Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17](Br)[CH:16]=[CH:15]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:23][CH:24]([OH:27])[C:25]#[CH:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(NCC)C>[CH2:1]([O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([C:26]#[C:25][CH:24]([OH:27])[CH3:23])[CH:16]=[CH:15]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1ccc2cc(Br)ccc2c1
Reactant: C#CC(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: CCCCCCCCCCOc1ccc2cc(C#CC(C)O)ccc2c1
Yield: 81 %

Procedure:
18.2 g (0.05 mol) of 6-decyloxy-2-bromonaphthalene (VI-59), 10.5 g (0.15 mol) of (+)-3-butyn-2-ol (VII*-59), 0.4 g of copper iodide, 0.7 g of triphenylphosphine, 0.4 g of bis(triphenylphosphine)palladium chloride and 100 ml of diethylamine were stirred under reflux for 12 hours in an atmosphere of nitrogen gas. After completion of the reaction, the reaction mixture was poured into ice/aqueous hydrochloric acid and extracted with 200 ml of ethyl acetate. The organic layer was further washed with water and concentrated under reduced pressure. The residue was purified by silica gel chromatography using toluene-ethyl acetate as eluent to obtain 14.3 g (yield 81%) of optically active (+)-6-decyloxy-2-(3-hydroxy-1-butynyl)naphthalene (I'-59), mp 74°-75° C. [α]D20 =+16.9° (c=1, chloroform).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:19]([CH:25]4[CH2:27][CH2:26]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:28]=[C:29]1[NH:33][C@H:32]([CH2:34][O:35]C(=O)C2C=CC=CC=2)[CH2:31][O:30]1>>[CH:22]1([C:21]2[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([N:33]5[C@H:32]([CH2:34][OH:35])[CH2:31][O:30][C:29]5=[O:28])=[N:7][CH:6]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=[C:19]([CH:25]3[CH2:27][CH2:26]3)[CH:20]=2)[CH2:24][CH2:23]1
Reactant: O=C(c1ccc(Br)nc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Product: O=C(c1ccc(N2C(=O)OC[C@H]2CO)nc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 53.4 %

Procedure:
By reaction and treatment in the same manner as in Example 19 and using (6-bromopyridin-3-yl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (880 mg) described in Preparation Example 112 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (650 mg), the title compound (510 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1([CH2:22][CH2:23][CH2:24][CH2:25]Br)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:8].[N:27]1([C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1([CH2:22][CH2:23][CH2:24][CH2:25][N:30]2[CH2:31][CH2:32][N:27]([C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)[CH2:28][CH2:29]2)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:8]
Reactant: COCCCNC(=O)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Product: COCCCNC(=O)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(3-methoxy-propyl)-amide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=1)[CH2:3][CH:4]([CH3:6])[CH3:5]>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:5][CH:4]([CH3:6])[CH2:3][C:2]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=1)=[O:1]
Reactant: COC(=O)c1ccc(C(O)CC(C)C)nc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)CC(C)C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of methyl 6-(1-hydroxy-3-methylbutyl)nicotinate (0.200 g, 0.896 mmol) in dichloromethane (10 mL) was added manganese dioxide (779 mg, 8.96 mmol). The reaction was stirred at room temperature overnight. The reaction was then filtered and concentration of the filtrate gave methyl 6-(3-methylbutanoyl)nicotinate (190 mg, 96%) as a yellow oil. 1H NMR (400 MHz, CDCl3, δ): 9.25 (s, 1H), 8.40-8.42 (d, 1H), 8.07-8.09 (d, 1H), 3.98 (s, 3H), 3.11-3.12 (d, 2H), 2.27-2.34 (m, 1H), 0.99-1.00 (m, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].[CH3:14][CH2:15][CH2:16]Br.O>CS(C)=O>[CH2:14]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[CH2:15][CH3:16]
Reactant: CCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCOc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
Methyl 4-hydroxybenzoate (15.4 g: 101.2 mmol) was dissolved in 150 ml of dimethylsulfoxide (DMSO), and an aqueous solution of potassium hydroxide (KOH/H2O: 7 g/15 ml) was added to the mixture. The resultant mixture was stirred until dissolving homogeneously. Next, 12.5 g (101.6 mmol) of n-propyl bromide was added thereto, and the reaction was carried out at a room temperature for 24 hours. The reaction mixture was poured into 1 L of an iced water and the resultant precipitate was collected by filtration. The obtained precipitate was dissolved in 300 ml of ethanol, and an aqueous solution of sodium hydroxide (NaOH/H2O: 5 g/100 ml) was added thereto. Thus obtained mixture was refluxed by heating for 1 hour, and water (the amount of the water: about 300 ml) was added thereto with removing ethanol (EtOH). After cooling to a room temperature, the transparent solution was acidified by adding a concentrated hydrochloric acid. The resultant white precipitate was filtered and recrystallized from toluene to give 17.5 g (97.2 mmol) of 4-n-propyloxybenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@H:11]2[C@H:19]3[N:14]([C:15]4[CH:23]=[CH:22][C:21](B5OC(C)(C)C(C)(C)O5)=[CH:20][C:16]=4[O:17][CH2:18]3)[C:13](=[O:33])[O:12]2)=[O:8])=[CH:4][CH:3]=1.[C:34]([NH:38][S:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1Br)(=[O:41])=[O:40])([CH3:37])([CH3:36])[CH3:35].C(=O)([O-])[O-].[Cs+].[Cs+].CC(=O)OCC>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@H:11]2[C@H:19]3[N:14]([C:15]4[CH:23]=[CH:22][C:21]([C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=5[S:39]([NH:38][C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:40])=[O:41])=[CH:20][C:16]=4[O:17][CH2:18]3)[C:13](=[O:33])[O:12]2)=[O:8])=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc3c(c2)OC[C@H]2[C@H](CNC(=O)c4ccc(Cl)s4)OC(=O)N32)OC1(C)C
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc2c(c1)OC[C@H]1[C@H](CNC(=O)c3ccc(Cl)s3)OC(=O)N21
Yield: 35.6 %

Procedure:
Compound 5-chloro-N-(((3S,3aS)-1-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-3-yl)methyl)thiophene-2-carboxamide (60 mg, 0.122 mmol) and N-t-butyl-o-bromobenzenesulfonamide (43 mg, 0.147 mmol) were dissolved in a mixed solvent of dioxane (5 ml) and water (0.5 ml). Cesium carbonate (80 mg, 0.245 mmol) was added, and tetrakis (triphenylphosphine) palladium (15 mg, 0.012 mmol) was added under the protection of Ar. The resulting mixture was allowed to react under agitation at 80° C. overnight. TLC (PE/EA=1/1) was employed to monitor the reaction. After the reaction completed, the mixture was filtered under reduced pressure, and the solvent was evaporated. Column chromatography (PE/EA=2/1) afforded off-white solid 25 mg, yield: 35.2%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:17][S:18]([O:9][CH2:8][CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC1CCCCO1
Temperature: 0 °C
Reaction time: 16 h
Yield: 110 %

Procedure:
2-(Tetrahydro-2H-pyran-2-yl)ethanol (465 mg) was dissolved in dry DCM (10 mL) and triethylamine (996 mg) was added. The stirred solution was cooled in an ice bath under nitrogen and methanesulphonyl chloride (359 mg) was added dropwise over 5 mins. The reaction was allowed to warm to room temperature as the ice bath melted and was left for 16 h. The mixture was then shaken with saturated sodium bicarbonate solution and the aqueous layer was extracted with DCM (×2). The combined organic extracts were washed with brine, dried using a hydrophobic frit and evaporated to give the title compound as a brown oil (718 mg).
Reaction SMILES: C(OP([CH:9]([CH2:17][C:18]1[N:19]=[CH:20][S:21][CH:22]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH2:25]=O>O1CCCC1>[S:21]1[CH:22]=[C:18]([CH2:17][C:9](=[CH2:25])[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[N:19]=[CH:20]1
Reactant: C=O
Reactant: CCOP(=O)(OCC)C(Cc1cscn1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(Cc1cscn1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
To a stirred solution of tert-butyl 2-(diethoxyphosphoryl)-3-(1,3-thiazol-4-yl)propanoate (step 1, 7.17 g, 20.5 mmol) in tetrahydrofuran (100 mL) was added sodiumhydride (60% dispersion in mineral oil, 820 mg, 20.5 mmol) at 0° C. under nitrogen. After 10 min, to the mixture was added paraformaldehyde (1.85 g, 61.5 mmol) and the mixture was stirred at room temperature for 45 min. The mixture was quenched with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (3/1) to afford 4.25 g (92%) of the title compound as a colorless oil:
Reaction SMILES: N1C(=O)C=[CH:3]N1.[C:7]1([N:13]2[C:17](=[O:18])[CH:16]=[CH:15][NH:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.S(OC)(OC)(=O)=O>C1(C)C=CC=CC=1>[CH3:3][N:14]1[CH:15]=[CH:16][C:17](=[O:18])[N:13]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=c1cc[nH]n1-c1ccccc1
Reactant: O=c1cc[nH][nH]1
Solvent: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Product: Cn1ccc(=O)n1-c1ccccc1
Temperature: 50 °C

Procedure:
The pyrazolinone prepared as described above in (a) (1.153 g, 7.2 mmol) in dry toluene (3 ml) was treated with dimethyl sulphate (8 mmol, 750 μl) and the whole refluxed under nitrogen for 5 hours. The reaction mixture was then allowed to cool and in doing so separated into two phases. The upper consisting mainly of toluene was carefully pipetted off and discarded. The remaining layer was then treated with water (1 ml), the whole warmed with stirring to 50° C. and then treated with 40% sodium hydroxide solution (1 ml) and stirred at 50° C. for a further 30 minutes. The resultant solution was subsequently extracted with three portions of benzene. The first two extracts were found to contain two products which has spectral properties consistent with 2-methyl-1-phenyl-3-pyrazolin-5-one and 2,4-dimethyl-1-phenyl-3-pyrazolin-5-one. These were separated by chromatography on silica (ethyl acetate) to give 2-methyl-1-phenyl-3-pyrazolin-5-one (95 mg). The third extracton (above) consisted solely of 2-methyl-1-phenyl-3-pyrazolin-5-one (208 mg) (Total yield, 24%). νmax (CHCl3) 1655, 1595, 1550, 1495 cm-1. δ(D6Acetone) 3.11 (3H, s, --NMe), 5.44 (1H, d, J4 Hz, C4 proton), 7.47 (5H, m, phenyl protons), 7.83 (1H, d, J4 Hz, C3 proton). Found: M+ 174.0798; C10H10N2O requires M; 174.0794.
Reaction SMILES: [CH3:1][C:2]1[C:15]([CH3:16])=[CH:14][C:13]2[C:12](=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[NH:18]O)[C:5](=[O:20])[C:4]=2[CH:3]=1.CO.COCCO.Cl>[Zn].O>[CH3:1][C:2]1[C:15]([CH3:16])=[CH:14][C:13]2[C:12](=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[NH2:18])[C:5](=[O:20])[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1C)C(=O)c1c(NO)cccc1C2=O
Agent: Cl
Agent: [Zn]
Solvent: COCCO
Solvent: O
Solvent: CO
Product: Cc1cc2c(cc1C)C(=O)c1c(N)cccc1C2=O
Temperature: 75 °C

Procedure:
50 Parts of 2,3-dimethyl-5-hydroxylaminoanthraquinone was stirred into a mixture of 700 parts of ethyleneglycol monomethyl ether, 200 parts of water and 60 parts of a 35 % aqueous hydrochloric acid, and the mixture was then heated to 75°C. To the mixture there was added little by little 16 parts of zinc dust over 1 hour. The reaction mixture was maintained at 75°C for additional 3 hours, then cooled to 25°C and filtered. The residue was washed with water and dried to obtain 43.6 parts of 2,3-dimethyl-5-aminoanthraquinone of a purity of 95 %.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][S:26][C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: Sc1ccncc1
Product: O=C(CCCSc1ccncc1)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 33 %

Procedure:
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 4-mercaptopyridine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 33% yield.
Reaction SMILES: [CH2:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[OH:11]OS([O-])=O.[K+].C(OCC)(=O)C>ClCCl.O>[N:8]([C:7]1[CH:9]=[CH:10][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1)=[O:11]
Reactant: CCCc1ccc(N)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1ccc(N=O)cc1
Reaction time: 1 h

Procedure:
To a solution of 4-propylaniline (541 μl, 3.7 mmol) in dichloromethane (12.5 ml) was added a solution of oxone (4.55 g, 7.4 mmol) in H2O (50 ml). The biphasic mixture was stirred vigorously under nitrogen for 1 h, at which time the color had become deep aqua green and the reaction was judged as complete by TLC (1:1 hexanes:ethyl acetate; Rf=0.83). The mixture was transferred to a separatory funnel and the organic layer was removed. The aqueous layer was extracted twice with dichloromethane (20 ml). The combined organics were subsequently washed with 20 ml each of 1M HCl, sat. NaHCO3, H2O, and brine and then dried over Na2SO4, filtered and removed of solvent in vacuo to provide nitrosyl-4-propylbenzene as a green oil. The crude product was immediately dissolved in glacial acetic acid (30 ml) and stirred under nitrogen, followed by the addition of 1,4-diaminobenzene (400 mg, 3.7 mmol) in dry DMSO (10 ml). The reaction was allowed to stir for 48 hrs, during which time the color turned orange-brown. The mixture was transferred to a separatory funnel containing 100 ml brine and extracted five times with ethyl acetate (50 ml). The combined organics were then washed with dilute NaCl (50 ml) six times to remove the DMSO and then dried of Na2SO4, filtered removed of solvent in vacuo. Silica gel chromatography through a wide column (40% ethyl acetate in hexanes) provided S6 as an orange solid (432 mg, 1.8 mmol, 49% yield): 1H (MeOD, 500 MHz): 0.95 (t, 3H, J=7.5); 1.66 (q, 2H, J=7.5); 2.62 (t, 2H, J=7.5); 6.74 (d, 2H, J=8.5); 7.26 (d, 2H, J=8) 7.70 (d, 4H, J=8.5). 13C (MeOD, 125 MHz): 12.7, 24.2, 37.4, 113.8, 121.7, 124.6, 128.7, 144.3, 144.4, 151.2, 151.8. HRMS (FAB+): calc'd for C15H18N3+—240.1495. found—240.1500 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[C@H:37]([NH2:39])[CH3:38].CC(P(C(C)(C)C)C1C(C2C(N(C)C)=CC=CC=2)=CC=CC=1)(C)C.C([O-])([O-])=O.[Cs+].[Cs+]>C(N(CC)CC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[C@H:37]([NH:39][C:3]1[CH:4]=[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:6]=[CH:7][C:2]=1[F:1])[CH3:38]
Reactant: C[C@@H](N)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(F)c(OS(=O)(=O)C(F)(F)F)c2)CC1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Product: C[C@@H](Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1F)c1ccc(Cl)cc1Cl
Temperature: 100 °C
Yield: 3666.7 %

Procedure:
To a mixture of t-butyl 4-(4-fluoro-3-(trifluoromethylsulfonyloxy)phenyl)piperazine-1-carboxylate (0.50 g, 1.17 mmol) and (IR)-1-(2,4-dichlorophenyl)ethanamine (0.58 g, 3.05 mmol), tBuDavePhos (0.025 g, 0.070 mmol), and Cs2CO3 (0.80 g, 2.44 mmol) in triethylamine (3 mL) was purged with nitrogen for 3 min. Addition of Pd2(dba)3 (0.034 g, 0.037 mmol) was followed, and the mixture was purged with nitrogen for 1 min. The resulting mixture was heated at 100° C. under nitrogen for 4 h. After cooling to room temperature, the suspension was filtered through a plug of Celite, and washed with ethyl acetate (25 mL). The filtrate was concentrated in vacuo and the resulting residue purified by flash chromatography (SiO2, 10-50% ethyl acetate in hexanes) to afford (R)-t-butyl 4-(3-(1-(2,4-dichlorophenyl)ethylamino)-4-fluorophenyl)piperazine-1-carboxylate (0.36 g, 42.9 mmol, 62%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[NH2:32][CH:33]1[CH2:38][CH2:37][CH:36]([C:39]([OH:41])=[O:40])[CH2:35][CH2:34]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][NH:32][C@H:33]4[CH2:38][CH2:37][C@H:36]([C:39]([OH:41])=[O:40])[CH2:35][CH2:34]4)=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Reactant: NC1CCC(C(=O)O)CC1
Product: O=C(O)[C@H]1CC[C@H](NCc2ccc(-c3noc(-c4nnn(-c5ccccc5F)c4-c4ccncc4)n3)cc2)CC1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (200 mg; 0.48 mmol) and 4-aminocyclohexanecarboxylic acid (138 mg; 0.97 mmol), to give Example 168 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.76-8.73 (2H, m), 7.95-7.88 (3H, m), 7.76-7.69 (1H, m), 7.64-7.49 (6H, m), 3.81 (2H, s), 2.58 (1H, d, J=5.6 Hz), 2.35 (1H, d, J=6.4 Hz), 1.96-1.85 (2H, m), 1.60 (2H, t, J=10.0 Hz), 1.53-1.44 (4H, m). LC/MS (Method C): 540 (M+H)+. HPLC (Method I) Rt 11.49 min (Purity: 93.8%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([CH3:18])[N:16]=[CH:15][C:14]=2/[CH:19]=[CH:20]/[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=2)=[O:22])=[CH:9][CH:8]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:1]([N:3]([CH2:4][CH3:5])[C:31](=[O:32])[CH2:30][C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:21](=[O:22])/[CH:20]=[CH:19]/[C:14]2[CH:15]=[N:16][N:17]([CH3:18])[C:13]=2[C:10]2[CH:9]=[CH:8][C:7]([F:6])=[CH:12][CH:11]=2)=[CH:29][CH:28]=1)[CH3:2]
Reactant: CCNCC
Reactant: Cn1ncc(/C=C/C(=O)Nc2ccc(CC(=O)O)cc2)c1-c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)Cc1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 59.9 %

Procedure:
A mixture of diethylamine (0.17 g), [4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)phenyl]acetic acid (0.70 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.35 g), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.44 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ((2E)-N-{4-[2-(diethylamino)-2-oxoethyl]phenyl}-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylamide as colorless crystals (0.48 g, yield 62%) from a fraction eluted with ethyl acetate-methanol (20:1, v/v). Recrystallization thereof from acetone-hexane gave colorless prism crystals. melting point: 175-176° C.
Reaction SMILES: [CH3:1][C:2]([N+:8]([O-:10])=[O:9])([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12].O>N1C=CC=CC=1>[CH3:1][C:2]([N+:8]([O-:10])=[O:9])([CH3:7])[CH2:3][CH2:4][CH2:5][O:6][S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(CCCO)[N+](=O)[O-]
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCC(C)(C)[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-methyl-4-nitro-1-pentanol (7 gm) in pyridine (40 ml) was cooled in an ice bath and treated with tosyl chloride (19 gm) added in portions over 20 mins. When the addition was complete the mixture was stirred at room temperature for 1 hr. Water (20 ml) was then added and the mixture stirred for 15 mins. The mixture was poured into water and extracted twice with ethyl acetate. The ethyl acetate solution was washed successively with water, citric acid solution, water, sodium bicarbonate solution, water and brine. The solution was dried over magnesium sulphate and evaporated. The product was obtained by crystallisation from ether: 60/80 petroleum ether. Yield 8.18 gm.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[C:27](O)=[C:26]([Cl:29])[C:25]([Cl:30])=[C:24]([Cl:31])[C:23]=1[Cl:32].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[Cl:21][C:22]1[C:27]([O:19][C:18](=[O:20])[CH2:17][NH:16][C:14](=[O:15])[C@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[C:26]([Cl:29])[C:25]([Cl:30])=[C:24]([Cl:31])[C:23]=1[Cl:32]
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl

Procedure:
In 300 ml of tetrahydrofuran were dissolved 40.0 g of N-t-butoxycarbonyl-leucyl-glycine and 38.8 g of pentachlorophenol, after which 30.0 g of dicyclohexylcarbodiimide (DCC) was added with ice-cooling, and the resulting mixture was subjected to reaction overnight. The insoluble material was collected by filtration and the solvent was removed by distillation to obtain a solid, which was recrystallized from ethyl acetate and petroleum ether to obtain N-t-butoxycarbonyl-leucyl-glycine-pentachlorophenyl ester. Yield: 65.9 g (88.5%). [α]D24 =-23.4° (C=1, dimethylformamide). Melting point (Mp): 155°-157° C.