Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[C:31]([F:34])([F:33])[F:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:78][CH:79]1[CH2:84][CH2:83][N:82]([C:85]([O:87][C:88]([CH3:91])([CH3:90])[CH3:89])=[O:86])[CH2:81][CH2:80]1>CN(C)C=O>[C:88]([O:87][C:85]([N:82]1[CH2:81][CH2:80][CH:79]([NH:78][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:14])([F:13])[CH2:12][N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:7]=4[N:20]=3)=[C:23]([C:31]([F:33])([F:32])[F:34])[CH:24]=2)[CH2:84][CH2:83]1)=[O:86])([CH3:91])([CH3:90])[CH3:89]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3C(F)(F)F)ncc21
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)cc3C(F)(F)F)ncc21
Reaction time: 0.17 h
Yield: 34.2 %

Procedure:
To a mixture of 0.075 g (0.155 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-trifluoromethyl-benzoic acid (I-204) and 8 mL of dimethylformamide was added 0.0313 g (0.232 mmole) of 1-hydroxybenzotriazole, 0.088 g (0.232 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.080 g (0.617 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0465 g (0.232 mmole) of 4-amino-1-Boc-piperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-90:10) gave 0.0354 g of 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-trifluoromethyl-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-211) as a white solid.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[CH:11][C:12](OCC)=O)[CH2:8]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:23]1CCCC1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[C:11]([OH:23])[CH3:12])[CH2:8]2
Reactant: C1CCOC1
Reactant: CCOC(=O)C=C1C2CC3CC(C2)CC1C3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(O)=C1C2CC3CC(C2)CC1C3
Temperature: 25 °C

Procedure:
Ethyl adamantylideneacetate (7) (31 g) in tetrahydrofuran (50 cm3) was added dropwise to a suspension of lithium aluminium hydride (5.2 g) in tetrahydrofuran (30 cm3). When the addition was complete, the reaction 0° C., allowed to warm up to room temperature and poured onto crushed ice. Work up gave the alcohol (8) (8.8 g) as a colourless oil which partially crystallised.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][C:3]=1[OH:39].C([O-])([O-])=O.[K+].[K+].C1(=O)O[CH2:49][CH2:48][O:47]1.O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[N:10]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:9]=2)=[CH:4][C:3]=1[O:39][CH2:49][CH2:48][OH:47]
Reactant: O=[N+]([O-])c1ccc2c(c1)c(-c1ccc(F)c(O)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(c1)c(-c1ccc(F)c(OCCO)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 160 °C
Reaction time: 4 h

Procedure:
A mixture of 3-(4-fluoro-3-hydroxyphenyl)-5-nitro-1-trityl-1H-indazole 7AU (1.25 g, 2.42 mmol), K2CO3 (402 mg, 2.91 mmol) and ethylene carbonate (2.6 mL, 24.00 mmol) in DMF (10 mL) was stirred in a sealed tube at 160° C. for 4 h and cooled to rt. H2O was added to quench the reaction. The resulting mixture was extracted with EtOAc, which was washed with H2O, brine, dried (MgSO4) and concentrated to give a yellow oil. Chromatograph on silica gel (4:1, hexanes/EtOAc) gave 3-[4-fluoro-3-(2-hydroxy-ethoxy)-phenyl]-1-trityl-5-nitro-1H-indazole 14AX (1.4 g) as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:17]([O:27][C@@H:28]2[O:57][C@H:56]([CH2:58]F)[C@@H:47]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C@H:38]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@H:29]2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:16]([CH2:60][O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[O:15][C@@H:10]1[O:11][CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:69]1CCC[CH2:70]1>CO.Cl[Pd]Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:17]([O:27][C@@H:28]2[O:57][C@H:56]([CH2:58][O:69][CH3:70])[C@@H:47]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C@H:38]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@H:29]2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:16]([CH2:60][O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[O:15][CH:10]1[O:11][CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: C=CCO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O[C@@H]2O[C@H](CF)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: Cl[Pd]Cl
Solvent: CO
Product: C=CCOC1O[C@H](COCc2ccccc2)[C@@H](O[C@@H]2O[C@H](COC)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 83 %

Procedure:
The compound (1.80 g, 1.92 mmol) synthesized in Example 8 (8a) was dissolved in methanol (30 mL) and tetrahydrofuran (6 mL) and palladium chloride (II) (67.4 mg, 0.38 mmol) was added thereto, followed by stirring of the mixture at room temperature for 14 hours. After the reaction mixture was subjected to celite filtration, the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 5:1-4:1-3:1, V/V) to obtain the desired title compound (1.43 g, yield 83%) as colorless amorphous matter.
Reaction SMILES: [F:1][CH:2]([F:27])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH2:18][CH3:19])[C:4]=1[S:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1C=C(Cl)C=C(C(OO)=[O:36])C=1.C1C=C(Cl)C=C(C(O)=O)C=1>>[F:27][CH:2]([F:1])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH2:18][CH3:19])[C:4]=1[S:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:36]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(Sc2ccccc2)c1CC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C(O)c1cccc(Cl)c1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(S(=O)c2ccccc2)c1CC

Procedure:
Prepared from product of Example 8 (6.1 g, 15.1 mmol) and MCPBA (2.9 g of an 85% mixture with MCBA, 15.1 mmol) as described above. Recrystallization (ether/petroleum ether) afforded the product as a white solid (4.46 g).
Reaction SMILES: [C:1](=[O:12])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])OC(C)(C)C.[F:13][C:14]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[C:15]=1C(O)=O>CN(C)C1C=CN=CC=1.CC(O)(C)C>[F:13][C:14]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[C:15]=1[C:1]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:12]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: O=C(O)c1c(F)cc(F)cc1F
Agent: CN(C)c1ccncc1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)c1c(F)cc(F)cc1F
Temperature: 40 °C
Yield: 100.2 %

Procedure:
Di-tert-butyl carbonate (4.95 g, 22.7 mmol) was added to a solution of 2,4,6-trifluorobenzoic acid (2.0 g, 11.3 mmol) and 4-dimethylaminopyridine (139 mg, 1.14 mmol) in tBuOH (30 mL) and the reaction mixture was heated at 40° C. for 18 hours. The reaction mixture was then quenched with aqueous 1M HCl and extracted into EtOAc. The combined organics were washed with aqueous 1M NaOH, followed by brine, dried and concentrated in vacuo to afford the title compound as a pale yellow oil (2.63 g, 52% yield):
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[NH:22][C:23](=[O:29])[O:24][CH2:25][CH2:26][O:27][CH3:28].[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH3:28][O:27][CH2:26][CH2:25][O:24][C:23]([NH:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:15]=1[CH2:14][O:1][C:2]1[C:3]2[N:4]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1)=[O:29]
Reactant: COCCOC(=O)Nc1cccc(C)c1CCl
Reactant: Cc1nc2c(O)cccn2c1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COCCOC(=O)Nc1cccc(C)c1COc1cccn2c(C)c(C)nc12
Yield: 22.5 %

Procedure:
Analogously to Example 5, 2.0 g (12.4 mmol) of 8-hydroxy-2,3-dimethylimidazo[1,2-a]pyridine, 3.6 g (13.9 mmol) of 2-methoxyethyl 2-chloromethyl-3-methylphenylcarbamate, 0.18 g of sodium iodide and 1.3 g of sodium carbonate are reacted in 30 ml of acetone. 1.07 g (22.5%) of the title compound of m.p. 107°-108° C. are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>C1COCC1.CCO.[Pd]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[CH:3][C:2]=1[OH:1]
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])c(O)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C(=O)O)c1ccc(N)c(O)c1
Reaction time: 3 h

Procedure:
To a stirred solution of 2-(3-hydroxy-4-nitro-phenyl)-propionic acid (1.28 g) in THF (20 mL) and EtOH (20 mL) was slowly added 10% Pd/C (0.12 g) at room temperature. After being hydrogenated for 3 h with H2 balloon, the reaction mixture was filtered through celite pad and washed with EtOH. The filtrate was concentrated in vacuo to afford the product as yellow solid. (1.08 g, 98.4%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]([CH:9]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)=[N:7][CH:8]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([CH:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)=[N:5][CH:4]=1
Reactant: COc1cnc(C2CCN(C(=O)OC(C)(C)C)C2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cnc(C2CCNC2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of tert-butyl 3-(5-methoxypyrimidin-2-yl)pyrrolidine-1-carboxylate (13 mg, 0.047 mmol) in dry CH2Cl2 (0.5 mL) was added TFA (20% in CH2Cl2, 2 mL) at 0° C. The formed solution was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo to give the crude product (8 mg), which was used for next step without purification.
Reaction SMILES: [P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[C:25]3[N:24]=[CH:23][N:22]=[C:20]([NH2:21])[C:19]=3[N:18]=[CH:17]2)[C@H:13]([OH:26])[C@@H:12]1[OH:27])([O:4]P(O)(O)=O)(=[O:3])[OH:2].P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.OP([O-])(O)=O.OP([O-])([O-])=O.[Na+].[Na+].[Na+].[Cl-].[Cl-].[K+].[K+].C(O)C(N)(CO)CO.Cl.[Mg]>>[CH:23]1[N:22]=[C:20]([NH2:21])[C:19]2[N:18]=[CH:17][N:16]([C@@H:14]3[O:15][C@H:11]([CH2:10][O:9][P:1]([OH:4])([OH:3])=[O:2])[C@@H:12]([OH:27])[C@H:13]3[OH:26])[C:25]=2[N:24]=1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O

Procedure:
A second embodiment of the luminometer of the present invention is provided wherein an additional reagent flow is included for feeding very pure adenosine diphosphate (ADP) reagent, with respect to ATP, into the processing fluid downstream of the junction (5) where detergent is added, but upstream of the luminometer. The ADP reagent (99.95% pure with respect to ATP) is added at a flow and concentration such as to produce a concentration of 0.5 mM in the final flow. The processing fluid is pH 7.4 phosphate buffered saline or TrisHCl pH 7.8 including 0.2 mM magnesium ions.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C(=O)(O)[O-].[Na+].Br[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19]>O>[CH3:19][C:18]([CH3:20])=[CH:17][CH2:16][CH2:15][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: CC(C)=CCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)=CCCn1ccnc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 16 h

Procedure:
To a solution of 2-nitroimidazole (3.0 g, 27 mmol) in dry dimethylformaide (25 mL), was added anhydrous sodium bicarbonate (4.2 g, 50 mmol) followed by 5-bromo-2-methyl-2-pentene (5.0 g, 30.67 mmol). The reaction mixture was heated at 60-70° C. with stirring under nitrogen for 16 hours. Solvent dimethylformamide and the unreacted bromide were removed under reduced pressure (<1 mm) at 50-60° C. to yield a paste which was dissolved in water (50 mL) and extracted with ethyl acetate (5×50 mL). The combined organic extracts were dried and concentrated to give a brown oil which was recrystallized from petroleum ether (b.p. 40-60° C.) to yield a yellow solid. Yield: 4.8 g, m.p. 51-52° C. 1H NMR (CDCl3) δ 1.55 (s, 3H, CH3), 1.75 (s, 3H, CH3), 2.7 (q, 2H, olefinic CH2), 4.5 (t, 2H, N—CH2), 5.2 (t, 1H, olefinic H), 7.1 (s, 1H, imidazole H), 7.2 (s, 1H, imidazole H). M.S. [M+H]+ 196, [M+NH4]+ 213.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]N3N=NC(CC4C=CC(Cl)=C(Cl)C=4)=N3)[C:6](=[O:31])[N:5]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:4]=2[N:3]=1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[NH:48][N:47]=C(CCCO)C=2)=[CH:40][CH:39]=1>>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][C:15]3[CH:16]=[C:44]([C:41]4[CH:42]=[CH:43][C:38]([Cl:37])=[CH:39][CH:40]=4)[NH:48][N:47]=3)[C:6](=[O:31])[N:5]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:4]=2[N:3]=1
Reactant: CCCCCn1c(=O)n(CCCCCn2nnc(Cc3ccc(Cl)c(Cl)c3)n2)c(=O)c2[nH]c(Cl)nc21
Reactant: OCCCc1cc(-c2ccc(Cl)cc2)[nH]n1
Product: CCCCCn1c(=O)n(CCCc2cc(-c3ccc(Cl)cc3)[nH]n2)c(=O)c2[nH]c(Cl)nc21
Yield: 30 %

Procedure:
Prepared as with 8-chloro-1-(5-{5-[(3,4-dichlorophenyl)methyl]-2H-tetrazol-2-yl}pentyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione (Comparative Example C) using 3-[5-(4-chlorophenyl)-1H-pyrazol-3-yl]-1-propanol. The final product material was washed with ether to yield the title compound as a cream solid (30%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:23]=[CH:22][C:8]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][O:18]C(=O)C)=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.[OH-].[Na+]>C(O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][OH:18])=[N:15][CH:16]=2)=[CH:22][CH:23]=1)(=[O:4])=[O:3]
Reactant: CC(=O)OCc1ccc(OCc2ccc(S(C)(=O)=O)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(COc2ccc(CO)nc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.4 %

Procedure:
Acetic acid 5-(4-methanesulfonyl-benzyloxy)-pyridin-2-ylmethyl ester (10.4 g, 31 mmol) was suspended in a water (20 mL) and ethanol (80 mL). To this was added NaOH (2.2 g, 55 mmol) and the reaction was heated to reflux for 2 h. The reaction mixture was cooled to rt and stirred for 24 h and then concentrated under reduced pressure. The resulting residue was partitioned between water and ethyl acetate. The organic layer was dried over Na2SO4, filtered and volatiles were removed under reduced pressure to yield [5-(4-methanesulfonyl-benzyloxy)-pyridin-2-yl]-methanol (4.04 g, 44%) as a light yellow solid.
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]([F:42])([F:41])[C:5]1[CH:6]=[C:7]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:12][C@H:11]1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([CH3:33])[CH:27]=1)=[O:9].C(=O)(O)[O-].[Na+]>>[ClH:1].[ClH:1].[F:42][C:4]([F:3])([F:41])[C:5]1[CH:6]=[C:7]([CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=1)[C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:12][C@H:11]1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([CH3:33])[CH:27]=1)=[O:9]
Reactant: Cc1ccc(C[C@@H]2CN(CC#Cc3ccccn3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccc(C[C@@H]2CN(CCCc3ccccn3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C

Procedure:
(2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(2-pyridyl)-2-propynyl]piperazine dihydrochloride (0.2 g) was made free with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue dissolved in methanol (10 ml) and the solution was hydrogenated over 10% palladium on activated carbon (50 mg) at room temperature under 2-3 atoms. After removal of catalyst by filtration, the filtrate was concentrated under reduced pressure. The residue was treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(2-pyridyl)propyl]piperazine dihydrochloride.
Reaction SMILES: Cl.[O:2]1[C:8]2[CH:9]=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]3)[CH:11]=[CH:12][C:7]=2[CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[C:31]1([CH2:37][S:38](Cl)(=[O:40])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[C:31]1([CH2:37][S:38]([N:5]2[CH2:6][C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:14][CH2:15][N:16]([C:19](=[O:21])[CH3:20])[CH2:17][CH2:18]4)=[CH:9][C:8]=3[O:2][CH2:3][CH2:4]2)(=[O:40])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(=O)N1CCN(c2ccc3c(c2)OCCNC3)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(c2ccc3c(c2)OCCN(S(=O)(=O)Cc2ccccc2)C3)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.6 %

Procedure:
To a solution of 1-(4-(2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-8-yl)piperazin-1-yl)ethanone hydrochloride (80 mg, 0.26 mmol) and N,N-diisopropylethylamine (0.17 mL, 0.94 mmol) in dichloromethane (1.5 mL) was added phenylmethanesulfonyl chloride (76 mg, 0.39 mmol) and the reaction was stirred at ambient temperature for 16 hours. The reaction was then concentrated and purified by preparative reverse phase HPLC to yield 61 mg of 1-[4-(4-phenylmethanesulfonyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-8-yl)-piperazin-1-yl]-ethanone. 1H NMR (400 MHz, DMSO) δ 7.38-7.27 (m, 5H), 7.03 (d, J=8.3 Hz, 1H), 6.63-6.58 (m, 1H), 6.58-6.55 (m, 1H), 4.36 (s, 2H), 4.22 (s, 2H), 3.96-3.90 (m, 2H), 3.59-3.51 (m, 4H), 3.51-3.46 (m, 2H), 3.18-3.12 (m, 2H), 3.12-3.04 (m, 2H), 2.02 (s, 3H); LCMS (m/z) ES+ 430.1 [M+1]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:17][O:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=2)[CH:8]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[S:27]1[CH2:33][C:31](=[O:32])[NH:30][C:28]1=[S:29].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:13]([C:9]1[CH:8]=[C:7]([CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([CH:23]=[C:33]3[S:27][C:28](=[S:29])[NH:30][C:31]3=[O:32])=[CH:25][CH:26]=2)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]=1[O:11][CH3:12])([CH3:14])([CH3:15])[CH3:16]
Reactant: COc1c(C(C)(C)C)cc(COc2ccc(C=O)cc2)cc1C(C)(C)C
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1c(C(C)(C)C)cc(COc2ccc(C=C3SC(=S)NC3=O)cc2)cc1C(C)(C)C
Temperature: 70 °C
Yield: 22.7 %

Procedure:
In a round bottom flask under nitrogen purge 4-[[3,5-di (t-butyl)-4-methoxyphenyl]methoxy]benzaldehyde (530 mg, 1.5 mmol) is admixed with rhodanine (240 mg, 1.8 mmol) and sodium acetate (490 mg, 6.0 mmol) in 10 ml of acetic acid. The reaction mixture is then refluxed overnight with stirring. After the refluxing, the reaction mixture was allowed to cool to 70° C. The precipitate was removed by filtration and washed lightly with acetic acid. The precipitate was triturated with ethyl ether, filtered, triturated with water, and then filtered again and washed with ethyl ether. The solvents were removed in vacuo to yield 160 mg (23%) of the title product. mp 213-218° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([NH:17][CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])[CH3:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:15]([N:17]([CH2:18][CH:19]([O:20][CH2:21][CH3:22])[O:23][CH2:24][CH3:25])[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH3:16]
Reactant: CCNCC(OCC)OCC
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(CN(CC)c1c([N+](=O)[O-])cc(C)cc1[N+](=O)[O-])OCC

Procedure:
4-Chloro-3,5-dinitrotoluene (4.32 grams; 0.02 mole), N-ethyl-N-(2,2-diethoxyethyl)amine (3.2 grams; 0.02 mole), triethylamine (2.02 grams; 0.02 mole) and toluene (100 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at reflux overnight resulting in the formation of a precipitate. The reaction mixture was then filtered and the filtrate washed with water, dried and stripped of solvent to yield the desired product N-ethyl-N-(2,2-diethoxyethyl)-2,6-dinitro-p-toluidine.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[C:19]([NH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CN1C(=O)CCC1>[C:6]([C:5]1[CH:14]=[CH:15][C:2]([N:30]2[CH2:29][CH2:28][CH:27]([NH:26][C:19](=[O:20])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:32][CH2:31]2)=[C:3]([N+:16]([O-:18])=[O:17])[CH:4]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(C(=O)c3ccccc3)cc2[N+](=O)[O-])CC1
Yield: 95 %

Procedure:
Method 1 was followed using 4-chloro-3-nitrobenzophenone (1.0 eq), 4-(N-Boc-amino) piperidine (1.1 eq), and TEA (2.0 eq) in NMP yielding tert-butyl 1-(4-benzoyl-2-nitro phenyl)piperidin-4-ylcarbamate (95%). LCMS (m/z): 426.2 (MH+); LC Rt=3.46 min.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH2:13][C:14](=[O:16])[CH2:15][C:11]=2[C:10]([C:17]([NH2:19])=O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(Cl)=NC(Cl)=NC=1Cl>CN(C=O)C>[CH2:1]([N:8]1[C:12]2[CH2:13][C:14](=[O:16])[CH2:15][C:11]=2[C:10]([C:17]#[N:19])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1nn(Cc2ccccc2)c2c1CC(=O)C2
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Product: N#Cc1nn(Cc2ccccc2)c2c1CC(=O)C2
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
To a solution of the intermediate from step E (5.25 mmol) in DMF (60 mL) was added cyanuric chloride (3.12 g, 17 mmol) in three portions. After 30 minutes at room temperature, the reaction was quenched with water and extracted with ethyl acetate (2×). The organic layer was washed with water, brine and dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (SiO2) using 30% ethyl acetate-hexanes to give the desired product (0.95 g) as a yellow solid.