Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[C:3]([NH:5][CH:6]1[C:17](=[O:18])[N:8]2[C:9]([C:14]([O-:16])=[O:15])=[C:10]([CH3:13])[CH2:11][S:12][C@H:7]12)=[O:4].FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[OH:1][CH:2]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[C:3]([NH:5][CH:6]1[C:17](=[O:18])[N:8]2[C:9]([C:14]([OH:16])=[O:15])=[C:10]([CH3:13])[CH2:11][S:12][C@H:7]12)=[O:4]
Reactant: CC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(O)c3cccs3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(O)c3cccs3)[C@H]2SC1
Yield: 90.6 %

Procedure:
Diphenylmethyl (6R,7R,2'R and S)-7-(2' -hydroxy-2'-[thien-2-yl]-acetamido)-3-methylceph-3-em-4-carboxylate (543mg, 1.05mmole) was dissolved in anisole (4ml) and stirred with trifluoroacetic acid (4 ml) at +20 to +25° for 7 mins. The anisole and trifluoroacetic acid were evaporated and the residue partitioned between 3%-aqueous sodium bicarbonate solution (ca 50ml) and ethyl acetate (ca 50ml). The aqueous layer was washed with ethyl acetate (3×ca 50ml), layered with ethyl acetate and adjusted to pH 2.5. The ethyl layer was combined with the ethyl acetate backwash of the aqueous layer, dried, and evaporated to give (6R,7R,2'R and S)-7-(2' -hydroxy-2'-[thien-2-yl]-acetamido)-3-methylceph-3-em-4-carboxylic acid as a foam (337mg, 91%). This foam was dissolved in acetone (3ml) and stirred with a solution of sodium 2-ethylhexanoate (186mg, 1.05 mmole) in acetone (2ml) and ether (2ml). The precipitated material was filtered off, washed with ether, and dried to give the title compound containing 2mole-equivalents of water (i.r., microanalysis and 1/6 mole-equivalents of ether (n.m.r., microanalysis) as a pale-brown solid (183mg, 0.486 mmole, 46.4%); λmax (pH6-buffer) 237.5nm, inflexion at 255nm (ε12,640 and 9,250 respectively); νmax (nujol) 3380 (NH,H2O), 1760 (azetidin-2-one), 1680 and 1528 (CONH), and 1600 cm-1 (CO2 -); τ (Me2SO-D6) 1.48 and 1.63 (total 1H, 2d,J9Hz,NH), 2.54 to 3.10 (3H, m, thiophene protons), 4.46 (ca 1H, m, C7 -H), 4.60 and 4.62 (total ca 1H, 2S, CHOH), 5.00 (1H,d,J4.5Hz, C7 -H), 6.49 and 6.87 (2H, ABq, J18Hz, C2 -H2), 8.01 (3H,s, C3 -CH3). A signal at τ 8.89 revealed the presence of 1/6 mole-equivalent of diethyl ether. (Found: C,41.1, 41.4; H,3.6, 3.8;N,6.6, 7.0; S,14.5. C14H13N2NaO5S2. 1/6 C2H5OC2H5. 2H2O (424.7) requires C,41.5; H,4.4; N,6.5; S,15.1%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:9]=[O:10])=[C:4]([CH3:18])[CH:3]=1.[H-].[Na+].[Br:21][CH2:22][CH2:23]Br>C1COCC1>[Br:21][CH2:22][CH2:23][O:10][CH:9]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH3:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: BrCCBr
Reactant: Cc1ccccc1C(C=O)c1ccc(F)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1C(=COCCBr)c1ccc(F)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(4-Fluoro-2-methylphenyl)-(2-methylphenyl)acetaldehyde (3.5 g, 0.0144 mol) was dissolved in dry THF (20 ml) and added dropwise to a suspension of sodium hydride (60% oil dispersion) (0.63 g, 0.0158 mol) in dry tetrahydrofuran (30 ml). The mixture was stirred at room temperature for 1 h and heated at reflux for 0.5 h. After cooling 1,2-dibromoethane (12.4 ml, 10 equiv.) was added, and the reaction mixture was allowed to stand at room temperature for 192 h. The reaction mixture was filtered and evaporated. The residue was pumped in vacuo, but still contained ca. 30% starting aldehyde, so the above procedure was repeated.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].FC1C=CC(N)=CC=1>C(Cl)Cl.C1(C)C=CC=CC=1.FC1C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:3])[CH:10]=1
Reactant: BrBr
Reactant: Nc1ccccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Nc1ccc(F)cc1
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: Fc1ccccc1
Solvent: ClCCl
Product: Nc1ccc(Br)cc1F

Procedure:
In a suitable aprotic solvent (e.g., CH2Cl2, toluene, fluorobenzene, or the like) 1 mole of tetrabutylammonium bromide is dissolved and stirred as 1 mole of Br2 (bromine) is added. This mixture of tetrabutylammonium trihalide and solvent is cooled to 10° before 1 mole of 2-fluoroaniline or 4-fluoroanilin, or a mixture of both, is added. The reaction takes place immediately to produce 4-bromo-2-fluoroaniline.HBr, or 2-bromo-4-fluoroaniline.HBr, or a mixture of the two. The salt is then collected and dried before carrying it up to the next step. Catalyst and solvent are recovered for recycle.
Reaction SMILES: [CH:1]1[C:11]2[N:10]3[CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C(Cl)Cl>[Cl:22][C:23]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:24]=1[C:25]([N:6]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[N:10]2[CH:12]=[CH:13][CH:14]=[C:9]2[CH2:8][CH2:7]1)=[O:26]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Reactant: c1ccc2c(c1)NCCc1cccn1-2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1CCc2cccn2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.6 %

Procedure:
To a solution of 0.28 g of 6,7-dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepine in 6 ml of methylene chloride is added 0.30 g of triethylamine followed by 0.50 g of 2-chloro-4-nitrobenzoyl chloride in 0.5 ml of methylene chloride. The reaction mixture is stirred at room temperature for 1 hour then quenched with 5 ml of saturated NaHCO3. The methylene chloride is evaporated in vacuo and the residue is diluted with 5 ml of water and extracted with 20 ml of ethyl acetate. The organic layer is separated washed with saturated NaHCO3 and brine, dried with Na2SO4 and evaporated in vacuo to give 0.59 g of a yellow foam which is triturated with ether-hexanes to give 0.56 g of the desired product as off-white solid. MS(CI): 368(M+H)(Cl35) 370 (M+H) (Cl37)
Reaction SMILES: [C:1]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])=[CH:12][CH:13]=2)[NH:8][C:7]=1[CH2:25][CH2:26][CH3:27])(=[O:5])[CH:2]([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[Cl:37][C:38]1[CH:46]=[CH:45][CH:44]=[CH:43][C:39]=1[C:40](Cl)=[O:41]>ClCCl.CN(C)C1C=CN=CC=1>[Cl:37][C:38]1[CH:46]=[CH:45][CH:44]=[CH:43][C:39]=1[C:40]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH:10]=2)[C:6]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[C:7]1[CH2:25][CH2:26][CH3:27])=[O:41]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CCCc1[nH]c2cc(C(=O)OCc3ccccc3)ccc2c1C(=O)C(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1c(C(=O)C(C)C)c2ccc(C(=O)OCc3ccccc3)cc2n1C(=O)c1ccccc1Cl
Temperature: 20 °C
Yield: 115.4 %

Procedure:
To a stirred mixture of benzyl 3-isobutyryl-2-propylindole-6-carboxylate (207 mg) and diisopropylethylamine (295 mg) in dichloromethane (6 ml) were added 2-chlorobenzoyl chloride (299 mg) and 4-dimethylaminopyridine (12 mg) at 0° C. The reaction mixture was refluxed for 15 hours. The reaction mixture was cooled to 20° C. and washed with 1N hydrochloric acid, water, saturated sodium bicarbonate, water and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:10) to give benzyl 1-(2-chlorobenzoyl)-3-isobutyryl-2-propylindole-6-carboxylate (330 mg) as yellow crystals.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[C:14]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[CH:13][N:12]=[CH:11]2)[CH:6]=[CH:5][N:4]1C1C=CC=CC=1.Cl[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]=1.IC1C=CC=CC=1>>[F:38][C:37]([F:40])([F:39])[C:33]1[N:32]=[C:31]([N:4]2[CH:5]=[CH:6][C:7]([CH2:9][N:10]3[C:14]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=4)=[CH:13][N:12]=[CH:11]3)=[CH:8][C:3]2=[O:2])[CH:36]=[CH:35][CH:34]=1
Reactant: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3ccccc3)c(=O)c2)cc1
Reactant: FC(F)(F)c1cccc(Cl)n1
Agent: Cl
Solvent: Ic1ccccc1
Product: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3cccc(C(F)(F)F)n3)c(=O)c2)cc1

Procedure:
4-[3-(6-'Triflouromethyl-2-oxo-2H-[1,2']bipyridinyl-4-ylmethyl)-3H-imidazol-4-ylmethyl]-benzonitrile was prepared in a manner substantially similar to the procedure described above for 4-[3-(2-oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl]benzonitrile, hydrochloride, but substituting 2-chloro-6-trifluoromethylpyridine for the iodobenzene in Step 3.
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[CH:6][C:5]=1[C:21]1[CH:26]=[CH:25][N+:24]([O-])=[CH:23][CH:22]=1)([CH3:3])[CH3:2]>O=P(Cl)(Cl)Cl>[CH:1]([C:4]1[C:9]([C:10]([F:13])([F:11])[F:12])=[C:8]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[CH:6][C:5]=1[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1c(-c2cc[n+]([O-])cc2)ccc(Sc2ccccc2)c1C(F)(F)F
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1c(-c2ccncc2)ccc(Sc2ccccc2)c1C(F)(F)F
Yield: 89.6 %

Procedure:
Then, 2-chloro-4-(4-(2-isopropyl-phenylsulfanyl-3-trifluoromethyl-phenyl)-pyridine 76 was prepared as follows. Compound 75 (3.19 g, 8.19 mmol) was treated with POCl3 (50 mL) at 100° C. for 10 hours. The reaction mixture was concentrated on a rotovap, and the residue was treated with crushed ice (20 g). Water (100 mL) was added, the aqueous solution was then extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (3×100 mL), dried over MgSO4, filtered and concentrated. The crude product was purified by chromatography to give the title compound 76 as a brown oil (2.74 g, 82%). 1H-NMR (CDCl3, 400 MHz) δ 1.19 (d, J=6.8 Hz, 6H), 3.51 (heptet, J=6.8 Hz, 1H), 6.91 (d, J=8.5 Hz, 1H), 7.25–7.28 (m, 1H), 7.37 (dd, J=1.7 Hz, 5.1 Hz, 1H), 7.45–7.52 (m, 5H), 7.87 (d, J=2.0 Hz, 1H), 8.43 (d, J=5.4 Hz, 1H). MS (DCI) m/z 408, 409, 410 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][S:9]([O-:12])(=[O:11])=[O:10].[CH3:13][N+:14]1[N:15]([CH3:26])[C:16](Cl)=[CH:17][C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH3:7][O:8][S:9]([O-:12])(=[O:11])=[O:10].[CH3:26][N+:15]1[N:14]([CH3:13])[C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:17][C:16]=1[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1c(Cl)cc(-c2ccccc2)[n+]1C
Reactant: C1CCNCC1
Agent: COS(=O)(=O)[O-]
Solvent: CCO
Product: Cn1c(-c2ccccc2)cc(N2CCCCC2)[n+]1C

Procedure:
Piperdine (2.56 g, 0.03 mole) is added to 1,2-dimethyl-3-chloro-5-phenylpyrazolium methyl sulfate (4.77 g, 0.015 mole) in absolute ethanol (30 ml) and the mixture stirred with a bar magnet and heated under reflux for 4 hours. After cooling, the reaction mixture is evaporated under reduced pressure to a brown oil, and the dissolved in 50 ml of aqueous saturated sodium bicarbonate solution. The aqueous layer is extracted with ether and this organic layer discarded, then with chloroform. Evaporation of the chloroform layer affords 1,2-dimethyl-3-phenyl-5-piperidinopyrazolium methyl sulfate as a viscous oil. The oil is redissolved in water and saturated aqueous potassium iodide solution is added. An immediate copious white precipitate of 1,2-dimethyl-3-phenyl-5-piperidinopyrazolium iodide is formed, then filtered and washed with ice cold water to give 3.37 g, (56%) of product having a melting point ranging from 179° to 180° C. The melting point is unchanged by dissolving in chloroform, filtering and reprecipitating with diethyl ether and filtering off the solid. The analysis of resultant product is set forth below in Table I, compound 1, following Example 12, hereinbelow.
Reaction SMILES: [N:1]1([C@:4]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:5]2[C@@H:6]2[C@@:19]([CH3:22])([CH2:20][CH2:21]3)[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:42])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]3[CH2:31][CH2:30][C@@H:29]([C:32]([O:34]CC5C=CC=CC=5)=[O:33])[CH2:28][CH:27]=3)=[CH:12][CH2:11]4)[CH2:8][CH2:7]2)CC1.[CH:49]([N:52]([CH2:56][CH3:57])[CH:53]([CH3:55])[CH3:54])([CH3:51])C.C1C[O:61]CC1>>[C@H:51]12[CH2:54][C@H:53]([N:52]([CH2:56][CH2:57][NH:1][C@:4]34[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:5]3[C@@H:6]3[C@@:19]([CH3:22])([CH2:20][CH2:21]4)[C@@:18]4([CH3:23])[C@@H:9]([C@:10]5([CH3:42])[C@@H:15]([CH2:16][CH2:17]4)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]4[CH2:31][CH2:30][C@@H:29]([C:32]([OH:34])=[O:33])[CH2:28][CH:27]=4)=[CH:12][CH2:11]5)[CH2:8][CH2:7]3)[CH2:49]1)[CH2:55][O:61]2
Reactant: C=C(C)[C@@H]1CC[C@]2(N3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC[C@H](C(=O)OCc7ccccc7)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C1CCOC1
Reactant: CCN(C(C)C)C(C)C
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CO4)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC[C@H](C(=O)O)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 100 °C
Reaction time: 70 h
Yield: 62.8 %

Procedure:
To a mixture of (R)-benzyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (50 mg, 0.077 mmol), 4° A mol. sieves (100 mg, 0.077 mmol) and N,N-diisopropylethyl amine (0.094 mL, 0.538 mmol) in THF (2 mL) was added (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane, HCl (52.2 mg, 0.385 mmol). The reaction was stirred at 100° C. After 70 h, the reaction was cooled to rt, purified by prep-HPLC using prep-HPLC method 15 and dried under vacuum at 50° C. to give the title compound (47.2 mg, 0.048 mmol, 62.8% yield) as a white solid. LC/MS: m/e 749.6 (M+H)+, 4.62 min (method 9). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.75-7.44 (m, 2H), 7.43-7.29 (m, 5H), 5.35 (br. s., 1H), 5.17 (d, J=4.6 Hz, 1H), 5.14 (s, 2H), 4.78 (s, 1H), 4.69 (s, 1H), 4.65 (br. s., 1H), 4.27 (br. s., 1H), 4.18 (d, J=10.3 Hz, 1H), 3.81 (d, J=9.8 Hz, 1H), 3.71 (d, J=16.1 Hz, 2H), 3.51-3.28 (m, 3H), 2.81-2.67 (m, 1H), 2.65-2.54 (m, 1H), 2.34 (br. s., 2H), 2.26-2.10 (m, 4H), 2.10-1.80 (m, 6H), 1.79-1.71 (m, 2H), 1.69 (s, 3H), 1.64-1.23 (m, 12H), 1.07 (s, 3H), 1.01 (s, 3H), 0.93 (s, 3H), 0.92 (s, 3H), 0.86 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Br[CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C(OCC)(=O)C>[CH2:10]([N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)CCn1cc([N+](=O)[O-])cn1
Temperature: 55 °C
Reaction time: 12 h
Yield: 94.8 %

Procedure:
A mixture of 4-Nitro-1H-pyrazole (234 mg, 2.06 mmol, 1.0 eq), 1-Bromo-3-methylbutane (0.30 ml, 2.48 mmol, 1.2 eq), and Cesium carbonate (1.01 g, 3.10 mmol, 1.5 eq) in 5.0 mL 1,2-Dimethoxyethane was stirred at 55° C. for 12 hours. The reaction mixture was cooled to room temperature and diluted with 25 mL ethyl acetate and filtered. The filtrate was then concentrated and the residue was dissolved in 5 mL dichloromethane and purified by flash column chromatography (silica, 0-80% ethyl acetate in heptane in 30 minutes) to yield 357.6 mg (94.32%) of Isopentyl-4-nitro-1H-pyrazole as a white solid. LCMS (ESI) m+H=184.1 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 8.06 (s, 1H), 4.20-4.14 (m, 2H), 1.80 (dd, J=14.8, 7.1, 2H), 1.60 (dp, J=13.4, 6.7, 1H), 0.97 (d, J=6.6, 6H).
Reaction SMILES: Cl.[CH3:2][O:3][C@H:4]([CH2:27][CH3:28])[CH2:5][C@H:6]1[CH2:17][CH2:16][C:15]2[S:14][C:13]3[N:12]=[CH:11][N:10]=[C:9]([O:18][CH:19]4[CH2:24][CH2:23][CH:22]([NH:25][CH3:26])[CH2:21][CH2:20]4)[C:8]=3[C:7]1=2.C=O.[BH3-][C:32]#N.[Na+]>CO>[CH3:2][O:3][C@H:4]([CH2:27][CH3:28])[CH2:5][C@H:6]1[CH2:17][CH2:16][C:15]2[S:14][C:13]3[N:12]=[CH:11][N:10]=[C:9]([O:18][CH:19]4[CH2:20][CH2:21][CH:22]([N:25]([CH3:32])[CH3:26])[CH2:23][CH2:24]4)[C:8]=3[C:7]1=2
Reactant: [BH3-]C#N
Reactant: CC[C@H](C[C@H]1CCc2sc3ncnc(OC4CCC(NC)CC4)c3c21)OC
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC[C@H](C[C@H]1CCc2sc3ncnc(OC4CCC(N(C)C)CC4)c3c21)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
A solution of 4-[[(3R)-3-[(2R)-2-methoxybutyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-N-methylcyclohexan-1-amine hydrochloride (120 mg, 0.28 mmol, 1.00 equiv) and HCHO (0.8 mL in methanol (6 mL) was stirred at room temperature. The resulting solution was stirred for 0.5 h at room temperature. Then NaBH3CN (97.02 mg, 1.54 mmol, 5.48 equiv) was added. The resulting solution was allowed to react, with stirring, for an additional 2 h at room temperature. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×50 mL of chloroform/iso-propanol (3/1) and the organic layers combined and concentrated under vacuum. The crude product (100 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-016(Waters)): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with 50 mL HCOOH and CH3CN (5.0% CH3CN up to 45.0% in 11 min, up to 95.0% in 2 min, down to 5.0% in 2 min); Detector, UV 254/220 nm. This resulted in 34.2 mg (30%) of Compound I-117 as a colorless oil. 1H NMR (CD3OD, 300 MHz): δ 8.47 (1H, s), 5.26-5.27 (1H, m), 3.31-3.35 (1H, m), 3.26-3.30 (4H, m), 3.08-3.11 (1H, m), 2.95-3.00 (1H, m), 2.64 (1H, m), 2.20-2.42 (10H, m), 1.97-2.08 (3H, m), 1.47-1.75 (7H, m), 0.96-1.01 (3H, t). MS: m/z 404 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:14]([NH:17][CH2:18][CH2:19][N:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])([CH3:16])[CH3:15]>>[CH3:26][CH:24]([N:20]([CH:21]([CH3:23])[CH3:22])[CH2:19][CH2:18][N:17]([CH:14]([CH3:16])[CH3:15])[S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11])[CH3:25]
Reactant: CC(C)NCCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)N(CCN(C(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(C)C

Procedure:
p-Nitrobenzenesulfonyl chloride was reacted with N,N',N'-triisopropyl ethylene diamine to obtain the free base of N-[2-[bis(1-methylethyl)amino]ethyl]-N-(1-methylethyl)-4-nitrobenzene sulfonamide as a yellow solid, m.r. 98°-100° C.
Reaction SMILES: C(O)(=O)C(O)=O.[CH:7]([NH:10][OH:11])([CH3:9])[CH3:8].[OH-].[Na+].[Br:14][CH:15]([CH2:19]Br)[C:16](Cl)=[O:17].C(Cl)Cl>O>[Br:14][CH:15]1[CH2:19][O:11][N:10]([CH:7]([CH3:9])[CH3:8])[C:16]1=[O:17]
Reactant: O=C(Cl)C(Br)CBr
Reactant: CC(C)NO
Agent: O=C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)N1OCC(Br)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
To a stirred mixture of 6 g (25 mmol) of N-isopropylhydroxylamine oxalate and 1N sodium hydroxide (50 ml) in water (100 ml) cooled to 0° C. there was added 2,3-dibromopropionyl chloride (12.5 g, 50 mmol), followed by the addition of 50 ml of 1N sodium hydroxide. Ten minutes later, 150 ml of methylene chloride and 60 ml of 1N sodium hydroxide were added. The mixture was stirred continuously for one hours following which the organic phase was separated, dried over anhydrous magnesium sulfate and concentrated. The concentrate was chromatographed on silica gel with 40% ethyl acetatehexane to afford 3.3 g of 4-bromo-2-isopropyl-3-isoxazolidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:15])([F:14])[F:13].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[SH:26].C[O-].[Na+]>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([S:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[F:19])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:15])([F:14])[F:13]
Reactant: Fc1ccccc1S
Reactant: C[C@@](O)(C(=O)Nc1ccc(I)cc1Cl)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@@](O)(C(=O)Nc1ccc(Sc2ccccc2F)cc1Cl)C(F)(F)F
Reaction time: 18 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.147 g) was added to a deoxygenated mixture of (R)-N-(2-chloro-4-iodophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 197) (1.0 g), 2-fluorothiophenol (0.263 ml) and sodium methoxide (0.288 g) in ethanol (50 ml). The mixture was then further deoxygenated by evacuation and refilling with argon (3 cycles), and then heated under reflux with stirring under argon for 18 hours. The mixture was treated with a further portion of tetrakis(triphenylphosphine)palladium(0) (0.147 g), heated for a further 24 hours then cooled and filtered. Volatile material was removed by evaporation and the residue was purified by flash chromatography eluting with 20% ethyl acetate/hexane to give the title compound (0.906 g) as an oil. NMR (CDCl3): 1.75 (s, 3H), 3.58 (s, 1H), 7.1 (t, 2H), 7.2-7.35 (m, 3H), 7.37 (d, 1H), 8.3 (d, 1H , 8.82 (brs, 1H); MS (ESP−): 392.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:7]=[CH:6][C:5]=1[NH:15][C:16](=[O:18])[CH3:17].[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][S:21]([CH3:20])(=[O:23])=[O:22])[CH:7]=[CH:6][C:5]=1[NH:15][C:16](=[O:18])[CH3:17]
Reactant: COC(=O)c1cc(OCCCO)ccc1NC(C)=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OCCCOS(C)(=O)=O)ccc1NC(C)=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2-acetylamino-5-(3-hydroxypropoxy)benzoic acid methyl ester (689 mg, 2.6 mmol) in dichloromethane (25 mL) cooled to 0° C. were added methanesulfonyl chloride (1 mL, 12.9 mmol) and triethylamine (3.6 mL, 25.8 mmol). The mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with ethyl acetate (100 mL) and washed with 1 N HCl (aq.) (1×50 mL), sat. NaHCO3 (aq.) (1×50 mL) and brine (1×50 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Crude 2-acetylamino-5-(3-methanesulfonyloxypropoxy)benzoic acid methyl ester thus obtained was used without further purification in the next step.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1.CC1C=CC(CC)=CN=1.O>C1(C)C(C)=CC=CC=1.C(O)(=O)C>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:17][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: CCc1ccc(C)nc1
Solvent: Cc1ccccc1C
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccnc1NCc1ccc(Cl)cc1

Procedure:
A solution of 26.5 g of 2-chloro-3-nitropyridine, 23.7 g of 4-chlorobenzylamine and 25 ml of 2-methyl-5-ethylpyridine in 200 ml of xylene is refluxed for 12 hours. The reaction mixture is then cooled, water and acetic acid are added and the resulting mixture is then extracted with ether. The organic phase is dried over magnesium sulfate, filtered and then evaporated under vacuum to give an oil which crystallizes from isopropyl ether. The crystals are filtered off and then dried to give 27 of 2-(4-chlorophenylmethylamino)-3-nitropyridine in the form of crystals melting at 100° C.