Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].[N+:8]([C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:20]=1[NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:18][CH:17]=[CH:16][CH:15]=2)([O-])=O.[H][H]>[Pt].C1(C)C=CC=CC=1>[NH2:8][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:20]=1[NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCNc1c(N)cnc2ccccc12
Yield: 80.5 %

Procedure:
Platinum on carbon (1.0 g of 10%) and sodium sulfate (2 g) were added to a slurry of 1,1-dimethylethyl N-(2-[(3-nitroquinolin4-yl)amino]ethyl}carbamate (100 g, 0.30 mol) in toluene (500 mL). The reaction vessel was placed on a Parr apparatus under 50 psi (3.5 Kg/cm2) hydrogen pressure overnight at ambient temperature. The reaction mixture was filtered through a layer of Celite® filter aid to remove the catalyst. The filtrate was concentrated under vacuum to provide 73 g of 1,1-dimethylethyl N-{2-[(3-aminoquinolin-4-yl)amino]ethyl}carbamate as a dark gold oil. Thin layer chromatography (silica gel; 10% methanol in dichloromethane) analysis indicated that the material was pure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Cl[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[N:29]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[N:29]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: Cc1nccc(Cl)n1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccnc(C)n5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-chloro-2-methyl-pyrimidine following a procedure analogous to that described for Intermediate 12. LC (method 2): tR=1.00 min; Mass spectrum (ESI+): m/z=451 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[CH:31]=[CH:30][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27](O)=[O:28])=[O:20])=[CH:17][CH:16]=1.C(N(CC)CC)C.ClC(OCC)=O.[NH2:45][OH:46]>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[CH:31]=[CH:30][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([NH:45][OH:46])=[O:28])=[O:20])=[CH:17][CH:16]=1
Reactant: NO
Reactant: O=C(O)CCCCCNC(=O)c1ccc(C=NN=C2C(=O)Nc3ccc(F)cc32)cc1
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCCCCNC(=O)c1ccc(C=NN=C2C(=O)Nc3ccc(F)cc32)cc1)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
6-(4-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)benzamido)hexanoic acid (424 mg, 1 mmol), triethylamine (151 mg, 1.5 mmol) and 20 ml of DMF were stirred at 0° C. while ethyl chloroformate (163 mg, 1.5 mmol) was added. The mixture was stirred at 0° C. for 2 hours, and then 50% aqueous solution of hydroxylamine (1.32 g, 20 mmol) was added. The mixture was stirred for 3 hours at room temperature, and then diluted with 1000 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (224 mg, 51%) as a brown solid. LC-MS (m/z) 440 (M+1).
Reaction SMILES: [F-].[Si]([O:9][CH2:10][CH:11]([N:24]([CH3:41])[S:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23])(C(C)(C)C)(C)C>O1CCCC1>[OH:9][CH2:10][CH:11]([N:24]([CH3:41])[S:25]([C:28]1[CH:29]=[CH:30][C:31]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:32][CH:33]=1)(=[O:26])=[O:27])[CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23]
Reactant: CN(C(CO[Si](C)(C)C(C)(C)C)CN1C(=O)c2ccccc2C1=O)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C(CO)CN1C(=O)c2ccccc2C1=O)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Yield: 28.6 %

Procedure:
After addition of 1M solution of tetrabutylanimonium fluoride (19.11 ml, 19.11 mmol) in tetrahydrofuran to a solution of (±)-1-(tert-butyldimethylsilyloxymethyl)-N-methyl-N-(4-phenoxybenzenesulfonyl)-2-phthalimidoethylamine (7.40 g, 12.74 mmol), the product of (4) above, in tetrahydrofuran (50 ml), the mixture was stirred at room temperature for 1 hour. The solvent of the reaction mixture was evaporated under reduced pressure. To the resulting residue, water was added and this was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=2/1 as the eluant to afford the desired compound (1.70 g, yield 29%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18](O)=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.S(Cl)(Cl)=O.[CH3:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH:28]([CH3:32])[NH:27]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]([N:27]2[CH:28]([CH3:32])[CH2:29][CH2:30][CH2:31][CH:26]2[CH3:25])=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: O=C(O)c1cc(-c2ccccc2Cl)nc2ccccc12
Reactant: CC1CCCC(C)N1
Solvent: O=S(Cl)Cl
Product: CC1CCCC(C)N1C(=O)c1cc(-c2ccccc2Cl)nc2ccccc12

Procedure:
2-(2-Chlorophenyl)-quinoline-4-carboxylic acid (5.7 g) and thionyl chloride (15 ml) are heated under reflux for 1 hour. The thionyl chloride is evaporated off, the residue is taken up in toluene (40 ml) and the toluene is also evaporated off. Toluene (50 ml) is then added to the residue obtained, followed by the dropwise introduction of 2,6-dimethylpiperidine (6.78 g), with stirring. The mixture is stirred for 1 hour at ambient temperature, the precipitate is filtered off and the filtrate is evaporated under reduced pressure. The residue is taken up in water (50 ml) and chloroform (50 ml). The organic phase is decanted and the aqueous phase is extracted with chloroform (50 ml). The organic phases are combined, dried over magnesium sulphate and evaporated under reduced pressure.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][C:52]([F:59])=[C:53]([F:58])[CH:54]=4)[O:49][C:48]=3[C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][C:52]([F:59])=[C:53]([F:58])[CH:54]=4)[O:49][C:48]=3[C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(F)c(F)cc4c3=O)cc2)CCC1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(F)c(F)cc4c3=O)cc2)CCC1
Yield: 92 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(6,7-difluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a white solid (67 mg, 92%). 1H NMR (400 MHz, DMSO-d6): δ 8.08-7.99 (m, 2H), 7.43-7.32 (m, 7H), 7.16-7.13 (m, 2H), 2.43-2.35 (m, 2H), 2.20-2.11 (m, 2H), 2.07-1.96 (m, 1H), 1.72-1.61 (m, 1H). LCMS (Method E): RT=3.75 min, [M+H]+=404.
Reaction SMILES: [NH:1]([C:3]1[C:8]([CH2:9][CH2:10][CH3:11])=[N:7][C:6]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:5][N:4]=1)[NH2:2].[CH3:18][CH:19]([C:25](OCC)=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH3:18][CH:19]([C:25]1[N:4]2[CH:5]=[C:6]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:7]=[C:8]([CH2:9][CH2:10][CH3:11])[C:3]2=[N:1][N:2]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: CCCc1nc(-c2cccnc2)cnc1NN
Product: CCCc1nc(-c2cccnc2)cn2c(C(C)C(=O)OCC)nnc12

Procedure:
In a manner analogous to that described in Example 1, by condensing 2-hydrazino-3-propyl-5-(3-pyridyl)pyrazine with diethyl methylmalonate there is obtained ethyl rac-α-methyl-8-propyl-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetate, MS: 339 (M)+, which by saponification analogously to Example 1 is converted into the above acid which is used directly in the next step.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][NH:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[CH2:5][CH2:4]1.Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(OCC)C>CN(C=O)C>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([N:7]([CH2:6][CH:3]2[CH2:5][CH2:4]2)[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:9][C:10]=1[C:16]([F:17])([F:18])[F:19])#[N:13]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1ccc(NCC2CC2)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN(CC1CC1)c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 7.5 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
Sodium hydride (60%, 2.0 g, 50 mmol) was added to a stirred solution of 4-[(cyclopropylmethyl)amino]-2-(trifluoromethyl)benzonitrile (6.0 g, 25 mmol), and tert-butyl bromoacetate (6.82 g, 35 mmol) in 20 mL of DMF at 0° C. over 20 minutes. The mixture was then stirred at 5-10° C. for 30 minutes. Diethyl ether (200 mL) was added to the mixture and the resulting slurry was extracted with water (3×50 mL). The organic phase was dried (MgSO4), filtered, and then concentrated under reduced pressure. The residue was purified with silica gel chromatography (eluent:hexane-EtOAc; 3:1) to obtain 6.55 g (74%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J=8.8 Hz, 1H), 6.92 (d, J=2.6 Hz, 1H), 6.77 (dd, J=8.8, 2.7 Hz, 1H), 4.10 (s, 2H), 3.33 (d, J=6.6 Hz, 2H), 1.43 (s, 9H), 1.05 (m, 1H), 0.62 (m, 2H), 0.26 (m, 2H).
Reaction SMILES: [C:1]([C:9]1[C:18]([CH2:19][S:20]([CH3:22])=[O:21])=[N+:17]([O-:23])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N+:10]=1[O-:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[C:1]([C:9]1[C:18]([CH2:19][S:20]([CH3:22])(=[O:33])=[O:21])=[N+:17]([O-:23])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N+:10]=1[O-:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)Cc1c(C(=O)c2ccccc2)[n+]([O-])c2ccccc2[n+]1[O-]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)Cc1c(C(=O)c2ccccc2)[n+]([O-])c2ccccc2[n+]1[O-]

Procedure:
A solution of 3.44 g. (0.01 mol) of 2-benzoyl-3-methylsulfinylmethylquinoxaline 1,4-dioxide and 2.20 g. (0.01 mol.) of 85% pure 3-chloroperbenzoic acid in 150 ml. of chloroform is stirred at room temperature overnight. The reaction mixture is washed with 5% sodium bicarbonate solution, dried, and evaporated in vacuo to afford crude 2-benzoyl-3-methylsulfonylmethylquinoxaline 1,4-dioxide.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]([S:22][CH3:23])[O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[C:17][Si](C)(C)C)=[CH:9]2.[OH-].[Na+].Cl>C(O)C.O>[C:16]([C:10]1[CH:11]=[N:12][C:13]2[C:8]([CH:9]=1)=[CH:7][C:6]([O:5][CH:4]([S:22][CH3:23])[C:3]([OH:24])=[O:2])=[CH:15][CH:14]=2)#[CH:17]
Reactant: COC(=O)C(Oc1ccc2ncc(C#C[Si](C)(C)C)cc2c1)SC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C#Cc1cnc2ccc(OC(SC)C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To a solution of methylsulfanyl-(3-trimethylsilanylethynyl-quinolin-6-yloxy)-acetic acid methyl ester (5 g) from Step 1, in ethanol (50 ml), a 2M solution of sodium hydroxide in water (9.74 ml) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice-cold water (200 ml) and acidified with a 2 M solution of hydrochloric acid in water (9.74 ml). The precipitate was filtered off and washed with water to give (3-ethynyl-quinolin-6-yloxy)-methylsulfanyl-acetic acid as yellowish solid (3.53 g).
Reaction SMILES: [CH3:1]OC1C=C(C=O)C=C(I)C=1O.[C:13]1([CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:27])[CH2:24][C:25]#[N:26])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.NCCC(O)=O>C(O)C>[C:13]1([CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:24](=[CH2:1])[C:25]#[N:26])=[O:27])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CCC(=O)NCCCc1ccccc1
Reactant: COc1cc(C=O)cc(I)c1O
Agent: NCCC(=O)O
Solvent: CCO
Product: C=C(C#N)C(=O)NCCCc1ccccc1
Yield: 71 %

Procedure:
0.69 g, of 5-iodo vaniline, 0.5 g N-3-phenyl-n-propyl cyanoacetamide and 50 mg β-alanine in 30 ml ethanol were refluxed 5 hours. Evaporation gave an oil which was triturated with benzene-hexane and filtered to give 3-(4-hydroxyl-3-iodo-5-methoxyphenyl-2[(3-phenyl-n-propyl)aminocarbonyl acrylnitrile as a bright yellow solid (0.82 g, 71% yield, mp-83° C.). (3-methoxy 4 hydroxy 5-iodo α-cis cinnamone (3'phenyl propane) amide). (Should be kept solid and protected from light. Material in solution, 2 weeks at room light deteriorated partially.) NMR CDCl3 δ 8.12(1H,S), 7.75(1H,d,J=2.0 Hz), 7.68 (1H,d,J=2.0 Hz), 7.30-7.10(5H,m), 3.96 (3H,S,OCH3), 3.45 (2H,q,J=6.0 Hz), 2.70 (2H,t,J=6.0 Hz), 1.95 (2H, quin, J=6.0 Hz). MS-462 (M+, 53), 357 (M--CH2)3Ph,18), 335(M-I,100), 327(M--NH(CH2), Ph, 31), m/e.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][OH:7])=[O:5])[CH3:3].CO.[CH3:10][C:11]([CH:13]=O)=O.[OH-].[Na+]>O>[CH3:3][C:2]1[N:1]=[C:11]([CH3:13])[CH:10]=[N+:6]([O-:7])[C:4]=1[OH:5]
Reactant: C[C@H](N)C(=O)NO
Reactant: CC(=O)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c[n+]([O-])c(O)c(C)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 3.6 %

Procedure:
407 mmol (42.4 g) alanine hydroxamic acid were cooled to −10° C. in 200 ml water and methanol each, 400 mmol (57 ml 40% solution) methylglyoxal were added dropwise and subsequently the pH was adjusted to approximately pH 11 with 19 ml 30% NaOH. Heating up to 0° C. was carried out within 2 h and then pH 3 was adjusted with 20% NaOH. The solution was concentrated until dryness under vacuum distillation, the residue was heated to reflux with 50 ml ethanol, after cooling filtering was carried out and the filtrate again concentrated until dryness. 44 g of the solid residue were dissolved in 50 ml water and 15 mmol (4.06 g) FeCl3*6H2O were added, heated up to 50° C. for 30 minutes, concentrated and stored at 5° C. for 4 h. The precipitated solid was filtered off and dried. 3.7 g solid in 50 ml water and 10 ml ethanol were adjusted to pH 11 with 6 ml 1 M NaOH, stirred over night and centrifugalized. The supernatant was decanted, pH 3 was adjusted with 3 ml 1 M HCl and concentrated until dryness. 4.2 g solid were refluxed in 20 ml ethanol, cooled and filtered off. The filtrate was again concentrated until dryness and the obtained 2.8 g solid were suspended with 10 ml water, heated up to 50° C. and left for cooling over night. The suspension was centrifugalized, the supernatant decanted and concentrated until dryness. 2.0 g (3.5% yield) of the title compound were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]1)([O-])=O>CO>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:7]=[CH:6][C:5]=1[N:14]1[CH2:15][CH2:16][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(C(F)(F)F)cc2N)CC1
Yield: 97 %

Procedure:
Following the method of Example 49 (Method 2), tert-butyl 1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-4-yl-carbamate in MeOH was reduced yielding tert-butyl 1-(2-amino-4-(trifluoromethyl)phenyl)piperidin-4-ylcarbamate (97%). LCMS (m/z): 360.1 (MH+); LC Rt=3.20 min.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:8]2[C:9]([CH3:19])=[C:10]([CH2:14][CH2:15][CH2:16][CH:17]=O)[CH:11]=[CH:12][CH:13]=2)=O)=[CH:4][CH:3]=1.[C:22]([CH:27]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:24]CC)=[O:23]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:8]2[C:9]([CH3:19])=[C:10]([CH2:14][CH2:15][CH2:16][CH:17]=[CH:27][C:22]([OH:24])=[O:23])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1c(CCCC=O)cccc1C(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1c(CCCC=CC(=O)O)cccc1Cc1ccc(Cl)cc1
Reaction time: 17 h
Yield: 41 %

Procedure:
A mixture of 4.5 g of the said butyraldehyde and 5.48 g of carbethoxy methylene triphenyl phosphorane in 100 ml of toluene was refluxed under an inert atmosphere with stirring for 17 hours and the toluene was then evaporated. The residue was saponified with 30 ml of 2 N sodium hydroxide and 50 ml of methanol at 75°-80° C. and the methanol was then removed. Water was added to the mixture which was then washed with ether containing 20% of methylene chloride, was treated with activated carbon and filtered. The filtrate was acidified with concentrated hydrochloric acid and was extracted with ether. The ether extracts were treated with activated carbon, filtered and evaporated to dryness. The residue was chromatographed over silica and eluted with a 95:5 methylene chloride-methanol mixture. The product was crystallized from isopropyl ether to obtain 2.015 g of 6-[3'-(4-chlorobenzyl)-2'-methylphenyl]-hex-2-enoic acid melting at 115° C.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[C:13]([O:19]CC2C=CC=CC=2)[CH:12]=[CH:11][C:10]=1[C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])C1C=CC=CC=1.CSC.CS(O)(=O)=O>>[OH:8][C:9]1[C:14]([C:15]([F:16])([F:17])[F:18])=[C:13]([OH:19])[CH:12]=[CH:11][C:10]=1[C:27](=[O:31])[CH:28]([CH3:29])[CH3:30]
Reactant: CC(C)C(=O)c1ccc(OCc2ccccc2)c(C(F)(F)F)c1OCc1ccccc1
Agent: CS(=O)(=O)O
Solvent: CSC
Product: CC(C)C(=O)c1ccc(O)c(C(F)(F)F)c1O
Temperature: 33 °C
Yield: 69.2 %

Procedure:
Stir 1-(2,4-bis-benzyloxy-3-trifluoromethyl-phenyl)-2-methyl-propan-1-one (1460 g, 3.07 mol) in dimethyl sulfide (8 L, 108.81 mol), treat with methanesulfonic acid (2.5 L, 38.13 mol), then gently reflux overnight. Cool mixture to 33° C. and treat with cracked ice (˜6 Kg) at such a rate as to keep the mixture below reflux. Transfer mixture to a separatory funnel, separate layers, and extract water layer with ethyl acetate (6 L). Wash organic layers with water (4 L), saturated sodium chloride solution (4 L), dry with magnesium sulfate, filter, and evaporate to a brown solid. Re-crystallize the solid from toluene (4 L) to afford 527 g of 1-(2,4-dihydroxy-3-trifluoromethyl-phenyl)-2-methyl-propan-1-one as a tan solid (3 crops). The filtrate is concentrated to 380 g of a black gritty oil and filtered through a pad of silica gel to provide 216 g of a yellow solid, which is re-crystallized from toluene to afford 69 g of additional material. All lots are combined to provide the title compound (596 g, 78% yield): HPLC Rt=4.98 min; 1H NMR (DMSO-d6) δ 14.15 (s, 1H), 11.70 (s, 1H), 8.06 (d, J=8.0 Hz, 1H), 6.57 (d, J=8.0 Hz, 1H), 3.62 (hept, J=8.0 Hz, 1H), 1.11 (d, J=8.0 Hz, 6H); 19F NMR (DMSO-d6) δ-54.50; MS (m/z): 249.0 (M+1).
Reaction SMILES: [O-]S([O-])(=O)=O.[Na+].[Na+].[CH2:8]([NH:15][CH:16]=[CH:17][C:18](=[O:20])[CH3:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:41]=[CH:42][C:43]=1[O:44][CH3:45])[C:26]([N:28]([CH2:35][CH2:36]/[CH:37]=[CH:38]/[CH:39]=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>C(Cl)Cl.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Sc+3]>[C:18]([C:17]1[CH:37]([CH2:36][CH2:35][N:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:26](=[O:27])[C:25]2[CH:41]=[CH:42][C:43]([O:44][CH3:45])=[C:23]([O:22][CH3:21])[CH:24]=2)[CH:38]=[CH:39][N:15]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:16]=1)(=[O:20])[CH3:19]
Reactant: COc1ccc(C(=O)N(CC/C=C/C=O)c2ccccc2)cc1OC
Reactant: CC(=O)C=CNCc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C(=O)N(CCC2C=CN(Cc3ccccc3)C=C2C(C)=O)c2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.4 %

Procedure:
To a suspension of Sc(OTf)3 (10% mol), Na2SO4 (3 equiv) in dry CH2Cl2 (15 mL) is added a solution of enamine 30 (332 mg, 1.9 mmol) and enal 35 (644 mg, 1.9 mmol) in dry CH2Cl2 (5 mL). The reaction mixture was stirred at room temperature for 48 h. The reaction solution is filtered on Celite and the solvent removed under pressure. The residue obtained is purified on SiO2 (gradient of EtOAc in Petroleum ether) to afford the title compound 32 as a yellow oil (Yield 551 mg, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:11]([O:30][CH2:31][C@@H:32]1[CH2:34][O:33]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(C)([O-])C.[K+].[OH-].[Na+]>C1(C)C=CC=CC=1.COCCOCCOC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:34][C@H:32]([OH:33])[CH2:31][O:30][C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: c1ccc(C(OC[C@@H]2CO2)(c2ccccc2)c2ccccc2)cc1
Reactant: N#Cc1cc(Cl)ccc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: Cc1ccccc1
Product: N#Cc1cc(Cl)ccc1OC[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 105 °C
Reaction time: 23 h
Yield: 85 %

Procedure:
To a diglyme (1.1 L) solution of 5-chloro-2-hydroxybenzonitrile (the compound of Reference Example 1; 270 g, 1.8 mol) and (2S)-2-[(trityloxy)methyl]oxirane (465 g, 1.47 mol) was added potassium tert-butoxide (33 g, 0.29 mol) at room temperature, followed by stirring the reaction mixture at 105° C. for 23 hours. The reaction mixture was cooled with ice, to which toluene (2 L) and a 1N sodium hydroxide aqueous solution (1.35 L) were then added to separate an organic layer. The organic layer was washed 3 times each sequentially with the 1N sodium hydroxide aqueous solution (1.35 L) and warm water (3 L), followed by vacuum concentration. Toluene (3 L) was added to the concentrate, to dissolved it, followed by cooling and filtering the precipitated crystal to obtain 590 g of the title compound (yield: 85%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([CH2:19]Cl)[CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1.[CH2:21]([O:23][P:24]([O:28]CC)[O:25][CH2:26][CH3:27])[CH3:22]>>[Br:1][C:2]1[CH:18]=[C:17]([CH:16]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=2)[CH:3]=1)[CH2:19][P:24](=[O:28])([O:25][CH2:26][CH3:27])[O:23][CH2:21][CH3:22]
Reactant: FC(F)(F)c1ccc(Oc2cc(Br)cc(CCl)c2)nc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1cc(Br)cc(Oc2ccc(C(F)(F)F)cn2)c1)OCC
Temperature: 160 °C
Yield: 63.3 %

Procedure:
2-(3-Bromo-5-(chloromethyl)phenoxy)-5-(trifluoromethyl)pyridine (4.7 g, 12.82 mmol) was dissolved in triethylphosphite (18.7 mL, 107.7 mmol) and refluxed at 160° C. for 4 h. It was then purified by silica gel column chromatography (30-40% ethyl acetate/hexane) to give the title compound (3.8 g, 63%). 1H NMR (500 MHz, CDCl3): δ 8.42 (s, 1H), 7.91 (d, J=10.75 Hz, 1H), 7.33 (s, 1H), 7.24 (s, 1H), 7.07 (s, 1H), 7.02 (d, J=8.6 Hz, 1H), 4.04 (q, J=7.5 Hz, 4H), 3.14 (s, 1H), 3.10 (s, 1H), 1.25 (t, J=7 Hz, 6H); m/z (468.1, 470.1, M+ H+).