulb to bulb distillation of this crude material (oven temperature 175° C., ca 0.1 mmHg) then gave the title compound (4.90 g, 26%) as a colourless oil.
Reaction SMILES: [O-]CC.[Na+].[C:5]([NH:8][CH:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:7])[CH3:6].Br[CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1>CS(C)=O>[C:15]([C:9]([NH:8][C:5](=[O:7])[CH3:6])([CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:16]
Reactant: CCOC(=O)C(C#N)NC(C)=O
Reactant: BrC1Cc2ccccc2C1
Agent: CC[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C#N)(NC(C)=O)C1Cc2ccccc2C1

Procedure:
Sodium ethoxide (40 gms) was stirred in 1 L of dimethyl sulfoxide until solution was complete. Then, 100 g of ethyl acetamido-cyanoacetate was added, and again stirred until solution was complete. 2-Bromoindane (101 g) was slowly added, using a few ml of DMSO to wash the container and addition funnel. The solution was stirred over a weekend.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([CH2:9][O:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1cccc(Br)c1
Reactant: BrCc1ccccc1
Product: Brc1cccc(OCc2ccccc2)c1

Procedure:
The title compound was synthesized (4.8 g, quant.) following a similar procedure as set out earlier in Description 54 starting from 3-bromophenol (3 g, 17.3 mmol) and benzylbromide (2.1 ml); Rt (HPLC): 6.42 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[C:8]([CH3:14])([CH3:13])[C:7](=[O:15])[C:6]([C:16]([NH:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])=[C:5]2[OH:27].C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[C:8]([CH3:14])([CH3:13])[C:7](=[O:15])[C:6]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:5]2[OH:27]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)c(F)cc2C(C)(C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2cc(Cl)c(F)cc21
Yield: 100.4 %

Procedure:
A solution of 1,1-dimethylethyl N-((6-chloro-7-fluoro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (0.255 g, 0.641 mmol) in TFA (5.00 mL, 67.3 mmol) was stirred at 25° C. for 10 minutes. The mixture was concentrated, azeotroped in DCM (2×50 mL), and dried in vacuo to give the title compound (0.220 g). MS m/e=342.4 (M+H)+. Calculated for C15H13ClFNO5 341.05.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C:10]([CH3:14])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[CH:11]([C:30](=[O:31])[NH:29][C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)[C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC1=NN(c2ccc(Cl)cc2)C(=O)C1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC1=NN(c2ccc(Cl)cc2)C(=O)C1C(=O)Nc1ccc(F)cc1
Reaction time: 8 h

Procedure:
The suspension of 3.1 g of 1-(p-chlorophenyl)-3-methyl-2-pyrazolin-5-one in 100 ml of benzene is treated with 1.8 g of triethylamine, warmed until dissolution and combined with 2.1 g of p-fluorophenylisocyanate while stirring. After standing overnight at room temperature it is evaporated, the residue taken up in methanol and the solution treated with the mixture of 10 ml of 5 N hydrochloric acid and 250 ml of water. The mixture is extracted with ethyl acetate, the extract washed with water, dried and evaporated. The crude solid is dissolved in 2 N aqueous sodium hydroxide, the solution filtered and acidified with 5 N hydrochloric acid. The precipitate is collected, washed with water and recrystallized from ethyl acetate-petroleum ether, to yield the 1-(p-chlorophenyl)-3-methyl-4-(p-fluorophenylcarbamoyl)-2-pyrazolin-5-one melting at 240°-242° with decomposition.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH:22][C@H:23]2[C@@H:27]3[O:28][C:29]([CH3:32])([CH3:31])[O:30][C@@H:26]3[C@@H:25]([CH2:33][OH:34])[CH2:24]2)=[N:12][C:13](S(C)(=O)=O)=[N:14][C:15]=1[O:16][CH3:17].[OH-].[NH4+:36].O>O1CCOCC1>[NH2:36][C:13]1[N:12]=[C:11]([NH:22][C@H:23]2[C@@H:27]3[O:28][C:29]([CH3:32])([CH3:31])[O:30][C@@H:26]3[C@@H:25]([CH2:33][OH:34])[CH2:24]2)[C:10]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[C:15]([O:16][CH3:17])[N:14]=1
Reactant: COc1nc(S(C)(=O)=O)nc(N[C@@H]2C[C@H](CO)[C@H]3OC(C)(C)O[C@H]32)c1-c1nc2ccccc2s1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1nc(N)nc(N[C@@H]2C[C@H](CO)[C@H]3OC(C)(C)O[C@H]32)c1-c1nc2ccccc2s1
Temperature: 80 °C

Procedure:
A mixture of Compound 8 (1.36 g, 2.458 mmol) and ammonium hydroxide (25 ml, 180 mmol) in 1,4-dioxane (25 ml) was heated in a sealed tube at 80° C. for a period of 1 hr. The solution was cooled to room temperature, and water was added. The aqueous layer was extracted twice by dichloromethane and the combined organic extracts were dried (Na2SO4), filtered and concentrated under vacuum. The residue was then purified by column chromatrography on silica gel (EtOAc/hexanes) to give the title compound. 1H NMR (CDCl3) δ 10.65-10.64 (m, 1H), 7.89-7.43 (m, 2H), 7.43-7.39 (m, 1H), 7.30-7.26 (m, 1H), 4.99 (s, 2H), 4.71-4.69 (m, 1H), 4.63-4.58 (m, 2H), 4.08 (s, 3H), 3.90-3.86 (m, 2H), 2.59-2.54 (m, 1H), 2.47-2.46 (m, 1H), 2.17 (s, 1H), 1.84-1.76 (m, 2H), 1.54 (s, 3H), 1.27 (s, 3H); LCMS 2.01 min, 444 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH:18]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH2:19]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH2:19][CH2:18][S:20]([CH3:23])(=[O:22])=[O:21])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Reactant: C=CS(C)(=O)=O
Solvent: C1COCCO1
Product: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 92 %

Procedure:
To 1-[3-(methyloxy)-4-nitrophenyl]piperazine (0.4 g, 1.74 mmol) in 10 mL of dioxane was added, methyl vinyl sulfone (0.46 g, 4.34 mmol). The mixture was heated to 120° C. for 1 h. The solvent was rotovaped down and the crude product was purified by flash chromatography to give the title compound of step B (0.55 g, 1.6 mmol, 92%). 1H NMR (400 MHz, CDCl3) δ ppm 7.97 (d, J=9.34 Hz, 1H), 6.41 (dd, J=9.34, 2.56 Hz, 1H), 6.31 (d, J=2.38 Hz, 1H), 3.93 (s, 3H), 3.36-3.43 (m, 4H), 3.19 (t, J=6.41 Hz, 2H), 3.03 (s, 3H), 2.92-2.99 (m, 2H), 2.60-2.68 (m, 4H).
Reaction SMILES: [CH3:1]N(C)C(=O)C.[CH:7]1([C:13]2[CH:44]=[CH:43][C:16]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[N:26]=[C:27]([N:30]([CH2:32][C:33]5[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=5)[CH3:31])[S:28][CH:29]=4)=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CCCCCC>[CH:7]1([C:13]2[CH:44]=[CH:43][C:16]([CH2:17][N:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[N:26]=[C:27]([N:30]([CH2:32][C:33]5[CH:34]=[CH:35][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:41][CH:42]=5)[CH3:31])[S:28][CH:29]=4)=[CH:21][CH:20]=3)[CH3:1])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC(=O)N(C)C
Reactant: COC(=O)c1ccc(CN(C)c2nc(-c3ccc(NCc4ccc(C5CCCCC5)cc4)cc3)cs2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1ccc(CN(C)c2nc(-c3ccc(N(C)Cc4ccc(C5CCCCC5)cc4)cc3)cs2)cc1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
Under an argon stream, N,N-dimethylacetamide (351 ml, 5.0 v/w) was added to methyl 4-(N-(4-(4-(4-cyclohexylbenzylamino)phenyl)-2-thiazolyl)-N-methylaminomethyl)benzoate (70.3 g, 0.134 mol) obtained in Example 1(5) and potassium carbonate (73.9 g, 0.535 mol) was carefully added with stirring. After stirring the mixture at room temperature for 20 min., dimethyl sulfate (50.6 ml, 0.535 mol) was added. After stirring at 50° C. for 1 hr., potassium carbonate (18.4 g, 0.134 mol) and dimethyl sulfate (12.7 ml, 0.134 mol) were added and the mixture was stirred at 60° C. for 2 hr. After cooling to room temperature, n-hexane (422 ml, 6.0 v/w) was added, and the mixture was stirred for 1 hr. After ice-cooling, distilled water (562 ml, 8.0 v/w) was added. After stirring at room temperature for 1 hr., the resulting crystals were collected by filtration and washed with methanol (352 ml, 5.0 v/w) in a slurry form. Tetrahydrofuran (180 ml) was added to the obtained orange solid and insoluble materials were filtered off. The filtrate was concentrated to give the title compound (42.1 g, yield 58.3%) as a pale-yellow solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]1[CH2:12][CH2:11][CH:10]([C@H:13]([NH2:17])[C:14](O)=[O:15])[CH2:9][CH2:8]1.O.[OH-].[Na+]>C1COCC1>[NH2:17][C@@H:13]([CH:10]1[CH2:11][CH2:12][CH2:7][CH2:8][CH2:9]1)[CH2:14][OH:15]
Reactant: N[C@H](C(=O)O)C1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N[C@H](CO)C1CCCCC1
Temperature: 80 °C
Yield: 54.9 %

Procedure:
To a stirred mixture of LiAlH4 (724 mg, 19.08 mmol) in anhydrous THF (20 mL) at rt was added portionwise L-(+)-2-cyclohexylglycine (1 g, 6.36 mmol). The mixture was heated at 80° C. for 4 h. The mixture was cooled to 0° C. and then water (1 mL), 1M aq NaOH (1 mL), and water (3 mL) were added sequentially. The mixture was filtered and the filtrate was partitioned between a mixture of DCM, 1M aq NaOH, and saturated aq sodium potassium tartrate. The organic layer was separated and further washed with 1M aq NaOH. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to afford (S)-2-amino-2-cyclohexylethanol (500 mg) which was not purified further. LCMS (ESI) m/z 144 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH:12]([OH:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=O)[CH3:3].C(OCC)(=O)[CH2:16][C:17]([CH3:19])=[O:18]>S(=O)(=O)(O)O>[CH3:3][CH:2]([N:4]1[CH:5]([CH2:16][C:17](=[O:18])[CH3:19])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]1=[O:13])[CH3:1]
Reactant: CC(C)N1C(=O)c2ccccc2C1O
Reactant: CCOC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)CC1c2ccccc2C(=O)N1C(C)C
Yield: 50.1 %

Procedure:
A solution of 2-(1-methylethyl)-3-hydroxy-1,3-dihydro-2H-isoindol-1-one (6.1 g, described in Example 12) and ethyl acetoacetate (12.4 g) in conc. sulfuric acid (60 ml) is stirred at 40° C. for 24 hr and poured into ice. The solution is extracted with ethyl acetate and the organic extract is washed with 5% aqueous sodium bicarbonate and water, dried and evaporated. The residue is chromatographed on silica gel using hexane-ethyl acetate (2:3) and the eluates are evaporated to give 3.7 g of the title compound, nmr (DMSO-d6) δ 1.25 (d, 3H), 1.35 (d, 3H), 2.05 (s, 3H), 2.5-3.4 (m, 2H), 3.95 (m, 1H), 4.9 (m, 1H) and 7.4 (m, 4H).