Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[SH:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:15][C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Sc1nccs1
Product: CC(C)(C)OC(=O)N1CCC(Sc2nccs2)CC1

Procedure:
By a similar manner to Reference Example 35, 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.01 g, 5.0 mmol) was reacted with 2-mercaptothiazole (0.70 g, 6.0 mmol) to give the titled compound as pale yellow oily substance (1.33 g, 89%).
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)(=O)=O.O[C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][O:32][C:33]3[CH:46]=[CH:45][C:36]4[C@H:37]([CH2:40][C:41]([O:43][CH3:44])=[O:42])[CH2:38][O:39][C:35]=4[CH:34]=3)[CH:26]=2)=[C:20]([CH3:47])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:44][O:43][C:41](=[O:42])[CH2:40][C@H:37]1[C:36]2[CH:45]=[CH:46][C:33]([O:32][CH2:31][C:27]3[CH:26]=[C:25]([C:21]4[C:22]([CH3:24])=[CH:23][C:18]([O:5][CH:6]5[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]5)=[CH:19][C:20]=4[CH3:47])[CH:30]=[CH:29][CH:28]=3)=[CH:34][C:35]=2[O:39][CH2:38]1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O)cc4C)c3)ccc21
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CN(C(=O)OC(C)(C)C)C5)cc4C)c3)ccc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
tert-Butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate 14a (100 mg, 0.40 mmol, prepared by a method disclosed in PCT patent application WO2011097958”), (S)-methyl 2-(6-((4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 3 h (80 mg, 0.19 mmol) and cesium carbonate (130 mg, 0.40 mmol) were dissolved in 10 mL of N,N-dimethylformamide. The reaction solution was heated to 80° C. and stirred for 12 hours. The resulting solution was mixed with 10 mL of water, and extracted with ethyl acetate (30 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound (S)-tert-butyl 3-((3′-(((3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-6-yl)oxy)methyl)-2,6-dimethylbiphenyl-4-yl)oxy)azetidine-1-carboxylate 14b (60 mg, yield 50.0%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20]C(B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][C:1]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCCCC(=O)c1ccc(C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCCCC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.9 %

Procedure:
To a solution of 1-(4-methylphenyl)-1-pentanone (1.00 g, 4.15 mmol) in DME (20 mL) and water (10 mL) was added 4-(trifluoromethyl)benzeneboronic acid (870 mg, 4.57 mmol) and Na2CO3 (1.10 g, 10.38 mmol). After 10 minutes under nitrogen, Pd(PPh3)4 (480 mg, 0.42 mmol) was added portion-wise, and the mixture heated to reflux and stirred under nitrogen for 2 hours. The reaction mixture was then allowed to cool to rt and the solvents removed under vacuum. The resulting residue was partitioned between water and EtOAc, the layers separated and the aqueous re-extracted with EtOAc (3×30 mL). The combined organic extract was separated and dried (MgSO4), and the solvent removed under vacuum. Purification by flash chromatography (silica), eluting with cyclohexane:EtOAc (19:1) afforded the title compound as a white solid (850 mg).
Reaction SMILES: [C:1]([O:4][CH:5]=[CH:6][CH:7]1[NH:10][C:9](=[O:11])[CH2:8]1)(=[O:3])[CH3:2]>[Pd].C(OC(=O)C)C>[C:1]([O:4][CH2:5][CH2:6][CH:7]1[NH:10][C:9](=[O:11])[CH2:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC=CC1CC(=O)N1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)OCCC1CC(=O)N1
Reaction time: 0.17 h
Yield: 101.9 %

Procedure:
A mixture of 4-(2-acetoxyvinyl)-azetidin-2-one (3.00 g), 10% Pd/C (0.15 g) and ethylacetate (EtOAc) (120 ml) is hydrogenated in a 500 ml glass bomb on a Parr shaker at an initial pressure of 39 psi. After shaking 10 mins (final pressure of 20 psi), the mixture is filtered through a pad of MgSO4 to remove the catalyst. The filtrate is concentrated in vacuo and the residue stripped with anhydrous benzene to provide 4-(2-acetoxyethyl)-azetidin-2-one (3.098 g) as a clear oil: ir(neat) 3.01, 5.66, 5.75, 7.28, 8.05, and 9.61 cm-1 ; nmr (CDCl3) δ1.95 (m, 2), 2.07 (s, 3), 2.60 (m, 1), 3.12 (m, 1), 3.70 (m, 1), 4.15 (m, 2), and 6.77 (br s, 1).
Reaction SMILES: [C:1]1([C:11]2[C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]4([C:35]5[C:34](OC)=[CH:33][CH:32]=[C:31]([C:38]6[C:47]7[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=7)[CH:41]=[CH:40][CH:39]=6)[C:30]=5[C:29]5[C:24]4=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:15]=3[C:14](OC)=[CH:13][CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1(N2C(Cl)=NN=N2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:38]1([C:31]2[C:30]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:16]4([C:15]5[CH:14]=[CH:13][CH:12]=[C:11]([C:1]6[C:10]7[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=7)[CH:4]=[CH:3][CH:2]=6)[C:23]=5[C:22]5[C:17]4=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:35]=3[CH:34]=[CH:33][CH:32]=2)[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: COc1ccc(-c2cccc3ccccc23)c2c1C1(c3ccccc3-2)c2ccccc2-c2c(-c3cccc4ccccc34)ccc(OC)c21
Agent: Clc1nnnn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc2c(c1)-c1c(-c3cccc4ccccc34)cccc1C21c2ccccc2-c2c(-c3cccc4ccccc34)cccc21
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A well-stirred suspension of 31.5 g (50 mmol) of 4,4′-bis(naphth-1-yl)-1,1′-dimethoxy-9,9′-spirobifluorene, 18.1 g (100 mmol) of 1-phenyl-5-chloro-tetrazole and 27.6 g (200 mmol) of K2CO3 is heated under reflux for 18 h in 250 ml of acetone. After cooling, the precipitated solid is filtered off with suction and dried. The solid is dissolved in 200 ml of toluene, 6 g of 5% Pd/C are added, and the mixture is stirred at 40° C. for 8 h under a hydrogen atmosphere. After removal of the solvent, the residue is washed three times with 50 ml of ethanol:water (1:1, v:v) and three times with 100 ml of ethanol and subsequently recrystallised three times from DMF (about 10 ml/g). Yield: 18.7 g (33 mmol), 69.0%, purity: 99.9% (HPLC).
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:7]([N+:20]([O-])=O)[CH:6]=1)[CH3:2]>CO.[Pd]>[NH2:20][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[NH:11][CH2:12][CH2:13][N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)[C:4]([N:3]([CH2:1][CH3:2])[CH2:24][CH3:25])=[O:23]
Reactant: CCN(CC)C(=O)c1ccc(NCCN2CCOCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCN(CC)C(=O)c1ccc(NCCN2CCOCC2)c(N)c1
Reaction time: 2 h
Yield: 95.2 %

Procedure:
A mixture of N,N-diethyl-4-{[2-(4-morpholinyl)ethyl]amino}-3-nitrobenzamide (1.10 g, 3.14 mmol) and 10% Pd/C in MeOH (50 mL) was hydrogenated for 2 hours at 40 psi. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth. Removal of solvent provided the title compound (0.958 g, 95%) which was used without further purification. MS (ESI) (M+H)+=321.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH:11]=[O:12].[Cl:24][C:25](Cl)([Cl:30])[C:26]([F:29])([F:28])[F:27]>[Zn].CN(C)C=O>[Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH:11]([OH:12])[C:25]([Cl:30])([Cl:24])[C:26]([F:29])([F:28])[F:27]
Reactant: O=CCOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: FC(F)(F)C(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CN(C)C=O
Product: OC(COCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)C(Cl)(Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63.4 %

Procedure:
To a mixture of 2.01 g of 4-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyloxyacetaldehyde, 1.31 g of zinc dust and 10 ml of N,N-dimethylformamide was added 4.12 g of 1,1,1-trichlorotrifluoroethane. After stirring at room temperature for 1.5 hours, the reaction mixture was filtered. The filtrate was poured into 20 ml of diluted hydrochloric acid and extracted twice with 50 ml of ethyl acetate. The ethyl acetate layers were combined, washed with water, dried over magnesium sulfate and then evaporated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 1.76 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(3,3-dichloro-4,4,4-trifluoro-2-hydroxybutyloxy)butyloxy)benzene (yield, 63%), nD24.2 1.5188.
Reaction SMILES: [BH4-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH:17]=[O:18])=[CH:11][CH:10]=2)[N:4]=1>C(O)C>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH2:17][OH:18])=[CH:11][CH:10]=2)[N:4]=1
Reactant: O=C/C=C/c1ccc(-c2cccnn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC/C=C/c1ccc(-c2cccnn2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.3 %

Procedure:
Sodium borohydride (90 mg, 2.38 mmol) was added to a suspension of (2E)-3-[4-(3-pyridazinyl)phenyl]-2-propenal (400 mg, 1.90 mmol, prepared as described in Reference Example 61) in ethanol (5 mL) maintained in a room temperature water bath. After 20 min, the reaction was quenched with water (10 mL), allowed to stir for 10 min, and then concentrated to remove the ethanol. The solids were removed by filtration, washed with water, and dried in vacuo to provide 360 mg (89%) of the title compound. MS 213 (M+H)+.
Reaction SMILES: C([Li])CCC.[CH2:6]([Cl:8])[Cl:7].[CH2:9]([N:16]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:17]([C:25](O)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>CCCCCC.O1CCCC1.O>[Cl:7][CH:6]([Cl:8])[C:25](=[O:26])[C@@H:17]([N:16]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCCl
Reactant: O=C(O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: O=C(C(Cl)Cl)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.17 h
Yield: 99 %

Procedure:
Dehydrated tetrahydrofuran (15 ml) was cooled to −78° C. 1.53 M solution (6.5 ml) of n-butyllithium in hexane and then a solution of methylene chloride (0.8 ml) in dehydrated tetrahydrofuran (5 ml) were added thereto, and they were stirred for 10 minutes. A solution of benzyl ester (2.18 g) of N,N-dibenzyl-L-phenylalanine in dehydrated tetrahydrofuran (7 ml) was added to the obtained mixture, and they were stirred for 1 hour. 2 N hydrochloric acid (15 ml) and water (15 ml) were added to the reaction mixture to terminate the reaction. The temperature was elevated to room temperature. After the addition of water followed by the extraction with ethyl acetate, the obtained solutions in ethyl acetate were combined together and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered out. The solvent was evaporated under reduced pressure to obtain the intended (3S)-1,1-dichloro-3-dibenzylamino-4-phenyl-2-butanone (2.04 g) in a yield of 99%.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:15]([C:19]#[CH:20])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>C(OCC)(=O)C.[Cu](I)I>[CH3:16][C:15]([CH3:18])([CH3:17])[C:19]#[C:20][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Br
Reactant: C#CC(C)(C)C
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1C#CC(C)(C)C
Reaction time: 24 h
Yield: 84.5 %

Procedure:
Methyl 2-bromo-4-nitrobenzoate (2.0 g, 7.7 mmol) and t-butylacetylene (0.70 g, 8.5 mmol) were dissolved into 50 mLs. of dry triethylamine to which 2 mole % of copper iodide (0.029 g, 0.15 mmol) and 5 mole. % of tetrakis(triphenylphosine)palladium(0) (0.45 g, 0.38 mmol) were added. The reaction was stirred at 400° C. for 16 hours before an additional ½ equivalent of t-butylacetylene was added. The reaction continued for an additional 24 hours at which time the reaction was completed as determined by TLC. The reaction mixture was taken up in ethyl acetate, washed with distilled water and the organic layer dried over magnesium sulfate. After concentrating, the residue was purified by chromatography (1:9 ethyl acetate/hexanes ) to give the title compound (1.7 g, 85%) as a white solid. m.p. 88-89° C.; 1H NMR (300 MHz, CDCl3) δ 8.30 (d, J=2.2 Hz, 1H, Aromatic), 8.10 (dd, J=2.3, 8.6 Hz, 1H, Aromatic), 7.99 (d, J=8.7 Hz, 1H, Aromatic), 3.99 (s, 3H, OCH3), 1.35 (s, 9H, t-Butyl); 13C NMR (75 MHz, CDCl3) δ 165.9, 149.4, 137.7, 131.4, 128.7, 126.2, 121.8, 107.1, 76.5, 52.8, 30.8, 28.6; MS m/e calc'd 261.1001, found 261.1007.
Reaction SMILES: C(OC)(=O)/C=C/C=C/C(OC)=O.[Cl:13][C:14]1[CH:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]>CC(C)C(O)COC(CO)C.[Pd]>[Cl:13][CH:14]1[CH2:23][CH:22]([C:24]([O:26][CH3:27])=[O:25])[CH2:21][CH2:20][CH:15]1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)c1ccc(C(=O)OC)c(Cl)c1
Agent: [Pd]
Agent: CC(CO)OCC(O)C(C)C
Agent: COC(=O)/C=C/C=C/C(=O)OC
Product: COC(=O)C1CCC(C(=O)OC)C(Cl)C1
Temperature: 165 °C

Procedure:
In a Parr pressure reactor, a stirred suspension of trans,trans dimethyl muconate (6.1 g, 36 mmol) in dimethyldipropyleneglycol (120 ml, 0.3 M) is heated under vinyl chloride pressure (18 psi (0.124 MPa) at 23° C.) to 165° C. for 48 hours. After cooling to room temperature, the reaction mixture is diluted using the same solvent to 200 ml in a volumetric flask, transferred into a round-bottom flask equipped with a magnetic stirring bar, and Pd/C catalyst is added (360 mg of Johnson-Matthey 5 percent Pd/C #6, 0.2 mol percent) at room temperature. The flask is equipped with a reflux condenser, fritted gas dispersion tube, and internal T probe. Under N2 flow (190 ml/min) and stirring (190 rpm) the mixture is heated to reflux while samples are taken at appropriate intervals (t=0.0, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0 h) to monitor the progress of the reactions occurring. After 8 hour reaction time, dimethyl chloro-terephthalate is present. Some material also undergoes C—Cl bond cleavage and dimethyl 2-chloro-cyclohexane-1,4-dicarboxylate is also formed.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]([F:34])([F:33])[C:22]1[CH:23]=[C:24]([C:28]2[N:29]=[N:30][NH:31][N:32]=2)[CH:25]=[CH:26][CH:27]=1.[Cl:35][C:36]([Cl:52])=[CH:37][CH2:38][O:39][C:40]1[CH:49]=[C:48]([Cl:50])[C:43]([O:44][CH2:45][CH2:46]O)=[C:42]([Cl:51])[CH:41]=1>>[Cl:52][C:36]([Cl:35])=[CH:37][CH2:38][O:39][C:40]1[CH:49]=[C:48]([Cl:50])[C:43]([O:44][CH2:45][CH2:46][N:30]2[N:31]=[N:32][C:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:20])([F:33])[F:34])[CH:23]=3)=[N:29]2)=[C:42]([Cl:51])[CH:41]=1
Reactant: FC(F)(F)c1cccc(-c2nn[nH]n2)c1
Reactant: OCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: FC(F)(F)c1cccc(-c2nnn(CCOc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)n2)c1
Reaction time: 1 h
Yield: 112.7 %

Procedure:
Diisopropyl azodicarboxalate (0.056 gram, 0.00028 mole) was added to a stirred, cold (0° C.) mixture of 0.072 gram (0.00028 mole) of triphenylphosphine, 0.045 gram (0.00021 mole) of 5-(3-trifluoromethylphenyl)-2H-1,2,3,4-tetrazole and 0.075 gram (0.00023 mole) of 2-(4-(3,3-dichloroprop-2-enyloxy)-2,6-dichlorophenoxy)ethan-1-ol. The cold reaction mixture stirred for one hour at which time the mixture was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, eluting with hexanes:ethyl (80:20). The appropriate fractions were combined and concentrated under reduced pressure to yield 0.125 gram of an oil. This oil was combined with similarly obtained oils from three reactions preformed in a similar manner. The combined oil was further purified by column chromatography on silica gel, eluting with mixtures of hexanes, methylene chloride and ethyl acetate to yield 0.267 gram of the subject compound as an oil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.Cl.[F:24][CH:25]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:17][C:10]1[CH:9]=[C:8]([C:18](=[O:20])[CH3:19])[C:7]([N:27]2[CH2:28][CH2:29][CH2:30][CH:25]([F:24])[CH2:26]2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: FC1CCCNC1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCCC(F)C1
Temperature: 65 °C
Yield: 27.5 %

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (0.12 g, 0.34 mmol, from Example 47, Step 2), 3-fluoropiperidine hydrochloride (0.057 g, 0.41 mmol), palladium acetate (1.5 mg, 0.0068 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (6.3 mg, 0.010 mmol), and cesium carbonate (0.31 g, 0.95 mmol) in tetrahydrofuran (3 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over MgSO4 and evaporated to dryness. The residue was purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (28.7 mg, 28%). LCMS calculated for C16H17ClFN2O (M+H)+: m/z=307.1; Found 307.0.
Reaction SMILES: [CH3:1][CH:2]([CH3:45])[CH2:3][C@H:4]([N:15]([CH2:37][O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C:16](=[O:36])[C@@H:17]([NH:26][C:27](=[O:35])[CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:5]([O:7]CC1C=CC=CC=1)=[O:6]>CO.O.CO.[Pd]>[CH3:1][CH:2]([CH3:45])[CH2:3][C@H:4]([N:15]([CH2:37][O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C:16](=[O:36])[C@@H:17]([NH:26][C:27](=[O:35])[CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:5]([OH:7])=[O:6]
Reactant: CC(C)C[C@@H](C(=O)OCc1ccccc1)N(COC(=O)C(C)(C)C)C(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CC(C)C[C@@H](C(=O)O)N(COC(=O)C(C)(C)C)C(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
Referring to FIG. 45, a slurry of Pd/C (10%) (200 mg) in MeOH/water (9:1) (10 mL) was added to a solution of (S)-benzyl 4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenyl-N-((pivaloyloxy)methyl)butanamido)pentanoate (440 mg, 0.7 mmol) in MeOH (100 mL) and the suspension was stirred overnight under an atmosphere of hydrogen at RT. The reaction mixture was filtered over Celite, washed with MeOH and concentrated in vacuo to yield product (345 mg, 92%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:15]#[N:16])[CH:11]=3)[C:6]=2[C:5](=[O:17])[C:4]2[CH:18]=[C:19]([N+:30]([O-])=O)[C:20]([O:22][CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[CH:21][C:3]1=2.C([O-])(=O)C.[NH4+].C(=O)([O-])O.[Na+]>C(O)C.[Cl-].[Ti+3].[Cl-].[Cl-]>[NH2:30][C:19]1[C:20]([O:22][CH:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:21][C:3]2[C:2]([CH3:33])([CH3:1])[C:14]3[NH:13][C:12]4[C:7]([C:6]=3[C:5](=[O:17])[C:4]=2[CH:18]=1)=[CH:8][CH:9]=[C:10]([C:15]#[N:16])[CH:11]=4
Reactant: CN1CCC(Oc2cc3c(cc2[N+](=O)[O-])C(=O)c2c([nH]c4cc(C#N)ccc24)C3(C)C)CC1
Agent: [Ti+3]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CCO
Product: CN1CCC(Oc2cc3c(cc2N)C(=O)c2c([nH]c4cc(C#N)ccc24)C3(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 76.2 %

Procedure:
6,6-Dimethyl-8-(1-methyl-piperidin-4-yl oxy)-9-nitro-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound D1, 83 mg, 0.19 mmol) was dissolved in ethanol, added with aqueous solution of ammonium acetate and aqueous solution of titanium (III) chloride, and then the mixture was stirred at room temperature for 45 min. The reaction solution was added to saturated aqueous solution of sodium hydrogen carbonate and then extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues were concentrated under reduced pressure to obtain the title compound (yellow solid, 60 mg, 78%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:17]=[CH:16][C:9]([CH2:10][N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:8][C:7]=2[CH3:18])[CH2:2]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][C:29]([C:31](OCC)=[O:32])=[N:28][N:27]=2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[O:30][C:29]([C:31]([N:1]3[CH2:2][CH:3]([O:5][C:6]4[CH:17]=[CH:16][C:9]([CH2:10][N:11]5[CH2:12][CH2:13][CH2:14][CH2:15]5)=[CH:8][C:7]=4[CH3:18])[CH2:4]3)=[O:32])=[N:28][N:27]=2)=[CH:24][CH:25]=1
Reactant: Cc1cc(CN2CCCC2)ccc1OC1CNC1
Reactant: CCOC(=O)c1nnc(-c2ccc(Cl)cc2)o1
Product: Cc1cc(CN2CCCC2)ccc1OC1CN(C(=O)c2nnc(-c3ccc(Cl)cc3)o2)C1
Yield: 58 %

Procedure:
Using a similar protocol as described in Example 16 employing 19B (0.20 g, 0.80 mmol) and ethyl 5-(4-chlorophenyl)-1,3,4-oxadiazole-2-carboxylate (0.22 g, 0.88 mmol) as starting materials afforded 0.21 g (46%) of 19 as a solid. 1H NMR (500 MHz, CDCl3): δ 1.72-1.84 (m, 4H), 2.35 (s, 3H), 2.43-2.58 (m, 4H), 3.54 (s, 2H), 4.28-4.36 (m, 1H), 4.59-4.68 (m, 1H), 4.70-4.78 (m, 1H), 5.02-5.16 (m, 2H), 6.55 (d, 1H), 6.60 (s, 1H), 7.23 (d, 1H), 7.52 (d, 2H), 8.11 (d, 2H), MS (APCI+) m/z 453 [M+H]+, LC purity: 94%.