Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N+:14]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>CO.C(OCC)(=O)C.[Pd]>[C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH2:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1Oc1ccncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)c1ccccc1Oc1ccncc1N
Reaction time: 2 h
Yield: 97.9 %

Procedure:
137a (1.332 g, 4.891 mmol) was dissolved in a 1:1 mixture of methanol and ethyl acetate (30 mL). Palladium on charcoal (10%, 200 mg, 0.188 mmol) was added, and the mixture was stirred 2 h under hydrogen atmosphere (40 psi). The reaction mixture was filtered over Celite® and concentrated to afford 1.16 g (98% yield, 100% pure) of 4-(2-tert-butylphenoxy)pyridin-3-amine (137b) as a white solid. [M+H]+=243.17. 1H NMR (500 MHz, deuterochloroform) δ ppm 8.07 (s, 1H), 7.75 (d, 1H, J=5.0 Hz), 7.32 (d, 1H, J=10.0 Hz), 7.03 (m, 2H), 6.77 (d, 1H, J=5.0 Hz), 6.41 (d, 1H, J=5.0 Hz), 4.26 (br, 2H),1.27 (s, 9H); 13C (125 MHz, deuterochloroform) δ (ppm), 152.89, 150.65, 140.96, 139.93, 137.42, 134.21, 127.13, 126.93, 124.22, 120.56, 110.45, 34.19, 29.86.
Reaction SMILES: S(=O)(=O)(O)O.O1CCCCC1[O:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][C:28]2[CH:29]=[C:30]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([CH3:43])([OH:42])[CH3:41])[CH:31]=[CH:32][CH:33]=2)[CH:16]=[C:17]([O:19]C2CCCCO2)[CH:18]=1>C1COCC1.O>[OH:42][C:40]([CH3:43])([CH3:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][C:30]1[CH:29]=[C:28]([CH:27]=[CH:26][C:15]2[CH:14]=[C:13]([OH:12])[CH:18]=[C:17]([OH:19])[CH:16]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(O)CCCCCCc1cccc(C=Cc2cc(OC3CCCCO3)cc(OC3CCCCO3)c2)c1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)CCCCCCc1cccc(C=Cc2cc(O)cc(O)c2)c1

Procedure:
In a manner similar to Example 25(d), by reacting 0.06 ml of concentrated sulphuric acid with 1.15 g (2.21 mmol) of 8-(3-{2-[3,5-bis(tetrahydropyran-2-yloxy)phenyl]vinyl}phenyl)-2-methyloctan-2-ol in 20 ml of THF and 10 ml of water, after purification on a silica column (ethyl acetate 40-heptane 60), pinkish crystals (m=331 mg; Y=42%) are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C@@H:9]([CH3:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:4][C:3]=1[S:15]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C@@H:9]([CH3:14])[C:10]([F:11])([F:12])[F:13])[CH:5]=[CH:4][C:3]=1[SH:15]
Reactant: C[C@H](Oc1ccc(SC(c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1)C(F)(F)F
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](Oc1ccc(S)c(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
2-Chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-1-tritylsulfanyl-benzene (220 g, 441 mmol) was dissolved in dichloromethane (800 mL) and trifluoroacetic acid (165 mL, 2.15 mol) was added at room temperature, followed by triethylsilane (110 mL, 674 mmol, ice bath cooling necessary). After stirring for 30 min at room temperature, the mixture was concentrated in vacuo. A potassium hydroxide solution (2M in water, 1.1 L) was added to the residue, and the suspension was stirred for 15 min. After filtration, the remaining solid was washed with water. The combined filtrate was acidified to pH<2 by addition of hydrochloric acid (25% in water, 330 mL) and extracted with tert-butyl-methylether (3×500 mL). The combined organic extracts were washed with an aqueous potassium hydrogencarbonate solution (1M, 330 mL), dried over sodium sulfate, and concentrated in vacuo. The turbid oil was treated with heptane (80 mL) and filtered. The remaining solid was further washed with heptane (20 mL). The combined filtrate was concentrated and dried in vacuo to yield the title compound as a colorless liquid (105 g, 93%). 1H NMR (CDCl3, 400 MHz): δ 1.49 (dd, J=6.5 Hz, 0.5 Hz, 3H), 3.75 (s, 1H), 4.55 (qq, J=6.2 Hz, 6.2 Hz, 1H), 6.79 (dd, J=3.0 Hz, 8.9 Hz, 1H), 7.03 (d, J=2.7 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[Na+].[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: ClCCCCBr
Reactant: c1ccc2[nH]ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: ClCCCCn1ccc2ccccc21
Temperature: 60 °C
Yield: 60.2 %

Procedure:
1H-indole (11.7 g, 0.10 mol) was dissolved into 200 ml of 20% wt. sodium hydroxide, 4-chlorobromobutane (34.3 g, 0.20 mol) and tetrabutyl ammonium bromide (1.0 g) were added, and mixed for 5 min. The mixture was heated to 60° C., stirred to react for 2 hours. Then the reaction solution was cooled down to ambient temperature, 100 ml of dichloromethane was added for extraction and liquid separation. To the aqueous phase, 100 of dichloromethane was added for extraction. Organic phases were mixed, washed with 100 ml of saturated saline. Liquid was separated, and organic phase was evaporated to dryness to produce oily product. Oily products were separated and purified by chromatography with neutral Al2O3 to produce 12.5 g of 1-(4-chlorobutyl)-1H-indole, with a yield of 60.1%.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11](F)=[N:12][CH:13]=1.[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.CCOCC>[CH2:15]([S:22][C:11]1[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][N:12]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Fc1ccc(Cl)cn1
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Clc1ccc(SCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.8 %

Procedure:
To a suspension of cesium carbonate (3.76 g, 11.5 mmol) in DMF (20 mL) at room temperature was added 5-chloro-2-fluoropyridine (1.00 mL, 9.96 mmol) and benzylmercaptan (1.15 mL, 9.80 mmol). The reaction mixture was stirred at room temperature for 16 h and heated to 60° C. for 6 h. The reaction mixture was diluted with Et2O. The organic phase was washed with water (2×), brine and dried over MgSO4. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (5% to 10% EtOAc in heptane) to give the title compound (2.33 g, 9.88 mmol, 101% yield) as a colorless oil that was used without further purification in the next step. MS) m/z=236.1 [M+H]+. Calculated for C12H10ClNS 235.0.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[C:8](Br)[CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.CCO.COCCOC>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[C:8]([C:16]3[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=3)[CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: OB(O)c1cccnc1
Reactant: CON=C1CCc2c(Br)cccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: CON=C1CCc2c1cccc2-c1cccnc1
Temperature: 160 °C

Procedure:
4-Bromoindan-1-one O-methyloxime (720 mg, 3.0 mmol) was added to a mixture of pyridine-3-boronic acid (406 mg, 3.3 mmol), sodium carbonate (477 mg, 4.5 mmol) and Pd(dppf)Cl2.CH2Cl2 (122 mg, 0.15 mmol) in 7:2:3 DME:EtOH:H2O (15 mL). The stirred mixture was heated at 160° C. for 3 minutes on the microwave. After cooling to ambient temperature, the reaction mixture was filtered through celite, then silica gel with ethyl acetate. The filtrate was concentrated to a brown oil and chromatographed on silica gel with 70% ethyl acetate in hexane. Obtained 4-pyridin-3-yl-indan-1-one O-methyloxime (667 mg, 93%) as a yellow oil. MS (ESI) m/z: 239.1 [M+H]. 1H NMR (DMSO-d6) δ: 2.81 (m, 2H), 3.08 (m, 2H), 3.92 (s, 3H), 7.45 (m, 2H), 7.48 & 7.51 (pair of dd, 1H), 7.63 (dd, 1H), 7.94 & 7.97 (pair of dd, 1H), 8.60 (dd, 1H), 8.72 (dd, 1H).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.[Al+3].[Cl-].[Cl-].[Cl-].[CH:20]1C=CC=C[CH:21]=1>ClC(Cl)C>[Cl:15][C:14]1[C:6]([Cl:5])=[C:7]2[C:11]([CH2:20][CH2:21][C:8]2=[O:10])=[CH:12][CH:13]=1
Reactant: c1ccccc1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Product: O=C1CCc2ccc(Cl)c(Cl)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Thionyl chloride (5.73 mL, ˜79 mmol) and 2,3-dichloro-benzoic acid (commercially available from Aldrich) (10.0 g, 52.4 mmol) in benzene was heated to reflux until no more gas evolution was observed. After cooling to rt the mixture was concentrated. The concentrate was diluted with dichloroethane and added to AlCl3 (7.0 g, ˜53 mmol) in dichloroethane at 10-20° C. Ethylene was bubbled through the mixture for 4 h. The mixture was stirred overnight and quenched with 4 N HCl. The resulting layers were separated and the aqueous layer was extracted with Et2O (3×250 mL). The combined organic extracts were washed with H2O (3×150 mL), saturated NaHCO3 (3×150 mL), brine (1×50 mL), dried over MgSO4 and concentrated. The concentrate was added to a slurry of AlCl3 (9.0 g) and NaCl (2.4 g) at 130° C. The resulting mixture was stirred at 180° C. for 2 hours after which it was cooled to room temperature and quenched with ice followed by concentrated HCl. The mixture was extracted with CH2Cl2 (3×500 mL) and the combined organic extracts were concentrated and purified by column chromatography using 20% EtOAc:hexane eluant to give 6.8 g (80%) of 6,7-dichloro-1-indanone. Use of 6,7-dichloro-indan-1-one in Method NINETEEN produced 4-(4,5-dichloro-indan-2-yl)-1,3-dihydro-imidazole-2-thione (Compound 153).
Reaction SMILES: Cl.C([O:9][C@H:10]1[C@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([CH2:23][O:24]CC2C=CC=CC=2)[O:12][C@H:11]1[N:32]1[CH:40]=[N:39][C:38]2[C:33]1=[N:34][C:35]([F:42])=[N:36][C:37]=2[NH2:41])C1C=CC=CC=1>[H][H].[Pd](Cl)Cl>[C@@H:11]1([N:32]2[CH:40]=[N:39][C:38]3[C:33]2=[N:34][C:35]([F:42])=[N:36][C:37]=3[NH2:41])[O:12][C@H:13]([CH2:23][OH:24])[C@@H:14]([OH:15])[C@@H:10]1[OH:9]
Reactant: [H][H]
Reactant: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: Cl[Pd]Cl
Agent: Cl
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
reacting a mixture of 2-fluoro-9-(2,3,5-tri-O-benzyl-beta-D-arabinofuranosyl)adenine (VI) dissolved in a non-reactive solvent for (VI), with hydrogen and a molar amount of palladium chloride less than (VI) and concentrated hydrochloric acid in a molar excess to (VI) such that the weight of palladium chloride is between about 3 and 15% by weight of (VI) in a sealed vessel at elevated pressure above atmospheric pressure between about 30 and 50 psig to produce (VII) in the reaction mixture;
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:17][O:18][C:19](=[O:25])[C@H:20]([CH:22]([CH3:24])[CH3:23])[NH2:21]>>[CH3:17][O:18][C:19](=[O:25])[C@H:20]([CH:22]([CH3:24])[CH3:23])[NH:21][C:13](=[O:15])[C@H:11]([CH3:12])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Product: COC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc1ccccc1)C(C)C

Procedure:
Following General Procedure A and using N-(phenylacetyl)-L-alanine (fromo Example B1 above) and L-valine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid (mp=112-115° C.). The reaction was monitored by tlc (Rf=0.33 in 50% EtOAc/hexanes) and the product was not purified.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([S:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9].[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.[K]>CN(C)C=O>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([C:7]([S:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:32]2[C:28](=[O:38])[C:29]3[C:30](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:31]2=[O:33])[C:8]#[N:9])[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: COc1ccc(C(C#N)(CCCCCI)Sc2ccc(C)cc2)cc1OC
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: COc1ccc(C(C#N)(CCCCCN2C(=O)c3ccccc3C2=O)Sc2ccc(C)cc2)cc1OC
Yield: 77.8 %

Procedure:
A mixture of 6.12 g of α-(5-iodopentyl)-3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile and 2.22 g of potassium phthalimide and 50 mL of N,N-dimethylformamide is heated on a steam bath for 2 hours. The reaction solution is concentrated in vacuo and the residue is distributed between diethyl ether-water, with agitation. The organic layer is washed with 1N sodium hydroxide, followed by aqueous potassium bicarbonate. The solution is dried (sodium sulfate), and the volatiles removed in vacuo. Chromatography on silica gel, with gradient elution progressing from hexane to chloroform to methyl alcohol, affords 4.77 g of the desired product as a fluorescent oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=3)[C:17]([O:19]CC)=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:25])[C:6]=2[CH:26]=1.[OH-].[Na+]>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=3)[C:17]([OH:19])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:25])[C:6]=2[CH:26]=1
Reactant: CCOC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Br)cc3c2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccc(Br)cc12
Yield: 58 %

Procedure:
Ethyl 3-{[(5-bromo-3-methyl-1-benzothiophen-2-yl)sulfonyl]amino}benzoate (Intermediate 18) (42 mg, 0.093 mmol) was hydrolyzed with 1 M NaOH (1 mL) in EtOH (2 mL) at room temperature over night. The reaction mixture was acidified and extracted with EtOAc. The combined organic phases were washed with water and dried. Evaporation of the solvents gave 23 mg (58%) of the title compound. MS (ESI+) calcd for C16H12BrNO4S2 424.939112, found 424.939992.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:14]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:13][C@@H:12]1[CH3:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[O:39]1CCO[CH2:41][CH2:40]1>>[CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:14]([N:21]([C:40](=[O:39])[CH3:41])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:13][C@@H:12]1[CH3:29])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCO1
Reactant: C[C@H]1C[C@@H](NCc2ccccc2)c2ccccc2N1C(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(Cc1ccccc1)[C@@H]1C[C@H](C)N(C(=O)OCc2ccccc2)c2ccccc21

Procedure:
To a solution of Cis-2-Methyl-4-benzylamino-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester (300 mg, 0.776 mmol), diisopropyl ethyl amine (0.135 mL, 0.776 mmol) in dioxane (1.5 mL), was added anhydride acetic (0.732 mL, 7.76 mmol) with stirring. The mixture was heated under reflux over night, cooled and directly chromatographed on silica gel utilizing 50% ethyl acetate/hexane to provide the title compound (300 mg) as an oil. 1H NMR [CDCl3]: δ 7.6–6.9 (m, 14H), 5.5 (d, 1H), 5.3 (d, 1H), 5.2 (t, 1H), 4.8 (m, 1H), 4.4 (m, 2H), 3.8 (d, 1H), 2.4 (s, 3H), 1.5 (m, 1H), 1.2 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][NH2:23])[CH:18]=3)[C:13]([C:24]#[N:25])=[CH:12]2)=[CH:7][C:6]=1[O:26][CH2:27][O:28][CH3:29])[CH3:2].C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>ClCCl>[CH2:1]([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][NH:23][C:38](=[O:40])[CH3:39])[CH:18]=3)[C:13]([C:24]#[N:25])=[CH:12]2)=[CH:7][C:6]=1[O:26][CH2:27][O:28][CH3:29])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3ccc(OCCN)cc32)cc1OCOC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3ccc(OCCNC(C)=O)cc32)cc1OCOC
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.3 %

Procedure:
To a solution of 4-[6-(2-aminoethyloxy)-3-cyanoindol-1-yl]-2-methoxymethoxybenzoic acid ethyl ester (0.10 g) and triethylamine (0.076 g) in dichloromethane (5 mL) was added acetyl chloride (0.049 g) at room temperature, and this mixture was stirred at room temperature for 12 hours. This reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane:methanol=10:1) to give the title compound (0.083 g).
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[N-:25]=[C:26]=[O:27]>>[F:24][C:3]([F:2])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:26]([NH:25][CH:4]([CH2:5][CH3:6])[CH3:3])=[O:27])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: FC(F)(F)c1ccccc1C(OC1CNC1)c1ccc(Cl)cc1
Reactant: [N-]=C=O
Agent: Cl
Product: CCC(C)NC(=O)N1CC(OC(c2ccc(Cl)cc2)c2ccccc2C(F)(F)F)C1

Procedure:
This material was prepared from 3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]azetidine hydrochloride (98) and the corresponding isocyanate using the procedure described for compound (10).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C@H:5]([OH:8])[CH2:6][NH2:7].Cl.COC(=O)C[C@H](O)CN.C(=O)([O-])O.[Na+].[CH3:25][O:26][CH:27]([O:30][CH3:31])[CH:28]=O>CO.[Pd]>[CH3:1][O:2][C:3](=[O:9])[CH2:4][C@H:5]([OH:8])[CH2:6][NH:7][CH2:28][CH:27]([O:30][CH3:31])[O:26][CH3:25]
Reactant: COC(C=O)OC
Reactant: COC(=O)C[C@H](O)CN
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: COC(=O)C[C@H](O)CNCC(OC)OC
Reaction time: 4 h
Yield: 116.3 %

Procedure:
A solution of 2.50 g (14.7 mmol) of (S)-4-amino-3-hydroxy-butyric acid methyl ester; HCl (intermediate 24) in 18 ml of methanol was treated with 6.19 g (73.7 mmol) of natriumhydrogencarbonat, 2.2 ml (14.7 mmol) of dimethoxyacetaldehyde (in H2O 60%), 0.250 g of Pd/C (10%) and was stirred over H2-atmosphere for 4 h. After filtration, the solution was evaporated, dissolved in toluene, evaporated under reduced pressure (2×) to yield 3.781 g (70%) of the titled compound as yellow oil. MS: 222.13 (MH+).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[NH:30][C:31](=[O:33])[CH3:32])[C:21]3=[O:34])[CH2:16][CH:17]([OH:19])[CH3:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[NH:30][C:31](=[O:33])[CH3:32])[C:21]3=[O:34])[CH2:16][C:17](=[O:19])[CH3:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C(CC(C)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)cc1OC1CCCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1ccc(C(CC(C)=O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.6 %

Procedure:
A mixture of N-{2-[1-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxybutyl]-1,3-dioxoisoindolin-4-yl}acetamide (1.28 g, 2.74 mmol), pyridinium chlorochromate (1.18 g, 5.48 mmol) and celite (0.6 g) in methylene chloride (35 mL) was stirred at room temperature for 5 hours. The mixture was filtered through celite and the filtrate was washed with water (30 mL), brine (30 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography (Silica gel, methylene chloride:ethyl acetate 9:1) to give N-{2-[1-(3-cyclopentyloxy-4-methoxyphenyl)-3-oxobutyl]-1,3-dioxoisoindolin-4-yl}acetamide (1.09 g, 85%) as a white solide: mp 145-147° C.; 1H NMR (CDCl3) δ 9.53 (s, 1H), 8.70 (d, J=8.4 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 7.46 (d, J=7.3 Hz, 1H), 7.07-7.01 (m, 2H), 6.81 (d, J=8.2 Hz, 1H), 5.73-5.67 (dd, J=5.1, 9.8 Hz, 1H), 4.77 (m, 1H), 4.04-3.93 (dd, J 10.0, 18.1 Hz, 1H), 3.80 (s, 3H), 3.28-3.19 (dd, J=5.1, 18.0 Hz, 1H), 2.26 (s, 3H), 2.18 (s, 3H), 1.97-1.61 (m, 8H); 13C NMR (CDCl3) δ 205.22, 170.03, 169.15, 167.82, 149.83, 147.70, 137.33, 135.77, 131.23, 124.63, 119.88, 117.87, 115.28, 114.57, 111.72, 80.46, 55.99, 49.94, 44.82; 32.75, 30.14, 24.92, 24.05; Anal. Calcd. for C26H28N2O6; C, 67.23; H, 6.08; N, 6.03. Found: C, 66.96; H, 6.06; N, 5.89.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]([NH2:19])=[O:18])=[N:4][C:5]2[C:10]([C:11]=1[C:12]([F:15])([F:14])[F:13])=[CH:9][C:8]([Cl:16])=[CH:7][CH:6]=2.[C:20](CC(=O)C)(=O)[CH3:21]>OS(O)(=O)=O>[Cl:16][C:8]1[CH:7]=[CH:6][C:5]2[N:4]=[C:3]3[C:17](=[O:18])[NH:19][C:20]([CH3:21])=[N:1][C:2]3=[C:11]([C:12]([F:13])([F:15])[F:14])[C:10]=2[CH:9]=1
Reactant: NC(=O)c1nc2ccc(Cl)cc2c(C(F)(F)F)c1N
Reactant: CC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Product: Cc1nc2c(C(F)(F)F)c3cc(Cl)ccc3nc2c(=O)[nH]1
Temperature: 100 °C
Yield: 55 %

Procedure:
3-Amino-6-chloro-4-(trifluoromethyl)-2-quinolinecarboxamide (12, 172 mg, 0.594 mmol) was dissolved acetylacetone (5.9 mL). Three drops of H2SO4 were added and the reaction was heated to 100° C. for 30 minutes. The reaction was cooled to rt and the copious cream precipitate was collected and washed with cold CH3OH to provide the desired product (103 mg, 55%) requiring no further purification. 1H NMR (d6-DMSO, 300 MHz) δ12.73 (br s, NH), 8.35 (d, J=9.2 Hz, 1 H), 8.29 (s, 1H), 7.97 (dd, J=2.2, 9.1 Hz, 1H), 2.44 (s, 3H); 19F NMR (CDCl3, 300 MHz) δ−51.34; IR (KBr) νmax 3442, 3060, 2920, 1706, 1629, 1608, 1560, 1485, 1336, 1329, 1198, 1144, 1114, 961, 837, 710 cm−1.
Reaction SMILES: I[C:2]1[NH:6][C:5]([C@@H:7]2[CH2:11][C@H:10]([CH3:12])[CH2:9][N:8]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:4][C:3]=1[CH3:20].CO.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=2)=[CH:26][CH:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.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>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:2]3[NH:6][C:5]([C@@H:7]4[CH2:11][C@H:10]([CH3:12])[CH2:9][N:8]4[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:4][C:3]=3[CH3:20])=[CH:32][CH:31]=2)=[CH:28][CH:29]=1
Reactant: OB(O)c1ccc(-c2ccc(Br)cc2)cc1
Reactant: Cc1nc([C@@H]2C[C@H](C)CN2C(=O)OC(C)(C)C)[nH]c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1nc([C@@H]2C[C@H](C)CN2C(=O)OC(C)(C)C)[nH]c1-c1ccc(-c2ccc(Br)cc2)cc1
Temperature: 75 °C
Yield: 43.6 %

Procedure:
To a solution of tert-butyl (2S,4S)-2-(5-iodo-4-methyl-1H-imidazol-2-yl)-4-methyl-pyrrolidine-1-carboxylate (289 mg, 0.7387 mmol) in 6 mL of 5:1 toluene:methanol is sequentially added [4-(4-bromophenyl)phenyl]boronic acid (346.7 mg, 1.252 mmol), K3PO4 (199.3 mg, 0.9389 mmol) and Pd(PPh3)4 (71.85 mg, 0.06218 mmol). The reaction mixture is heated at 75° C. for 3 hours. The reaction mixture is concentrated, diluted with ethyl acetate, and washed with water and brine. The organic layer is concentrated to dryness. The residue is dissolved in dichloromethane and purified by flash column chromatography on silica gel (0-10% methanol/dichloromethane) to give (2S,4S)-tert-butyl 2-(5-(4′-bromo-[1,1′-biphenyl]-4-yl)-4-methyl-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate (160 mg, 0.322 mmol).