Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][NH2:3].CN(C)[C@@H]1CCN(CC2C=CC(C(O)=O)=CC=2)C1.FC(F)(F)C(O)=O.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)=[CH:32][C:31]=1[NH:41][C:42]([C:44]1[CH:49]=[CH:48][C:47](/[CH:50]=[CH:51]/[C:52](O)=[O:53])=[CH:46][CH:45]=1)=[O:43].CO>C(Cl)Cl>[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)=[CH:32][C:31]=1[NH:41][C:42](=[O:43])[C:44]1[CH:45]=[CH:46][C:47](/[CH:50]=[CH:51]/[C:52]([NH:3][OH:2])=[O:53])=[CH:48][CH:49]=1
Reactant: NO
Reactant: Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(/C=C/C(=O)O)cc1
Agent: CN(C)[C@@H]1CCN(Cc2ccc(C(=O)O)cc2)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(/C=C/C(=O)NO)cc1
Yield: 79 %

Procedure:
Following the same procedure as described in Example 1, step 6 (scheme 1), but substituting compound 4 for N-hydroxylamine hydrochloride salt and compound 7 for compound 226, the title compound 227 was obtained as a yellowish solid in 79% yield [purified by flash chromatography (eluent: 5% to 66% MeOH in DCM)].
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH:15]=[O:16])[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:3].C[Mg]Br.[CH3:20][S:21](Cl)(=[O:23])=[O:22].[CH3:25]CN(CC)CC>>[CH3:20][S:21]([O:16][CH:15]([CH:12]1[CH2:13][CH2:14][N:9]([C:7]2[O:6][N:5]=[C:4]([CH:2]([CH3:1])[CH3:3])[N:8]=2)[CH2:10][CH2:11]1)[CH3:25])(=[O:23])=[O:22]
Reactant: CCN(CC)CC
Reactant: CC(C)c1noc(N2CCC(C=O)CC2)n1
Reactant: CS(=O)(=O)Cl
Agent: C[Mg]Br
Product: CC(C)c1noc(N2CCC(C(C)OS(C)(=O)=O)CC2)n1
Yield: 83 %

Procedure:
(±)-1-{1-[3-(1-Methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl methanesulfonate (0.74 g, 49%) was prepared as a light brown oil from 1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinecarbaldehyde (1.07 g, 4.79 mmol) and methylmagnesium bromide (3M in Et2O, 3.51 mL, 10.54 mmol) then methanesulfonyl chloride (0.22 mL, 2.81 mmol) and Et3N (0.66 mL, 4.68 mmol) in a manner similar to Example 139, Steps 1-2. The crude product was used without further purification. 1H NMR (400 MHz, CDCl3): δ 4.70-4.60 (m, 1H), 4.30-4.15 (m, 2H), 3.10-2.95 (m, 5H), 2.87 (septet, 1H, J=7.0 Hz), 1.95-1.70 (m, 3H), 1.55-1.35 (m, 5H), 1.26 (d, 6H, J=6.8 Hz).
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][C:6](=O)[CH2:7][CH3:8].CN[CH:12]1[CH2:17][C:16](C)(C)[NH:15][C:14]([CH3:21])(C)[CH2:13]1>>[CH2:5]([C:13]1[CH:12]=[CH:17][C:16]([NH2:15])=[CH:21][CH:14]=1)[C:6]1[CH:12]=[CH:13][C:14]([NH2:15])=[CH:8][CH:7]=1
Reactant: CNC1CC(C)(C)NC(C)(C)C1
Reactant: CCC(C)=O
Solvent: ClC(Cl)Cl
Product: Nc1ccc(Cc2ccc(N)cc2)cc1

Procedure:
3.58 g (0.03 mol) chloroform; 14.42 g (0.20 mol) 2-butanone; and, 4.0 g (0.1 mol) 4-methylamino-2,2,6,6-tetramethylpiperidine are reacted in a manner analogous to that described in Example 1 hereinabove and the product worked up and recovered. The structure of the compound obtained is represented as follows: ##STR5## wherein n is in the range from 2 to about 5.
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.Br[CH2:31][C:32]([CH3:43])([CH3:42])[CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C(=O)C>C(OCC)(=O)C>[Si:35]([O:34][CH2:33][C:32]([CH3:43])([CH3:42])[CH2:31][N:6]1[C:7](=[O:28])[C:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=[C:2]([CH3:1])[N:29]=[C:5]12)([C:38]([CH3:39])([CH3:40])[CH3:41])([CH3:36])[CH3:37]
Reactant: CC(C)(CBr)CO[Si](C)(C)C(C)(C)C
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)c2nc(C)nn12
Temperature: 100 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
A mixture of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (5 g), (3-bromo-2,2-dimethylpropoxy)(tert-butyl)dimethylsilane (4.7 mL), cesium carbonate (8.1 g) and N,N-dimethylacetamide (50 mL) was stirred at 100° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (2 g, 28%).
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][NH2:23])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:24][C:25]1([CH3:41])[O:30][CH:29]([C:31]([NH:33][CH2:34][CH2:35][C:36](O)=[O:37])=[O:32])[C:28]([CH3:40])([CH3:39])[CH2:27][O:26]1>>[C:1]([O:20][CH2:21][CH2:22][NH:23][C:36](=[O:37])[CH2:35][CH2:34][NH:33][C:31]([CH:29]1[C:28]([CH3:39])([CH3:40])[CH2:27][O:26][C:25]([CH3:41])([CH3:24])[O:30]1)=[O:32])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCCN
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCNC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 30.9 %

Procedure:
2-Aminoethyl oleate (3.26 g) and 2.59 g of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid were reacted in the same manner as in Example 1 to obtain 1.75 g of the title compound (yield: 31%).
Reaction SMILES: CS([O:5][C@@:6]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[NH2:23])([C:11]#[C:12][CH:13]1[CH2:15][CH2:14]1)[C:7]([F:10])([F:9])[F:8])(=O)=O.[OH-].[Na+].[C:26]([O-])([O-])=[O:27].[Na+].[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[H][H]>>[CH:13]1([C:12]#[C:11][C@:6]2([C:7]([F:10])([F:9])[F:8])[C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=3[NH:23][C:26](=[O:27])[O:5]2)[CH2:15][CH2:14]1
Reactant: CS(=O)(=O)O[C@](C#CC1CC1)(c1cc(F)ccc1N)C(F)(F)F
Reactant: O=C([O-])[O-]
Reactant: [H][H]
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1Nc2ccc(F)cc2[C@](C#CC2CC2)(C(F)(F)F)O1
Temperature: 15 °C
Reaction time: 0.08 h

Procedure:
(R)-2-(2-Amino-5-fluorophenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol methanesulfonate (CN46619-MSA) of example 4 (14.0 g, 33.5 mmol) in ethyl acetate/heptanes (40 g, 6/4 v/v) was charged to a jacketed 150 mL-reactor with agitator and off-gas scrubber with caustic soda. After addition of aqueous Na2CO3 (12%-w/w, 26.9 g, 30.3 mmol) the mixture was stirred for 5 min at 15° C. The aqueous phase was separated and discarded. Aqueous Na2CO3 (12%-w/w, 34.1 g, 38.4 mmol) was charged to the organic phase, then triphosgene (3.73 g, 12.6 mmol) was added in portions over a period of 25 min at 10° C. The reaction mixture was stirred for 2 h at 8° C. The mixture was charged with heptanes (15.9 g), the phases were separated and the aqueous phase discarded. The organic phase was washed with water (12 mL), dried over MgSO4, filtered and concentrated to dryness. After drying under vacuum at 50° C., the product (R)-4-(cyclopropylethynyl)-6-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (CN46686, compound of formula I, wherein R1 is trifluoromethyl, R2 is cyclopropyl, R8 is 6-fluoro, R9 is hydrogen and R1° is hydrogen 9.78 g, 32.7 mmol, 97%) was obtained as a yellowish solid (99.4% purity, according to Method C).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1.[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:17](=[O:18])[N:9]([CH2:10][CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)[C:4]=2[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(Cl)cc1NCC1CCCCC1
Solvent: CC#N
Product: O=c1[nH]c2ccc(Cl)cc2n1CC1CCCCC1
Yield: 70.1 %

Procedure:
A mixture of 7.2 g of the compound obtained in step B) and 6.7 g of 1,1'-carbonyldiimidazole in 100 ml of acetonitrile is refluxed for 5 minutes. The solvent is evaporated off under vacuum, the residue is taken up with water, extracted with DCM, washed with a saturated solution of NaHCO3 and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/MeOH mixture (95/5; v/v) as the eluent to give 5.6 g of the expected product. M.p.=173° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:17]4[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:16]=4[O:15][N:14]=3)=[C:9]([CH2:23][CH2:24][CH3:25])[CH:8]=2)=[CH:4][CH:3]=1.[C:28]([O:33]C)(=[O:32])[C@@H:29]([CH3:31])O>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:17]4[CH:18]=[C:19]([O:22][C@@H:29]([CH3:31])[C:28]([OH:33])=[O:32])[CH:20]=[CH:21][C:16]=4[O:15][N:14]=3)=[C:9]([CH2:23][CH2:24][CH3:25])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2ccc(O)cc12
Reactant: COC(=O)[C@@H](C)O
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2ccc(O[C@@H](C)C(=O)O)cc12

Procedure:
The phenol from Step 6 (0.38 g, 1.0 mmol) and methyl (R)-lactate (0.16 g, 1.5 mmol) was reacted according the general procedure described in Step 11 of Example 1 to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][C:30]2([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[O:29][C@@H:28]([CH2:37][C:38]([O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[O:39])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][C:30]4([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[O:29][C@@H:28]([CH2:37][C:38]([O:40][CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]4)=[O:39])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: NCC[C@@H]1C[C@H](CC(=O)OC2CCCCC2)OC2(CCCCC2)O1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)OC2CCCCC2)OC2(CCCCC2)O1

Procedure:
According the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and cyclohexyl 2-((2R,4R)-4-(2-aminoethyl)-1,5-dioxaspiro[5.5]undecan-2-yl)acetate.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.Br[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1.[CH:37]([NH:40][N:41]1[C:53]2[C:52]3[CH:51]=[CH:50][C:49]([CH:54]=[CH2:55])=[CH:48][C:47]=3[N:46]=[C:45]([NH2:56])[C:44]=2[N:43]=[C:42]1[CH2:57][CH2:58][CH3:59])([CH3:39])[CH3:38]>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:37]([NH:40][N:41]1[C:53]2[C:52]3[CH:51]=[CH:50][C:49]([CH:54]=[CH:55][C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)=[CH:48][C:47]=3[N:46]=[C:45]([NH2:56])[C:44]=2[N:43]=[C:42]1[CH2:57][CH2:58][CH3:59])([CH3:39])[CH3:38]
Reactant: Brc1cccnc1
Reactant: C=Cc1ccc2c(c1)nc(N)c1nc(CCC)n(NC(C)C)c12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCc1nc2c(N)nc3cc(C=Cc4cccnc4)ccc3c2n1NC(C)C
Temperature: 120 °C
Reaction time: 15 h
Yield: 83.7 %

Procedure:
A suspension of palladium (II) acetate (0.067 g, 0.30 mmol) and tri-o-tolylphosphine (0.271 g, 0.891 mmol) in 10 mL of MeCN was placed in a 50 mL heavy wall glass pressure flask and placed under an atmosphere of nitrogen. The mixture was stirred until homogeneous. The mixture was treated with triethylamine (1.58 mL, 11.9 mmol), 3-bromopyridine (0.430 mL, 4.46 mmol) and N-isopropyl-2-propyl-7-vinyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.92 g, 3.0 mmol). Nitrogen was bubbled through the mixture for 1 min and then the flask was sealed. The reaction was heated to 120° C. After 15 h, the homogenous orange solution was cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between 75 mL of CHCl3 and 25 mL of 10% Na2CO3 solution. The phases were separated and the organic portion was washed with H2O (25 mL). The combined aqueous portions were back-extracted with CHCl3 (25 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield an orange solid. The solid was purified by chromatography (SiO2, 20–50% (80:18:2 CHCl3:MeOH:NH4OH) in CHCl3) to yield N1-isopropyl-2-propyl-7-(2-pyridin-3-yl-vinyl)-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.97 g) as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2Cl)=[CH:4][CH:3]=1.[CH2:13]([Mg]Cl)[CH2:14][CH2:15][CH3:16]>C(OCC)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CCCC[Mg]Cl
Reactant: Clc1nccc2ccc(Br)cc12
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCCc1nccc2ccc(Br)cc12
Temperature: 25 °C
Yield: 24.4 %

Procedure:
To a refluxing solution of 7-bromo-1-chloroisoquinoline (4.85 g, 23.28 mmol) in diethyl ether (75 mL) was added butylmagnesium chloride (17.8 mL, 2.0 M ether, 35.6 mmol) and the reaction maintained at reflux for 2 h. The reaction mixture was cooled to room temperature, carefully diluted with an equal volume of ethyl acetate, washed with saturated sodium bicarbonate, water, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure to give an brown oil. Purification by flash column chromatography (silica, 1–10% ether/hexanes) gave the desired 7-bromo-1-butylisoquinoline (1.50 g): ESI MS m/z 264 [M+H]+.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:4]=[C:5]([C@H:9]([NH2:20])[CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[O:6][C:7]=1[CH3:8].[CH3:21][CH2:22][CH2:23][CH2:24][C:25](=O)[CH2:26][CH2:27][CH2:28][CH3:29]>C(O)(C)C>[ClH:1].[CH2:24]([C:25]1([CH2:26][CH2:27][CH2:28][CH3:29])[C:12]2[NH:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]=2[CH2:10][C@H:9]([C:5]2[O:6][C:7]([CH3:8])=[C:3]([CH3:2])[N:4]=2)[NH:20]1)[CH2:23][CH2:22][CH3:21]
Reactant: Cc1nc([C@H](N)Cc2c[nH]c3ccccc23)oc1C
Reactant: CCCCC(=O)CCCC
Agent: Cl
Solvent: CC(C)O
Product: CCCCC1(CCCC)N[C@@H](c2nc(C)c(C)o2)Cc2c1[nH]c1ccccc21
Yield: 9.3 %

Procedure:
To a solution of (1R)-1-(4,5-dimethyl-1,3-oxazol-2-yl)-2-(1H-indol-3-yl)-1-ethanamine hydrochloride (1.2 g, 3.6 mmol) in isopropanol (20 ml) was added 5-nonanone (3.1 ml, 20 mmol) and the mixture was refluxed for about 24 hours. The solvent was evaporated under reduced pressure. To the residue was added water (20 ml) followed by NaHCO3 (10%) solution until neutral pH, followed by ethyl acetate (3×15 ml). After decantation and extraction the combined organic extracts were washed with water (20 ml) and dried over MgSO4. The solvent was evaporated under reduced pressure to afford an oil which was purified by column chromatography on silica gel using ethyl acetate/heptane 7:3 as eluent. The resulting oil was dissolved in ethyl acetate (15 ml) and a solution of HCl in ethyl acetate (1N) was slowly added at about 20° C. to give a precipitate. The suspension was stirred a few minutes and the precipitate collected by filtration, washed with diethyl ether, and dried to afford 0.14 g the desired product as the hydrochloride salt. Melting point: 128-134° C.
Reaction SMILES: [C:1]([C:3]([CH3:23])([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]CCCCCCCCCC)[CH3:4])#[N:2].C([Li])CCC.[CH:29]([NH:32]C(C)C)(C)C.[C:36](#N)C(C)C.BrCCCCCCBr>O1CCCC1>[C:29]([C:11]([CH3:12])([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:3]([C:1]#[N:2])([CH3:4])[CH3:23])[CH3:36])#[N:32]
Reactant: CCCCCCCCCCCCCCCCCCC(C)(C)C#N
Reactant: CC(C)NC(C)C
Reactant: CC(C)C#N
Agent: BrCCCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C#N)CCCCCCC(C)(C)C#N

Procedure:
By the procedure used to prepare the compound of Example 2, the title compound is prepared from 24 mL of a 2.5M n-butyllithium solution in hexanes, 6.07 g of diisopropylamine, 5.5 mL of isobutyronitrile, 7.32 g of 1,6-dibromohexane, and 120 mL of tetrahydrofuran. The IR and 1H NMR spectra of the white solid (7.7 g) obtained were consistent with structure of the desired product.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:19]([O:20]C(=O)C)[C@H:18]([O:24]C(=O)C)[CH2:17][S:16][C@H:6]1[S:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1)(=O)C.C[O-].[Na+]>CO>[S:7]([C:8]1[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[CH:12][CH:13]=1)[C@@H:6]1[S:16][CH2:17][C@@H:18]([OH:24])[C@H:19]([OH:20])[C@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccc(C#N)cc2)SC[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(S[C@@H]2SC[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
Under a nitrogen atmosphere, 8.5 g (21.10-3 mol) of 4-cyanophenyl 2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 1a) are suspended in 100 ml of methanol, and 2 ml of sodium methylate (8% w/v of Na in methanol) are then added. The reaction medium is stirred at room temperature until the starting material has completely dissolved (2 hours) and is then neutralized by the addition of Amberlite® IR 120 H+ resin. The methanol is evaporated off under reduced pressure; the crude product obtained is recrystallized from an ethanol/water mixture (65/25 v/v) to give 5.3 g (yield: 89.7%) of the expected product.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:9][CH2:8][N:7]([C:10]2[CH:39]=[CH:38][C:13]([C:14]([NH:16][C:17]3[CH:18]=[C:19]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH:20]=[CH:21][C:22]=3[NH:23]C(=O)OC(C)(C)C)=[O:15])=[CH:12][CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2].Cl>C(Cl)Cl.O1CCOCC1.CCOC(C)=O>[C:1]([NH:4][C@@H:5]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([NH:16][C:17]3[CH:18]=[C:19]([C:31]4[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=4)[CH:20]=[CH:21][C:22]=3[NH2:23])=[O:15])=[CH:38][CH:39]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H]1CCN(c2ccc(C(=O)Nc3cc(-c4ccc(F)cc4)ccc3NC(=O)OC(C)(C)C)cc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)N[C@@H]1CCN(c2ccc(C(=O)Nc3cc(-c4ccc(F)cc4)ccc3N)cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.4 %

Procedure:
To a suspension of 407 (0.280 g, 0.526 mmol) in DCM (5 mL) and dioxane (5.0 mL) was added HCl in dioxane (2.4 mL, 9.46 mmol). The mixture was stirred for 3 h at room temperature. The solvent was evaporated and the residue obtained was triturated in Et2O, filtered and dried under vacuum. The light pink solid obtained was suspended in EtOAc, washed with sat NaHCO3, brine, dried over MgSO4, filtered and evaporated to afford a beige solid that was triturated overnight with Et2O. The solid was then filtered and dried under vacuum to give the title compound 408 (167 mg, 69% yield).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[O:10][N:9]=[CH:8][C:7]=1[C:11](Cl)=[O:12].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:11]([C:7]2[CH:8]=[N:9][O:10][C:6]=2[CH3:5])=[O:12])=[CH:18][CH:17]=1
Reactant: COc1ccccc1
Reactant: Cc1oncc1C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)c2cnoc2C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of aluminium chloride (10 g) and 5-methylisoxazole-4-carbonyl chloride (2.7 g) in methoxybenzene (50 ml) was stirred at room temperature for 16 hours. The mixture was quenched with excess ice and extracted with ether (3×200 ml). The combined organic layers were washed with water (3×500 ml), dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness. The residue was purified by chromatography on silica eluted with a mixture of ethyl acetate and cyclohexane (1:10) followed by HPLC on silica eluted with a mixture of ethyl acetate and hexane (1:20) to give 4-(4-methoxybenzoyl)-5-methylisoxazole (compound 18, 0.35 g) as a white solid mp 78°-79° C.
Reaction SMILES: [S:1]([Cl:3])Cl.[Cl:4][C:5]1[CH:6]=[C:7]([NH:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:8]=[CH:9][C:10]=1[Cl:11].N1C=CC=CC=1>C(Cl)Cl>[Cl:3][S:1][N:12]([C:7]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:5]([Cl:4])[CH:6]=1)[C:13]([N:15]([CH3:16])[CH3:17])=[O:14]
Reactant: CN(C)C(=O)Nc1ccc(Cl)c(Cl)c1
Reactant: ClSCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C(=O)N(SCl)c1ccc(Cl)c(Cl)c1

Procedure:
A 5.7-g (0.055 mol) sample of sulfur dichloride was added dropwise to a mixture of 11.7 g (0.05 mol) of N-(3,4-dichlorophenyl)-N',N'-dimethyl urea and 4.7 g (0.06 mol) pyridine in 50 ml methylene chloride cooled in an ice bath. After the completion of the addition, the pyridine hydrochloride was filtered. Hexane was added to precipitate additional pyridine hydrochloride, which was removed by filtration. Evaporation of the resulting filtrate gave the product as a clear yellow oil. The NMR spectrum showed an N',N'-dimethyl singlet at 3.0 ppm (relative to tetramethylsilane). Elemental analysis showed:
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]([N:22]([C:29](=[O:31])[CH3:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH:13]2[CH3:32])=[O:11])=[CH:6][CH:5]=1.[Li].O>CO>[C:29]([N:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C@H:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]([C:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:33])=[O:2])=[CH:9][CH:8]=2)=[O:11])[C@@H:13]([CH3:32])[CH2:14]1)(=[O:31])[CH3:30]
Reactant: COC(=O)c1ccc(C(=O)N2c3ccccc3C(N(C(C)=O)c3ccccc3)CC2C)cc1
Agent: [Li]
Solvent: CO
Solvent: O
Product: CC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(C(=O)O)cc2)c2ccccc21
Yield: 103.3 %

Procedure:
A solution of 4-[4-(Acetyl-phenyl-amino)-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl]-benzoic acid methyl ester (50 mg) and lithium hydroxyde (0.283 mmol) in methanol (2 ml) and water (1 ml) was stirred at room temperature overnight. After addition of water, the mixture was washed with dichloromethane. The aqueous layer was acidified and then extracted using ethyl acetate. The organic layer is separated and dried over sodium sulfate. The solvent was removed to give the title compound (50 mg).
Reaction SMILES: [N:1]([C:4]1[C:19]([O:20]CC2C=CC=CC=2)=[CH:18][C:7]([C:8]([O:10]CC2C=CC=CC=2)=[O:9])=[C:6]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[C:5]=1[F:36])=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][C:4]1[C:19]([OH:20])=[CH:18][C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[C:5]=1[F:36]
Reactant: [N-]=[N+]=Nc1c(OCc2ccccc2)cc(C(=O)OCc2ccccc2)c(Nc2ccccc2Cl)c1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1c(O)cc(C(=O)O)c(Nc2ccccc2Cl)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of compound benzyl 4-azido-5-(benzyloxy)-2-((2-chlorophenyl)amino)-3-fluorobenzoate (22.97 g, 45.67 mmol) in MeOH (500 mL) was added and 10% palladium on carbon (3.80 g) under nitrogen atmosphere. Then the nitrogen atmosphere was completely changed to hydrogen atmosphere. The mixture was stirred for 3 h at ambient temperature. After the insoluble matter was filtered off, the solvent was evaporated under reduced pressure to give the desired product, which was used directly in the next step without further purification.