Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.Br.Br[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.[H-].[Na+]>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: Ic1ccc(Nc2ncccn2)cc1
Reactant: BrCc1ccncc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Product: Ic1ccc(N(Cc2ccncc2)c2ncccn2)cc1
Yield: 23.7 %

Procedure:
In the same manner as in Reference Example 22, N-(4-iodophenyl)pyrimidin-2-amine (300 mg) and 4-bromomethylpyridine hydrobromide (307 mg) were reacted in the presence of sodium hydride to obtain N-(4-iodophenyl)-N-((pyridin-4-yl)methyl)pyrimidin-2-amine (93 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:24]2([OH:30])[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1>>[OH:30][C:24]1([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH3:16])[CH:19]=2)[CH2:29][CH2:28][CH2:27][N:26]([C:6]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=2)=[O:7])[CH2:25]1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Product: COc1cccc(C2(O)CCCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)c1

Procedure:
The compound of Example 16 was prepared according to the general preparation protocol A from 3,4,5-trimethoxybenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:8](=[O:11])[CH:9]=[CH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:20]>CN(C=O)C>[CH:1]1([CH2:6][C@H:7]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:8]([C@H:9]2[CH2:10][O:20]2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C=CC(=O)[C@H](CC1CCCC1)NC(=O)OC(C)(C)C
Reactant: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCC1)C(=O)[C@H]1CO1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 43 %

Procedure:
A solution of (S)-tert-butyl (1-cyclopentyl-3-oxopent-4-en-2-yl)carbamate (854 mg, 3.20 mmol) in DMF (70 mL) was cooled to −20° C. and a bleach solution (9.50 mL, 12.8 mmol, 10% active spice) was added dropwise under nitrogen. The reaction mixture was warmed to 0° C. and stirred for 1.5 h. Water (70 mL) was added and the mixture was extracted with EtOAc (2×50 mL). The organic phases were combined, washed with brine (2×50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=80:1) to afford tert-butyl ((S)-3-cyclopentyl-1-((R)-oxiran-2-yl)-1-oxopropan-2-yl)carbamate as a viscous oil (390 mg, contaminated with some impurities, 43% yield) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][C:40]=2[S:42](Cl)(=[O:44])=[O:43])[CH:35]=[CH:34][CH:33]=1>>[CH:27]1([CH2:26][N:10]2[C:9]3[N:8]=[C:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][S:42]([C:40]5[CH:39]=[CH:38][CH:37]=[C:36]6[C:41]=5[N:32]=[CH:33][CH:34]=[CH:35]6)(=[O:43])=[O:44])=[CH:31][CH:30]=4)[NH:15][C:14]=3[C:13](=[O:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:11]2=[O:25])[CH2:28][CH2:29]1
Reactant: Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Product: O=c1c2[nH]c(Cc3ccc(NS(=O)(=O)c4cccc5cccnc45)cc3)nc2n(CC2CC2)c(=O)n1Cc1ccccc1F

Procedure:
This compound was prepared by the routes shown in schemes 2 and 4. 8-(4-Amino-benzyl)-3-cyclopropylmethyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione was condensed with 8-quinolinesulfonyl chloride under standard conditions to give the stated sulfonamide. Recrystallization from acetonitrile gave the pure product as an off white solid (53%); 1H NMR(DMSO-d6, 300 MHz) δH13.45 (s, 1H), 10.12 (s, 1H), 9.21 (dd, J=4.2, 1.1 Hz, 1H), 8.59 (dd, J=8.4, 1.8 Hz, 1H), 8.41 (dd, J=7.3, 1.5 Hz, 1H), 8.33 (dd, J=7.7, 1.5 Hz, 1H), 7.82–7.73 (m, 2H), 7.45–7.00 (m, 8H), 5.16 (s, 2H), 3.93 (s, 2H), 3.86 (d, J=7.3 Hz, 2H), 1.30–1.10 (m, 1H) and 0.50–0.30 (m, 4H); EI-HRMS m/e calculated for C32H27FN6O4S (M+) 610.1798, found 610.1804.
Reaction SMILES: [Na].[CH2:2]([O:4][C@H:5]1[CH2:22][C@@:21]2([CH3:23])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[C:19](=[N:24]O)[CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C:15]32OCC[O:26]3)[CH2:7][C@@H:6]1[OH:30])[CH3:3]>C(O)CC>[NH2:24][C@@H:19]1[CH2:18][C@@:16]2([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]2=[O:26])[C@H:11]2[C@H:20]1[C@:21]1([CH3:23])[C@@H:8]([CH2:9][CH2:10]2)[CH2:7][C@H:6]([OH:30])[C@@H:5]([O:4][CH2:2][CH3:3])[CH2:22]1
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=NO)C[C@@]2(C)[C@H]3CCC23OCCO3)C[C@@H]1O
Agent: [Na]
Solvent: CCCO
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@H](N)C[C@]2(C)C(=O)CC[C@@H]32)C[C@@H]1O

Procedure:
Sodium (7.5 g) was added portionwise to a refluxing solution of 2β-ethoxy-17,17-ethylenedioxy-3α-hydroxy-5α-androstan-11-one 11-oxime (5.7 g) in propanol (400 ml) under nitrogen. Most of the solvent was evaporated in vacuo, water was added and the precipitated material was extracted into ethyl acetate. The washed extract was evaporated in vacuo and the residue was partitioned between ether and 2 N-hydrochloric acid. The aqueous layer was basified, extracted into ethyl acetate, washed, dried (Na2SO4) and evaporated to afford a froth which crystallized from ether to give the title compound m.p. 144°-148°, [α]D +61.5°.
Reaction SMILES: C([O:5][C:6]1[CH:7]=[C:8]([CH:38]=[CH:39][CH:40]=1)[CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:31]S(C(C)(C)C)=O)([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([F:30])[CH:23]=1)[C:16]1[N:17]([CH3:21])[CH:18]=[N:19][CH:20]=1)(C)(C)C.Cl>CO.O1CCOCC1>[NH2:31][C:15]([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([F:30])[CH:23]=1)([C:16]1[N:17]([CH3:21])[CH:18]=[N:19][CH:20]=1)[CH2:14][CH2:13][CH2:12][CH2:11][O:10][CH2:9][C:8]1[CH:38]=[CH:39][CH:40]=[C:6]([OH:5])[CH:7]=1
Reactant: Cn1cncc1C(CCCCOCc1cccc(OC(C)(C)C)c1)(NS(=O)C(C)(C)C)c1ccc(C#N)c(F)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cn1cncc1C(N)(CCCCOCc1cccc(O)c1)c1ccc(C#N)c(F)c1
Reaction time: 1 h

Procedure:
2-Methyl-propane-2-sulfinic acid [5-(3-tert-butoxy-benzyloxy)-1-(4-cyano-3-fluoro-phenyl)-1-(3-methyl-3H-imidazol-4-yl)-pentyl]-amide (A) (0.396 g, 0.58 mmol) was dissolved in methanol (15 mL) and treated with 4M HCl in dioxane (9 mL). After 1 h, the reaction mixture was concentrated in vacuo, azeotroped with CH2Cl2 (3×), rinsed with CH2Cl2, and the solid collected to give enantiomer A of the title compound. MS (M+1) 409. Using the same procedure, diastereomer B (Step D) (0.110 g, 0.161 mmol) gave enantiomer B of the title compound.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([CH2:25][O:26]CC2C=CC(Cl)=CC=2)[O:14][C@@H:11]([O:12][CH3:13])[C@@H:10]1[O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CNC1C=CC=CC=1.CC([O-])(C)C.[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].[Cl-].[Cl-].[Zn+2]>[CH2:1]([O:8][C@H:9]1[C@H:16]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@@H:15]([CH2:25][OH:26])[O:14][C@@H:11]([O:12][CH3:13])[C@@H:10]1[O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@H]1O[C@H](COCc2ccc(Cl)cc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CNc1ccccc1
Product: CO[C@@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1O[Si](C)(C)C(C)(C)C
Yield: 80 %

Procedure:
The general procedure C using 22 (0.123 g, 0.20 mmol), N-methylaniline (26 μL, 0.24 mmol), Pd(OAc)2 (0.9 mg, 0.004 mmol), (o-biphenyl)P(t-Bu)2 (2.4 mg, 0.008 mmol) and NaOtBu (26.9 mg, 0.28 mmol) for 12 h at room temperature afforded a yellow oil. Cleavage of the aminated intermediate with ZnCl2 (240 μL 1.0 M in Et2O, 0.240 mmol) using general procedure D gave 78.2 mg (80%) of 28 as a colorless oil after purification by flash column chromatography on silica gel (25% EtOAc/Hexanes). [α]24D: −28.8° (c 1.32, CH2Cl2); IR (thin film) 3475, 2954, 2855, 1071 cm−1; 1H-NMR (CDCl3) δ 7.38–7.24 (m, 10H), 4.94 (d, J=11.3 Hz, 1H), 4.89 (d, J=11.3 Hz, 1H), 4.82 (d, J=11.0 Hz, 1H), 4.64 (d, J=10.7 Hz, 1H), 4.18 (d, J=7.3 Hz, 1H), 3.91–3.88 (m, 1H), 3.76–3.72 (m, 1H), 3.61–3.49 (m, 6H), 3.42–3.38 (m, 1H), 2.04–2.02 (m, 1H), 0.92 (s, 9H), 0.13 (s, 3H), 0.09 (s, 3H); C-NMR (CDCl3) δ 138.7, 138.1, 128.6, 128.4, 128.2, 128.1, 127.6, 127.5, 105.0, 85.7, 78.0, 75.7, 75.4, 75.2, 62.1, 57.4, 26.1, 18.4, −4.1, −4.2; FAB MS m/z (M+Na)+: calcd 511.2492, obsd 511.2492.
Reaction SMILES: C1(C2C=CC=CC=2)C=CC(OCC2OC(C(O)=O)=CC=2)=CC=1.Cl.[C:24]([O:28][C:29](=[O:35])[C@H:30]1[CH2:34][CH2:33][CH2:32][NH:31]1)([CH3:27])([CH3:26])[CH3:25].Cl.C(N=C=NCCCN(C)C)C>O1CCCC1>[C:24]([O:28][C:29]([CH:30]1[CH2:34][CH2:33][CH2:32][NH:31]1)=[O:35])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)c1ccc(COc2ccc(-c3ccccc3)cc2)o1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CCCN1
Yield: 61.1 %

Procedure:
A solution of 5-(biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (of Intermediate 8; 0.134 g, 0.46 mmol), D-proline tert-butyl ester hydrochloride (Bachem; 0.22 g, 1.1 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (Avocado; 0.18 g, 0.95 mmol), and N,N-dimethylaminopyridine (0.166 g, 1.36 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 16 h. The solvents were evaporated under reduced pressure, and water and ethyl acetate were added. The aqueous phase was extracted three times with ethyl acetate, and the combined organic layers were dried (sodium sulfate), filtered, evaporated, and purified using a Biotage Flash 40 purification system, eluting with methylene chloride/acetone 9:1, to give 5-(biphenyl-4-yloxymethyl)-furan-2-carbonyl]-D-pyrrolidine-2-carboxylic acid tert-butyl ester as a white solid (0.115 g, 56%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([CH3:28])=[N:10][C:11]2[N:12]([CH:22]=[C:23]([C:25]([OH:27])=O)[N:24]=2)[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C[N:32]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-].CCN(C(C)C)C(C)C>C1COCC1>[C:25]([C:23]1[N:24]=[C:11]2[N:10]=[C:9]([CH3:28])[C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[N:12]2[CH:22]=1)(=[O:27])[NH2:32]
Reactant: Cc1nc2nc(C(=O)O)cn2c(-c2ccc(Cl)cc2Cl)c1C(=O)OC(C)(C)C
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2nc(C(N)=O)cn2c(-c2ccc(Cl)cc2Cl)c1C(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 112.7 %

Procedure:
To a stirred solution of 6-(tert-butoxycarbonyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylic acid (Example 155, Step 1, 500 mg, 1.18 mmol) in THF (10 mL) at room temperature was added PyBOP (787 mg, 1.78 mmol), HOBt (240 mg, 1.18 mmol), NH4Cl (95 mg, 1.78 mmol) and iPr2NEt (0.4 mL, 2.37 mmol). After 24 h, the reaction was concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with 1N HCl, 1N NaOH and brine prior to drying over anhydrous MgSO4. Filtration, concentration under reduced pressure and purification by silica gel chromatography afforded tert-butyl 2-carbamoyl-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-6-carboxylate (560 mg, 100%) as a light yellow solid.
Reaction SMILES: Cl.[C:2](Cl)(=O)[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH2:11]([NH:13][C:14](=[S:17])[NH:15][NH2:16])[CH3:12].[OH-].[Na+]>N1C=CC=CC=1>[CH2:11]([N:13]1[C:2]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[N:16][NH:15][C:14]1=[S:17])[CH3:12]
Reactant: CCNC(=S)NN
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCn1c(-c2ccncc2)n[nH]c1=S
Yield: 57.5 %

Procedure:
The title compound (pale yellow solid, 16.7 g, 58%) was prepared from isonicotinoyl chloride hydrochloride (25.1 g, 140.8 mmol) and 4-ethyl-3-thiosemicarbazide (16.87 g, 141.5 mmol) in pyridine (185 ml) with sodium hydroxide (220 mL, 2M, 440 mmol) added to the intermediate formed to effect cyclization. 1H NMR (DMSO-d6) δ (ppm): 8.80 (dd, 2H), 7.72 (dd, 2H), 4.11 (q, 2H), 3.59 (t, 3H).
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[H-].[Na+].[O:6]=[C:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][C:9]([C:17]2[N:22]=[C:21]([CH2:23]S([O-])(=O)=O)[CH:20]=[CH:19][CH:18]=2)=[N:8]1.C(OCC)(=O)C>CN(C=O)C.O>[CH2:1]([S:3][CH2:23][C:21]1[N:22]=[C:17]([C:9]2[S:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:7](=[O:6])[N:8]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:2]
Reactant: O=c1nc(-c2cccc(CS(=O)(=O)[O-])n2)sc2ccccc12
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCSCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.4 %

Procedure:
Ethyl mercaptan (0.25 g, 3.30 mmol) and sodium hydride (60% in oil, 0.15 g, 3.60 mmol) were dissolved in DMF (30 ml), and 6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridylmethanesulfonate (1.05 g, 3.00 mmol) was added thereto. The reaction mixture was stirred at room temperature for 18 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (0.23 g, 24%) as pale yellow crystals.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5]=[C:6]([CH3:28])[CH:7]=[CH:8][CH:9]=[C:10]([C:12]1[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[CH:15]=[C:14]([CH:21]([CH3:23])[CH3:22])[C:13]=1[O:24][CH2:25][CH2:26][CH3:27])[CH3:11])C.[OH-].[Na+].Cl>CCO>[CH:21]([C:14]1[C:13]([O:24][CH2:25][CH2:26][CH3:27])=[C:12]([C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]([CH3:28])=[CH:5][C:4]([OH:29])=[O:3])[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[CH:15]=1)([CH3:22])[CH3:23]
Reactant: CCCOc1c(C(C)=CC=CC(C)=CC(=O)OCC)cc(C(C)C)cc1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCOc1c(C(C)=CC=CC(C)=CC(=O)O)cc(C(C)C)cc1C(C)C
Temperature: 80 °C
Yield: 81.9 %

Procedure:
A solution of 7-(3,5-diisopropyl-2-propoxy-phenyl)-3-methyl-octa-2, 4,6-trienoic acid ethyl ester (Compound 15, 2.45 g, 6.16 mmol) in EtOH (50 mL) was treated with 1M NaOH (25 mL, 25 mmol) and was heated to 80° C. for 4 h. The mixture was cooled to room temperature, acidified with 1M HCl, and was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by recrystallization from CH3CN to yield the title compound as a white solid (1.87 g, 82%).
Reaction SMILES: [CH3:1][C:2](/[CH:4]=[N:5]/O)=O.[C:7]1(=[O:14])[CH2:12][CH2:11][CH2:10][C:9](=O)[CH2:8]1.C(O)(=O)C.[OH-].[K+]>[Zn].O>[CH3:1][C:2]1[C:8]2[C:7](=[O:14])[CH2:12][CH2:11][CH2:10][C:9]=2[NH:5][CH:4]=1
Reactant: CC(=O)/C=N/O
Reactant: O=C1CCCC(=O)C1
Agent: [K+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Cc1c[nH]c2c1C(=O)CCC2
Temperature: 25 °C
Yield: 44.7 %

Procedure:
The subtitle compound was prepared according to the literature procedure (Hauptmann, S. et al., Z. Chem., 1966, 3, 107. Ravina, E. et al., Bio. Med. Chem. Lett., 1995, 5, 579.). A mixture of anti-pyruvic aldehyde 1-oxime (1.3 g, 15 mmol), 1,3-cyclohexanedione (1.7 g, 15 mmol), glacial acetic acid (12 mL) and water (3.0 mL) was stirred vigorously at room temperature. Zinc dust (3 g) was added slowly keeping the temperature below 60° C. After addition, this resulting brown solution was heated under reflux temperature for 2 hours. After cooling, the reaction mixture was basified by an addition of 1 M aqueous KOH. The whole was extracted with CH2Cl2 (50 mL×3), and the combined organic layers were dried over MgSO4, and concentrated in vaciio. The residue was purified by flash chromatography eluting with hexane-ethyl acetate (3:1→EtOAc only) to afford the subtitle compound (1.0 g, 46% yield) of as a yellow solid.
Reaction SMILES: Cl[C:2]1N=NC(NC)=C(C2C=CC=CC=2C)C=1.[Cl:17][C:18]1[N:23]=[N:22][C:21]([N:24]([CH3:41])[C:25](=[O:40])[C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([S:36]([CH3:39])(=[O:38])=[O:37])[CH:27]=2)=[C:20]([C:42]2[CH:47]=[CH:46][C:45](F)=[CH:44][C:43]=2OC)[CH:19]=1>>[Cl:17][C:18]1[N:23]=[N:22][C:21]([N:24]([CH3:41])[C:25](=[O:40])[C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([S:36]([CH3:39])(=[O:37])=[O:38])[CH:27]=2)=[C:20]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[CH3:2])[CH:19]=1
Reactant: COc1cc(F)ccc1-c1cc(Cl)nnc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Reactant: CNc1nnc(Cl)cc1-c1ccccc1C
Product: Cc1ccccc1-c1cc(Cl)nnc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 1, from (6-chloro-4-o-tolyl-pyridazin-3-yl)-methyl-amine and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 1, intermediate d) after a reaction time of 18 hours, applying a second purification step using preparative HPLC (Gemini NX column) with a gradient of methanol:water with 0.05% formic acid (80:20 to 98:2). Colorless foam (23%). MS (ESI+): m/z=484.070 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[OH:21])=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.Cl[CH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[N:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:26]([CH2:25][O:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:13]2[O:14][C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=3)=[N:11][N:12]=2)=[CH:27][CH:28]=1
Reactant: ClCc1ccnc2ccccc12
Reactant: Oc1ccccc1-c1nnc(Nc2cccc(C(F)(F)F)c2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cccc(Nc2nnc(-c3ccccc3OCc3ccnc4ccccc34)o2)c1
Temperature: 60 °C
Yield: 27.2 %

Procedure:
To a solution of 2-(5-(3-trifluoromethylphenylamino)-1,3,4-oxadiazol-2-yl) phenol (100 mg, 0.31 mmol; Reference Compound 9-(1)) and 4-chloromethylquinoline (55 mg, 0.31 mmol) in N,N-dimethylformamide (1.0 mL) was added potassium carbonate (86 mg, 0.62 mmol) at room temperature and then the mixture was stirred at 60° C. over night. The reaction solution was cooled to a room temperature and diluted with ethyl acetate (100 mL). The ethyl acetate solution was washed with a saturated brine solution (30 mL), dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The residue was purified with a silica gel column chromatography (hexane/ethyl acetate) to give 39 mg (27%) of the titled compound as a colorless solid.
Reaction SMILES: Br[CH2:2][C:3]([O:11][CH3:12])=[CH:4][C:5](=[O:10])[C:6]([Cl:9])([Cl:8])[Cl:7].[C:13]([O-:16])(=[O:15])[CH3:14].[Cs+].C(O)(=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[C:13]([O:16][CH2:2][C:3]([O:11][CH3:12])=[CH:4][C:5](=[O:10])[C:6]([Cl:9])([Cl:8])[Cl:7])(=[O:15])[CH3:14]
Reactant: COC(=CC(=O)C(Cl)(Cl)Cl)CBr
Reactant: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=CC(=O)C(Cl)(Cl)Cl)COC(C)=O

Procedure:
29.6 g (0.1 mol) of 5-bromo-1,1,1-trichloro-4-methoxypent-3-en-2-one, 19.1 g of cesium acetate, 5 g of tetrabutylammonium bromide and 8 g of acetic acid were stirred in 300 ml of acetonitrile at 25° C. for 8 h. The precipitate was filtered off and the organic phase was concentrated under reduced pressure.
Reaction SMILES: [C:1]([N:4]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:5]1[CH2:10][C:9]([CH:11]=O)=[N:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]1=[O:20])(=[O:3])[CH3:2].[CH3:28][N:29]([CH3:31])[NH2:30].Cl>CCO>[C:1]([N:4]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[N:5]1[CH2:10][C:9](/[CH:11]=[N:30]/[N:29]([CH3:31])[CH3:28])=[N:8][N:7]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C:6]1=[O:20])(=[O:3])[CH3:2]
Reactant: CN(C)N
Reactant: CC(=O)N(C(=O)OC(C)(C)C)N1CC(C=O)=NN(C(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCO
Product: CC(=O)N(C(=O)OC(C)(C)C)N1CC(/C=N/N(C)C)=NN(C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of tert-butyl 4-[acetyl(tert-butoxycarbonyl)amino]-6-formyl-3-oxo-5H-1,2,4-triazine-2-carboxylate (461 mg, 1.20 mmol) in EtOH was added N,N-dimethylhydrazine (0.110 mL, 1.44 mmol), followed by addition of 1 droplet of conc. HCl. The mixture was stirred at room temperature for 20 h followed by evaporation of the volatiles to give the title compound as a viscous oil. LCMS (Method K) RT 0.99 min. [M+H]+ 427.
Reaction SMILES: CCC.[CH2:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[N+:10]([O-])([OH:12])=[O:11]>>[N+:10]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)([O-:12])=[O:11]
Reactant: C1CCCCC1
Reactant: O=[N+]([O-])O
Solvent: CCC
Product: O=[N+]([O-])C1CCCCC1

Procedure:
Essentially the same manufacturing setup discussed above for propane nitration is used to nitrate cyclohexane and obtain nitrocyclohexane within product purity specifications. Cyclohexane is nitrated using about 30 weight percent dilute aqueous nitric acid as the nitrating agent at the following process conditions: about 1200 psig reactor pressure, about 220 degrees Celsius reactor temperature, a residence time of about 120 seconds, and a cyclohexane to nitric acid mole ratio of about 2:1. FIG. 3 illustrates an apparatus 300 for synthesizing nitrocyclohexane. A hydrocarbon feedstock 301, comprising cyclohexane, and aqueous nitric acid 302 are introduced into a reactor 303 and react to form a reaction product stream 304. A composition of a typical reaction product stream 304 from the reactor 303 is summarized in Table 3.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[C:8]([I:9])=[C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:25]=[N:26][N:27](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:28]=3)=[CH:14][CH:13]=2)[CH:6]=[C:5]([CH3:48])[N:4]=1>ClCCl.CO>[ClH:1].[CH3:2][C:3]1[C:8]([I:9])=[C:7]([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:25][N:26]=[N:27][N:28]=3)=[CH:16][CH:17]=2)[CH:6]=[C:5]([CH3:48])[N:4]=1
Reactant: Cc1cc(NCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(I)c(C)n1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(NCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(I)c(C)n1
Reaction time: 0.5 h

Procedure:
Concentrated hydrochloric acid (0.5 ml) was added to a suspension of 2,6-dimethyl-3-iodo-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methylamino]pyridine (A) (215 mg) in dichloromethane/methanol (4 ml) (1:3 v/v) and the mixture stirred for 30 minutes. Volatile material was removed by evaporation and the residue purified by recrystallisation from methanol to give 2,6-dimethyl-3-iodo-4-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methylamino]pyridine hydrochloride as a white solid, m.p. 238°-240° C. (decomposition); NMR (d6 -DMSO): 2.4(s,3H), 2.7(s,3H), 4.7(d,2H), 6.6(s,1H), 7.1(d,2H), 7.3(d,2H), 7.4-7.7(m,4H), 8.0(t,1H); mass spectrum (positive fast atom bombardment (+ve FAB), DMSO/nitrobenzyl alcohol): 483(M+H)+ ; microanalysis, found: C,48.1; H,4.1; N,16.1%; C21H19N6I.HCl requires: C,48.6; H,3.9; N,16.2%.