Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:5]1[C:18]2[NH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].[I:19]I>C(Cl)(Cl)Cl>[I-:19].[CH3:2][CH:1]([C:5]1[C:18]2[C:9](=[S+:10][C:11]3[C:16]([N:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[CH:7][CH:6]=1)[CH2:3][CH3:4]
Reactant: CCC(C)c1cccc2c1Nc1ccccc1S2
Reactant: II
Solvent: ClC(Cl)Cl
Product: CCC(C)c1cccc2[s+]c3ccccc3nc12
Product: [I-]
Temperature: 5 °C
Reaction time: 8 h
Yield: 114 %

Procedure:
The stirred solution of 2-chlorophenothiazine (5.02 g, 21.54 mmol) in anhydrous THF (50 mL) was cooled to −78° C. and under argon sec-butyl lithium (77 mL, 108 mmol) was added drop-wise. After all the addition, the resulting orange mixture was stirred at −78° C. for 3 h, then was allowed to warm to room temperature. The reaction was quenched by the slow addition of saturated ammonium chloride, extracted with ethyl acetate (2×400 mL). The combined organics were washed with brine, dried (MgSO4), filtered, concentrated, and purified by chromatography, using ethyl acetate-hexane gradient to afford 1-sec-butyl-10H-phenothiazine. MS (m/z): [M+H]+=256. To the solution of 1-sec-butyl-10H-phenothiazine (1.0 g, 4.14 mmols) in chloroform (30 mL), at 5° C. was added the solution of iodine (3.2 g, 12.61 mmol) in chloroform (125 mL) drop-wise. After the addition the resulting dark mixture was stirred at 5° C. overnight. Product was filtered, washed several times with chloroform, dried to afford the title compound (1.8 g, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([O:30][CH2:31][CH2:32]N)[C:6]=2[CH:34]=1.C=O.[C:37]([BH3-])#[N:38].[Na+].[C:41](=O)([O-])[O-].[K+].[K+]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([O:30][CH2:31][CH2:32][N:38]([CH3:37])[CH3:41])[C:6]=2[CH:34]=1
Reactant: O=C([O-])[O-]
Reactant: [BH3-]C#N
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCCN)c3cc(Cl)ccc32)cn1
Agent: C=O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCCN(C)C)c3cc(Cl)ccc32)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7-chloro-5-(2-aminoethoxy)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.16 g) in methanol (3 ml) are added 37% formaldhyde (0.3 ml) and sodium cyanoborohydride (0.06 g), and further thereto is added with stirring acetic acid (0.25 ml) at 10° C. The mixture is stirred at room temperature for 3 hours, and poured into ice-water. The mixture is made basic with potassium carbonate, and extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-dimethylaminoethoxy)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (58 mg) as colorless amorphous.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][C:15]([C:17]([F:20])([F:19])[F:18])=[C:14]([C:21]3[S:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=3)[CH:13]=2)=[CH:8][CH:7]=1.O>C(OC(=O)C)(=O)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[NH:16][C:15]([C:17]([F:19])([F:18])[F:20])=[C:14]([C:21]3[S:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=3)[C:13]=2[N+:1]([O-:4])=[O:3])=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])c1ccc(-c2cc(-c3ccc(Cl)cc3)[nH]c2C(F)(F)F)s1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2c(C(F)(F)F)[nH]c(-c3ccc(Cl)cc3)c2[N+](=O)[O-])s1
Temperature: 25 °C

Procedure:
A 90% nitric acid solution (0.02 g, 0.28 mmol) is added to a solution of 5-(p-chlorophenyl)-3-(5-nitro-2-thienyl)-2-(trifluoromethyl)pyrrole (0.13 g, 0.34 mmol) in acetic anhydride. The reaction mixture is stirred at room temperature for ten minutes, treated with additional 90% nitric acid solution (0.02 g, 0.28 mmol), stirred at room temperature for 15 minutes, poured into water, stirred at room temperature overnight and extracted with ether. The combined organic extracts are dried over MgSO4 and concentrated in vacuo to obtain the title product as a tan solid which is identified by 1HNMR spectral analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]2[C:14]3[S:15][CH:16]=[CH:17][C:13]=3[CH:12]=[C:11]([O:19][CH3:20])[C:10]=2[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=1.O.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25](S(O)(=O)=O)=[CH:24][CH:23]=1.C(O)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>>[CH2:20]([O:19][C:11]1[C:10]2[C:6]3[S:7][CH:8]=[CH:9][C:5]=3[CH:4]=[C:3]([O:2][CH2:1][CH2:18][CH2:3][CH2:4][CH2:5][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:22][CH3:32])[C:18]=2[C:14]2[S:15][CH:16]=[CH:17][C:13]=2[CH:12]=1)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH3:34]
Reactant: COc1cc2ccsc2c2c(OC)cc3ccsc3c12
Reactant: CCCCCCCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCCCCCCCCCCCOc1cc2ccsc2c2c(OCCCCCCCCCCCC)cc3ccsc3c12
Temperature: 25 °C
Yield: 225.8 %

Procedure:
Compound 4 (150 mg, 0.50 mmol) and p-toluenesulfonic acid monohydrate (15.2 mg, 0.080 mmol) were heated in dodecan-1-ol (3.7 g, 20 mmol) at 200° C. under nitrogen overnight. Upon cooling down to room temperature, the solvent was removed under vacuum and the residual was purified with silica gel column and eluted with CHCl3/hexane (1:4 and then 2:3) to give compound BB1 as a white solid (110 mg, about 36% yield). 1H NMR (500 MHz, CDCl3): δ 7.56 (d, J=5.0 Hz, 2H), 7.42 (d, J=5.0 Hz, 2H), 7.41 (s, 2H), 4.32 (t, J=6.5 Hz, 4H), 2.13 (quintet, J=7.5 Hz, 4H); 1.68 (quintet, J=7.5 Hz, 4H); 1.39 (m, 32H); 0.86 (t, J=6.0 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C([O-])([O-])=O.[K+].[K+].CC1(C)C(C)(C)OB([C:32]2[CH2:33][CH2:34][O:35][CH2:36][CH:37]=2)O1>O1CCOCC1>[O:35]1[CH2:34][CH:33]=[C:32]([C:2]2[CH:3]=[C:4]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])[CH2:37][CH2:36]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(Br)c2)CC1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CN1CCN(c2ccc([N+](=O)[O-])c(C3=CCOCC3)c2)CC1
Temperature: 25 °C
Yield: 36 %

Procedure:
1-(3-Bromo-4-nitro-phenyl)-4-methyl-piperazine (as prepared in Example 9, step (a)) (225.1 mg, 0.79 mmol), K2CO3 (310.9 mg, 2.25 mmol) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (Murata, M., et al, Synthesis, 778, (2000)) (157 mg, 0.75 mmol) in dioxane (5 mL) was heated at 80° C. overnight under Ar. The reaction mixture was allowed to cool to RT, concentrated, and the resulting residue was chromatographed on silica (10% EtOAc/hexane-20% MeOH/EtOAc) to obtain the title compound (82 mg, 36%). 1H-NMR (CDCl3; 400 MHz): δ 8.04 (d, 1H, J=9.4 Hz), 6.78 (dd, 1H, J=9.4, 2.6 Hz), 6.58 (m, 1H, J=2.6 Hz), 5.58 (m, 1H), 4.34 (m, 2H), 3.95 (t, 2H, J=5.3 Hz), 3.46 (m, 4H), 2.57 (m, 4H), 2.38 (s, 3H), 2.30 (m, 2H).
Reaction SMILES: OCCN(C)[C:5](=[O:11])[O:6][C:7]([CH3:10])(C)C.[N:13]1[CH:18]=CC=CC=1.C([Cl:29])(=O)[O:20]CC1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[ClH:29].[C:5](=[O:11])([OH:20])[O:6][CH2:7][CH2:10][NH:13][CH3:18]
Reactant: c1ccncc1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CN(CCO)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CNCCOC(=O)O
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Synthetic Example 1 and ethyl acetate (20 mL) were added pyridine (0.97 mL) and 4-dimethylaminopyridine (catalytic amount), and benzyl chlorocarbonate (1.57 mL) was added dropwise thereto. After stirring at room temperature for 2 hrs, pyridine (0.65 mL) and benzyl chlorocarbonate (1.28 mL) were further added. After stirring at room temperature for 5 days, pyridine (0.81 mL) was further added under ice-cooling, and a solution of benzyl chlorocarbonate (1.43 mL) in ethyl acetate (5 mL) was slowly added dropwise. The reaction solution was stirred at room temperature for 2 hrs, and added ethyl acetate (50 mL), then, washed with water (50 mL), 5% aqueous solution of citric acid (50 mL), and saturated saline (50 mL), followed by drying over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and to the residue was added 4N hydrogen chloride-ethyl acetate solution (10 mL). After stirring at room temperature for 2 hrs, diethyl ether (10 mL) was added, and the depositting solid was collected by filtration. The solid was dried under reduced pressure to give title compound as white solid (1.99 g).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[N:5][NH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([C:20]1[CH:21]=[C:22]([C:32]([O:34][CH3:35])=[O:33])[N:23]([C:25]2[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=2)[CH:24]=1)=[O:19]>C(#N)C>[Cl:31][C:30]1[C:25]([N:23]2[CH:24]=[C:20]([C:18](=[O:19])[CH2:17][N:5]3[N:6]=[N:7][C:3]([C:2]([F:9])([F:8])[F:1])=[N:4]3)[CH:21]=[C:22]2[C:32]([O:34][CH3:35])=[O:33])=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: FC(F)(F)c1nn[nH]n1
Reactant: COC(=O)c1cc(C(=O)CBr)cn1-c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(C(=O)Cn2nnc(C(F)(F)F)n2)cn1-c1ncccc1Cl
Temperature: 70 °C
Reaction time: 1 h

Procedure:
890 mg (1.61 mmol) of 5-(trifluoromethyl)-2H-tetrazole and 297 mg (2.14 mmol) of potassium carbonate were initially charged in 10 ml of acetonitrile and heated at reflux for 15 min. 630 mg (1.07 mmol) of methyl 4-(bromoacetyl)-1-(3-chloropyridin-2-yl)-1H-pyrrole-2-carboxylate, dissolved in 10 ml of acetonitrile, were added, and the reaction mixture was stirred at 70° C. for 1 h. The solvent was distilled off, the residue was taken up in water and the mixture was extracted twice with dichloromethane. The combined organic phases are washed with sodium chloride solution, dried over sodium sulphate and concentrated. The desired product was isolated by chromatographic purification.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][S:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.[CH3:15][N:16]=[C:17]=[O:18].CCOCC>C1C=CC=CC=1.CN(C)C>[CH3:15][NH:16][C:17](=[O:18])[O:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([S:5][CH2:4][CH:3]([O:2][CH3:1])[O:13][CH3:14])[CH:7]=1
Reactant: CN=C=O
Reactant: COC(CSc1cccc(O)c1)OC
Agent: CN(C)C
Solvent: c1ccccc1
Solvent: CCOCC
Product: CNC(=O)Oc1cccc(SCC(OC)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(2,2-Dimethoxyethylthio)phenol (1.80 grams) dissolved in benzene (5 ml) was charged into a glass reaction vessel equipped with a mechanical stirrer. Methyl isocyanate (12 ml) and trimethylamine (2 drops) were then added, and the resulting mixture was stirred at room temperature for a period of about 51/2 hours. The mixture was then allowed to stand overnight and was then stripped of excess methyl isocyanate and a portion of the benzene. The concentrated solution was then added to ether and cooled to -60° C., resulting in a precipitate. The precipitate was recrystallized from ether to yield the desired product O-[3-(2,2-dimethoxyethylthio)phenyl]-0 N-methylcarbamate having a melt point of 46° to 48° C.
Reaction SMILES: [CH2:1]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]/[CH:19]=[CH:20]/[C@H:21]([C:35](N2[C@@H](C(C)C)C(C3C=CC=CC=3)(C3C=CC=CC=3)OC2=S)=[O:36])[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[O:12][CH2:11][CH2:10][O:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[NH2:58][C@@H:59]([CH2:64][C:65]1[CH:70]=[CH:69][C:68]([O:71][CH2:72][CH2:73][CH2:74][CH3:75])=[CH:67][CH:66]=1)[C:60]([NH:62][CH3:63])=[O:61]>ClCCl>[CH2:72]([O:71][C:68]1[CH:67]=[CH:66][C:65]([CH2:64][C@H:59]([NH:58][C:35]([C@@H:21](/[CH:20]=[CH:19]/[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:8]2([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[O:9][CH2:10][CH2:11][O:12]2)[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:36])[C:60](=[O:61])[NH:62][CH3:63])=[CH:70][CH:69]=1)[CH2:73][CH2:74][CH3:75]
Reactant: CCCCOc1ccc(C[C@H](N)C(=O)NC)cc1
Reactant: CCCCCCCC1(CCCCCC/C=C/[C@H](C(=O)N2C(=S)OC(c3ccccc3)(c3ccccc3)[C@@H]2C(C)C)[C@@](O)(CCOC)C(=O)OC(C)(C)C)OCCO1
Solvent: ClCCl
Product: CCCCCCCC1(CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc2ccc(OCCCC)cc2)C(=O)NC)[C@@](O)(CCOC)C(=O)OC(C)(C)C)OCCO1
Yield: 52.6 %

Procedure:
No. 6801291, tert-butyl (E)-(2S,3S)-11-(2-heptyl-[1,3]dioxolan-2-yl)-2-hydroxy-3-((S)-4-isopropyl-5,5-diphenyl-2-thioxo-oxazolidine-3-carbonyl)-2-(2-methoxy-ethyl)-undec-4-enoate (62 mg, 0.0824 mmol) and (S)-2-amino-3-(4-butoxy-phenyl)-N-methyl-propionamide (23 mg, 0.0989 mmol) were dissolved in dichloromethane. The solvent was distilled off under reduced pressure. The resulting residue was reacted at 45° C. for 4 days. After confirming the consumption of the starting materials by LCMS, the reaction mixture was purified with SP1 to obtain No. 6801292, tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methylcarbamoyl-ethylcarbamoyl]-11-(2-hept yl-[1,3]dioxolan-2-yl)-2-hydroxy-2-(2-methoxy-ethyl)-undec-4-enoate (33 mg, 54% yield, ESI (LC/MS positive mode) m/z 762 (M+H); Rt 3.02 min.). To the obtained No. 6801292 (40 mg, 0.0526 mmol) were added dichloromethane (3.0 mL) and trifluoroacetic acid (1.0 mL), and the mixture was stirred at room temperature. After confirming the consumption of the starting materials by LCMS, the solvent was distilled off under reduced pressure. The residue was purified by preparative HPLC. The purified fraction was freeze-dried to obtain the title compound (27 mg, 78% yield, white powder).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[N:22]2[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[N:26][C:21]2=[N:20][CH:19]=1)CCC>>[C:9]([NH:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([C:18]2[N:22]3[CH:23]=[CH:24][C:25]([C:27]([F:28])([F:29])[F:30])=[N:26][C:21]3=[N:20][CH:19]=2)[N:7]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: CC(C)(C)Nc1cccc(Br)n1
Product: CC(C)(C)Nc1cccc(-c2cnc3nc(C(F)(F)F)ccn23)n1
Yield: 22 %

Procedure:
6-Bromo-N-(tert-butyl)pyridin-2-ylamine (0.36 g, 1.56 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.6 mmol) by the method of Example 1. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (20-80%) and trituration with isohexane gave N-(tert-butyl)-6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-ylamine (115 mg) as a pale yellow solid: δH (400 MHz, CDCl3) 1.56 (9H, s), 7.42 (1H, d, J 7), 7.45 (1H, d, J 8), 7.68 (1H, dd, J 8 and 8), 7.78 (1H, d, J 8), 8.53 (1H, s), 10.33 (1H, d, J 7).
Reaction SMILES: C(O[CH:9]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[C:19]([C:20](=[O:26])[CH:21](OCC)O)[C:11]=2[O:10]1)C1C=CC=CC=1.[F:27][C:28]1[CH:29]=[C:30]([CH2:35][C:36]([NH2:39])([CH3:38])[CH3:37])[CH:31]=[C:32]([F:34])[CH:33]=1.Cl>>[CH2:20]([O:26][C:17]1[CH:18]=[C:19]([CH:20]([OH:26])[CH2:21][NH:39][C:36]([CH3:37])([CH3:38])[CH2:35][C:30]2[CH:29]=[C:28]([F:27])[CH:33]=[C:32]([F:34])[CH:31]=2)[C:11]2[O:10][CH2:9][C:14](=[O:15])[NH:13][C:12]=2[CH:16]=1)[C:19]1[CH:11]=[CH:12][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(O)C(=O)c1cccc2c1OC(OCc1ccccc1)C(=O)N2
Reactant: CC(C)(N)Cc1cc(F)cc(F)c1
Agent: Cl
Product: CC(C)(Cc1cc(F)cc(F)c1)NCC(O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2

Procedure:
Prepared from 1.73 g (4.84 mmol) of benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 0.80 g (4.32 mmol) of 2-(3,5-difluorophenyl)-1,1-dimethylethylamine in the usual way. Yield: 1.50 g (58%, hydrochloride); melting point: 240° C.–244° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[CH2:3][C@H:4]([NH:21][C:22]1[N:27]=[CH:26][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[CH:24][CH:23]=1)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)=[CH:7][CH:6]=1.O1CCCC1.[OH-].[Li+]>CO>[CH3:1][CH:2]([CH3:38])[CH2:3][C@H:4]([NH:21][C:22]1[N:27]=[CH:26][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:24][CH:23]=1)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)=[CH:7][CH:6]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N[C@@H](CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cn3)cc2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C[C@H](Nc1ccc(C(=O)NCCC(=O)O)cn1)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 87 %

Procedure:
A mixture of (S)-ethyl N-({6-[(3-methyl-1-{4-[5-(trifluoromethyl)pyridin-2-yl]phenyl}butyl)amino]pyridin-3-yl}carbonyl)beta-alaninate (60.9 g, 115 mmol) was dissolved in methanol (230 ml) and tetrahydrofuran (115 ml) and treated with aqueous lithium hydroxide (115 ml, 0.230 mol, 2.0M). The reaction was heated to 50° C. for 30 minutes. The solution was concentrated in vacuo, and the resulting residue was diluted with water (approximately 500 ml). The mixture was then acidified with aqueous 1.0M hydrochloric acid (230 ml, to approximately pH 4.0). The precipitated solid was collected by filtration and washed with water (2×100 ml). Air was pulled through the filter cake over 12 hours to affect drying of the product. The crude solid was transferred into a 2-liter flask with a stirbar and the solid was suspended in ethyl acetate (approximately 1.5 L). Sodium sulfate (approximately 500 g) was added and the mixture was stirred vigorously for a further 1 hour. The cloudy mixture was filtered through a plug of celite, resulting in a clear solution. The solution was concentrated in vacuo and the remaining solid was suspended in diethyl ether (1 L) and concentrated in vacuo (the process was repeated twice). The resulting solid was pulverized with a mortar and pestle, and dried in a vacuum oven for 12 hours at 60° C. The final product (50.1 g, 87%) was obtained as a off-white solid. 1H NMR (400 MHz, DMSO-d6, δ): 9.01 (s, 1H), 8.39 (d, J=1.2 Hz, 1H), 8.26 (dd, J=8.4, 2.0 Hz, 2H), 8.15 (d, J=8.4 Hz, 1H), 8.10 (d, J=8.2 Hz, 2H), 7.84 (d, J=6.7 Hz, 1H), 7.55 (d, J=8.2 Hz, 2H), 6.66 (br. s., 1H), 5.15 (br. s., 1H), 3.33-3.43 (m, 2H), 2.45 (t, J=7.0 Hz, 2H), 1.74-1.86 (m, 1H), 1.62-1.72 (m, 1H), 1.51-1.62 (m, 1H), 0.95 (d, J=6.5 Hz, 3H), 0.92 (d, J=6.5 Hz, 3H). MS (M+1): 501.4.
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[S:21][C:20]3[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:19]=3[CH:18]=2)(=[O:16])=[O:15])[CH2:10][C:9]1=[O:27])(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[Cl:26][C:23]1[CH:24]=[CH:25][C:19]2[CH:18]=[C:17]([S:14]([N:11]3[CH2:12][CH2:13][N:8]([CH2:7][C:6]([OH:28])=[O:5])[C:9](=[O:27])[CH2:10]3)(=[O:15])=[O:16])[S:21][C:20]=2[CH:22]=1
Reactant: CC(C)(C)OC(=O)CN1CCN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN1CCN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC1=O
Yield: 99.7 %

Procedure:
[4-(6-Chlorobenzo[b]thiophene-2-sulfonyl)-2-oxopiperazine-1-yl]acetic acid tert-butyl ester (500 mg, 1.13 mmol) is dissolved in 1 mL of trifluoroacetic acid and 3 mL of CH2Cl2. The solvents are azeotropically removed with toluene. [4-(6-chlorobenzo[b]thiophene-2-sulfonyl)-2-oxopiperazine-1-yl]acetic acid (438 mg) is isolated as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([NH2:12])[CH2:9][CH2:10][NH2:11]>N1C=CC=CC=1>[NH2:11][CH2:10][CH2:9][CH2:8][NH:12][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: NCCCN
Reactant: Fc1ccccn1
Solvent: c1ccncc1
Product: NCCCNc1ccccn1

Procedure:
To a stirring solution of 2-fluoropyridine in pyridine (0.5 M) was added 1,3-propanediamine (5 eq), and the solution was refluxed overnight. The solution was then concentrated in vacuo and the residue was partitioned between ethyl acetate and 10% sodium carbonate. The phases were separated, and the organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (silica; 10:1:1 EtOH/NH4OH/H2O) to afford a viscous pale yellow oil. EI-MS m/z 152 (M+H)+
Reaction SMILES: [N:1]([CH:4]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:5][CH2:6][C@@H:7]1[C@@H:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10](=[O:23])[CH2:9][CH2:8]1)=[N+]=[N-].COC1C=C2[C@@]34[C@@H]5C[C@H]6C(CN5CC3)=CCO[C@H]3CC(=O)N([C@H]4[C@@H]63)C2=CC=1OC>[Pd]>[NH2:1][CH:4]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:5][CH2:6][C@@H:7]1[C@@H:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10](=[O:23])[CH2:9][CH2:8]1
Reactant: CCCCCC(CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC)N=[N+]=[N-]
Agent: [Pd]
Agent: COc1cc2c(cc1OC)[C@@]13CCN4CC5=CCO[C@H]6CC(=O)N2[C@H]1[C@H]6[C@H]5C[C@H]43
Product: CCCCCC(N)CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC

Procedure:
A 1.06 g. sample of ethyl 15-azido-9-oxo-prostanoate (Example 110) is hydrogenated using 100 mg. of 5% palladium on carbon in 50 ml. absolute alcohol for 16 hours. The filtration of the catalyst and evaporation of the solvent affords an oil. Silica gel chromatography gives 604 mg. of oil; λ max. 2.95, 6.30 (brucine) and 5.72 μ (carbonyl groups).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11]Br.C(=O)([O-])[O-].[K+].[K+]>>[Br:9][CH2:10][CH2:11][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: BrCCOc1ccc(I)cc1

Procedure:
The mixture of 4-iodophenol (6.0 g), 1,2-dibromoethane (26 ml) and potassium carbonate (5.28 g) was refluxed for 3 hours. The mixture was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=6/1) to give 1-(2-bromoethoxy)-4-iodobenzene (6.5 g).
Reaction SMILES: CN(C)C=O.[N+:6]([C:9]1[N:10]=[C:11](SC2C=CC=CC=2[N+]([O-])=O)[N:12]([CH2:14][C@:15]([OH:40])([CH3:39])[CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH:27]=[CH:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[O:24])[CH2:19][CH2:18]2)[CH:13]=1)([O-:8])=[O:7].CC(C)([O-])C.[Na+].O>C(OCC)(=O)C>[CH3:39][C@@:15]1([CH2:16][N:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][CH2:26][CH:27]=[CH:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:31][CH:30]=3)=[O:24])[CH2:21][CH2:22]2)[O:40][C:11]2=[N:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:13][N:12]2[CH2:14]1
Reactant: C[C@](O)(CN1CCN(C(=O)OCC=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Sc1ccccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@]1(CN2CCN(C(=O)OCC=Cc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
To N,N-dimethylformamide (0.9 ml) solution of 3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-{3-[4-nitro-2-(2-nitrophenylthio)imidazol-1-yl]-2-hydroxy-2-methylpropyl}piperazin-1-carboxylate (89 mg) was added sodium tert-butoxide (16 mg) at 0° C., and stirred at the same temperature for 30 minutes. To the reaction mixture was added water and ethyl acetate, the organic layer was taken by separation. The ethyl acetate layer was washed with an aqueous solution of 5% potassium carbonate, water, and an aqueous solution being saturated with sodium chloride, then dried over anhydrous sodium sulfate. The residue obtained by removal of the solvent by distillation was purified by use of a thin layer chromatography (eluent: dichloromethane/ethyl acetate/methanol=15/15/1), there was obtained 3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-[(2-methyl-6-nitro-2,3-dihydroimidazo-[2,1-b]oxazol-2-yl)methyl]piperazin-1-carboxylate (38 mg, yield: 59%) as pale yellow amorphous product.