Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([NH2:9])[C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22]>>[NH2:9][C:4]1[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]2[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:7]([Cl:8])=[CH:6][N:5]=1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1N
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1c(Cl)cnc(N)c1[N+](=O)[O-]
Yield: 72 %

Procedure:
In a similar fashion as for the synthesis of Compound A (X═Cl), 4,5-dichloro-3-nitro-pyridin-2-ylamine was reacted with N-((1R,2R)-2-amino-cyclohexyl)-methanesulfonamide to afford N-[(1R,2R)-2-(2-amino-5-chloro-3-nitro-pyridin-4-ylamino)-cyclohexyl]-methanesulfonamide (72%) which was subjected to hydrogenation with iron in acetic acid in a similar fashion as for Compound B to afford N-[(1R,2R)-2-(2,3-diamino-5-chloro-pyridin-4-ylamino)-cyclohexyl]-methanesulfonamide (66%). This latter material was then reacted with 2-methoxy-4-morpholin-4-ylmethyl-benzaldehyde in a similar fashion as for the synthesis of Compound III to afford the title compound as a yellow lyophilate (70%). 1H NMR (d-chloroform): 13.39 (br s, 1H), 8.30 (d, J=8 Hz, 1H), 8.23 (s, 1H), 7.19 (m, 1H), 7.12 (s, 1H), 7.03 (d, J=8 Hz, 1H), 6.76 (d, J=8 Hz, 1H), 5.05 (m, 1H), 4.97 (m, 1H), 4.12-3.81 (m, 6H), 3.64 (s, 3H), 3.48 (m, 1H), 3.25 (m, 1H), 3.12 (s, 3H), 3.06 (m, 1H), 2.83 (m, 1H), 2.22 (m, 2H), 2.01-1.60 (m, 4H), 1.44 (m, 2H), 1.25 (m, 1H). MS: 549.0 (M+H). HPLC retention time: 1.85 minutes (G Method).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])=[O:13])=[CH:7][CH:6]=1)[CH3:4].C[O-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27]>O>[CH2:27]([O:1][N:2]=[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])=[O:13])=[CH:9][CH:10]=1)[CH3:4])[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: CC(=NO)c1ccc(NC(=O)NCC(=O)OC(C)C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: C=CCON=C(C)c1ccc(NC(=O)NCC(=O)OC(C)C)cc1

Procedure:
A solution of the N-[4-(1-hydroxyiminoethyl)phenyl]-N'-isopropoxycarbonylmethylurea in 25% methanolic sodium methoxide (1.0 equivalent) is treated at room temperature with 1.1 equivalent of allyl bromide. The reaction mixture is stirred until the temperature falls to about 20° C. The reaction mixture is then poured into cold water and extracted with diethyl ether. The ether solution is dried over MgSO4 and filtered, and the solvent is removed by rotary evaporator to yield the product N-[4-(1-allyloxyiminoethyl)phenyl]-N'-isopropoxycarbonylmethylurea.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:7]=1.[CH2:14]([O:16][C:17]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])[C:18]#[CH:19])[CH3:15]>>[CH2:24]([O:23][C:17]([O:16][CH2:14][CH3:15])([O:20][CH2:21][CH3:22])[C:18]#[C:19][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:7]=1)[CH3:25]
Reactant: FC(F)(F)COc1cncc(Br)c1
Reactant: C#CC(OCC)(OCC)OCC
Product: CCOC(C#Cc1cncc(OCC(F)(F)F)c1)(OCC)OCC
Yield: 46 %

Procedure:
The title compound was synthesized from 3-bromo-5-(2,2,2-trifluoro-ethoxy)-pyridine and 3,3,3-triethoxypropyne using the procedure described in Example 43, step (e), in 46% yield. 1H NMR (CDCl3) δ 8.44 (bs, 1H), 8.35 (bs, 1H), 7.34 (m, 1H), 4.40 (q, 2H, J=7.9 Hz), 3.76 (q, 6H, J=7.1 Hz), 1.28 (t, 9H, J=7.1 Hz).
Reaction SMILES: [CH:1]([C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:14][C:15]([OH:17])=[O:16])[C:8]=2[CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2].S(=O)(=O)(O)O.C(=O)([O-])[O-].[K+].[K+].[CH2:29](O)[CH3:30]>>[CH:1]([C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:14][C:15]([O:17][CH2:29][CH3:30])=[O:16])[C:8]=2[CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nccc2c(CC(=O)O)cccc12
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)Cc1cccc2c(C(C)C)nccc12
Temperature: 0 °C

Procedure:
1-iso-Propylisoquinoline-5-acetic acid (0.5 g) was dissolved in 20 ml of ethanol, and 3 ml of conc. sulfuric acid was added. The mixture was heated under reflux for 3 hours. The reaction mixture was poured into ice water, made weakly alkaline with potassium carbonate, extracted with benzene, washed in water, and dried. The solvent was distilled off under reduced pressure to afford 0.5 g of ethyl 1-isopropylisoquinoline-5-acetate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][C:18]([CH3:25])([C:20]1[O:21][CH:22]=[CH:23][N:24]=1)[NH2:19]>>[CH3:17][C:18]([NH:19][C:14]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:20]1[O:21][CH:22]=[CH:23][N:24]=1)[CH3:25]
Reactant: CC(C)(N)c1ncco1
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Product: CC(C)(NC(=O)c1cccc(-c2cccc(Cl)c2)n1)c1ncco1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and α,α-dimethyl-2-oxazolemethanamine (CAN 1211519-76-4) as starting materials, MS (LC/MS): 341.9 [M+H]+.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29]Cl>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[N:3]=1
Reactant: COCCOCCl
Reactant: O=[N+]([O-])c1ccc2[nH]nc(I)c2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCn1nc(I)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46 %

Procedure:
To a solution of 3-iodo-5-nitro-1H-indazole (10.0 g, 34.6 mmol) in THF (50 ml) was added sodium bis(trimethylsilyl)amide (1M in THF, 48.4 mmol, 48.4 ml) and the solution stirred at room temperature for 20 minutes. 2-methoxyethoxymethyl chloride (4.9 g, 39.1 mmol, 4.5 ml) was added and the solution stirred at room temperature for 15 hours. The reaction was quenched with ammonium chloride (30 ml, saturated aqueous) and extracted into ethyl acetate (3×50 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (1:1 EtOAc:hexanes) to give the title compound as an orange solid (6.0 g). 1H NMR (400 MHz, CDCl3) δ 3.35 (3H, s), 3.50–3.52 (2H, m), 3.68–3.70 (2H, m), 5.86 (1H, s), 7.69 (1H, d), 8.38 (1H, d), 8.53 (1H, s). MS (ES+) m/e=378.
Reaction SMILES: [CH2:1]([O:3][P:4](Cl)[O:5][CH2:6][CH3:7])[CH3:2].[CH2:9]([Mg]Cl)[CH2:10][CH2:11][CH3:12]>CCOCC>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH3:12])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCCC[Mg]Cl
Reactant: CCOP(Cl)OCC
Solvent: CCOCC
Product: CCCCP(OCC)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
Diethylchlorophosphite (18.8 gm, 0.12 moles) and 120 ml dry ether are combined in a round bottom flask equipped with a dropping funnel and under N2 atmosphere. With a double tipped canula, butyl magnesium chloride (60 ml; 2.0M, 0.12 moles; Aldrich Chemical Co., Milwaukee, Wis.) is added to the dropping funnel. The round bottom flask is cooled in a salt water/ice bath and the contents of the dropping funnel are slowly added to the cooled flask. After the addition is complete, the bath is removed and the solution is allowed to stir at room temperature for three hours. The precipitate which forms during the course of the reaction is then quickly filtered and washed with ether. The filtrate is concentrated by rotary evaporator to yield 21.17 gm of diethylbutylphosphonite. 31P NMR (CDCl3): 182 ppm.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19]2[C@H:28]3[C@H:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[C:22](=[O:29])N(C(C)(C)C)N=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19]2[C@H:28]3[C@H:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[C:22](=[O:29])[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(C2=NN(C(C)(C)C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: NNc1ccccc1
Product: COc1ccc(C2=NN(c3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound A (see starting compounds) and phenylhydrazine as described for compound 14. Crystallized from ethyl acetate/petroleum ether (60°-95° C.). M.p. 122°-124° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3]F.[C:5]([O:9][C:10](=[O:30])[N:11]([C:13]1[CH:18]=CC(C2C=CC3C(C=2)=NON=3)=[C:15]([O:28][CH3:29])[CH:14]=1)[CH3:12])([CH3:8])([CH3:7])[CH3:6].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:5]([O:9][C:10](=[O:30])[N:11]([C:13]1[CH:18]=[CH:3][C:2]([Br:1])=[C:15]([O:28][CH3:29])[CH:14]=1)[CH3:12])([CH3:8])([CH3:7])[CH3:6]
Reactant: FCCBr
Reactant: COc1cc(N(C)C(=O)OC(C)(C)C)ccc1-c1ccc2nonc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(N(C)C(=O)OC(C)(C)C)ccc1Br
Temperature: 52.5 °C
Reaction time: 12 h

Procedure:
0.63 mL (1.25 eq.) 1-bromo-2-fluoroethane are added at room temperature to a stirred suspension of 2 g (6.6 mmol) (4-benzo[1,2,5]oxadiazol-5-yl-3-methoxy-phenyl)-methyl-carbamic acid tert-butyl ester and 3.2 g (1.5 eq.) cesium carbonate in 50 mL DMF. After stirring for 12 hours at 50 to 55° C., the reaction mixture is cooled to rt. And extracted with water/ethyl acetate. The combined organic phases are washed with brine, dried over magnesium sulfate and evaporated to yield the desired product as a yellow oil, which is used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[C:11]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[N:14]([CH3:23])[CH:13]=3)=[CH:10][C:9]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:8][C:6]=2[CH:7]=1)[CH3:2]>CO.[Pd]>[CH2:1]([CH:3]1[CH2:7][C:6]2[CH:8]=[C:9]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:10]=[C:11]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[N:14]([CH3:23])[CH:13]=3)[C:5]=2[O:4]1)[CH3:2]
Reactant: CCc1cc2cc(S(C)(=O)=O)cc(-c3cn(C)c(=O)c4ccccc34)c2o1
Agent: [Pd]
Solvent: CO
Product: CCC1Cc2cc(S(C)(=O)=O)cc(-c3cn(C)c(=O)c4ccccc34)c2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.5 %

Procedure:
To a solution of the title compound from Step 2 (130 mg, 340 umol) in MeOH (3 mL) was added Pd/C (70 mg, 10% w/w) in one portion. The reaction mixture was stirred at 25° C. under H2 atmosphere (15 psi) for 8 h. After this time, the mixture was filtered through celite. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC to give the title compound (12.4 mg) as a gray solid. 1H NMR (CDCl3, 300 MHz) δ 8.54-8.51 (d, J=7.5 Hz, 1H), 7.79-7.75 (m, 2H), 7.75-7.54 (m, 2H), 7.32-7.29 (d, J=8.1 Hz, 1H), 7.16 (s, 1H), 4.90-4.85 (m, 1H), 3.69 (s, 3H), 3.49-3.41 (m, 1H), 3.06-3.00 (m, 1H), 1.85-1.70 (m, 2H), 0.96-0.91 (t, J=7.5 Hz, 3H). LCMS: 384.0 (M+1)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=O.Cl[CH2:15][C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][O:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:2]2[O:1][CH:15]([C:16]#[N:17])[CH2:4][C:3]=2[CH:6]=1
Reactant: N#CCCl
Reactant: COc1cc(O)c(C=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)OC(C#N)C2
Temperature: 165 °C
Reaction time: 0.17 h
Yield: 50.8 %

Procedure:
2-Hydroxy-4,5-dimethoxybenzaldehyde (25.5 g, 0.14 mol), chloroacetonitrile (12.4 g, 0.168 mol) and potassium carbonate (116 g, 0.84 mol) was dissolved in DMF (150 ml). The mixture was stirred for 10 minutes at 165° C. The solvent was concentrated under reduced pressure. The residue was separated in two parts, water was added and the first part was extracted with diethyl ether and the second part extracted with DCM. The second part was evaporated under reduced pressure and dissolved in ether and washed once with water. The organic layers was combined and evaporated under reduced pressure. The crystalline residue was washed with warm methanol (700 ml) and filtered. The residue was dissolved in 225 ml DCM and diethyl ether (450 ml) was added. The crystals formed was collected giving 14.6 g (51% yield) of product. Mp. 162° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:13])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[OH-].[K+].Cl>C1C=CC=CC=1>[CH2:15]([O:12][CH2:11][CH:10]([CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[O:13][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: OCC(O)COCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCOCC(COCc1ccccc1)OCCCCCCCCCCCCCCCC
Reaction time: 16 h
Yield: 138.7 %

Procedure:
3-O-Benzylglycerol (9.0 g, 0.05 mole) and 25 g (0.08 mole) of 1-bromohexadecane are dissolved in 50 ml of dry benzene, 8.8 g (0.16 mole) of potassium hydroxide is added to the solution, and the mixture is heated under reflux with stirring for 16 hours. The reaction mixture is neutralized by adding hydrochloric acid then extracted with 50 ml of ethyl acetate. The extract is washed in sequence with 2.5% potassium hydrogen carbonate and water and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure to give 35 g of an oily residue.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][C:3]=1[NH:9][CH3:10].[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([O:21][CH3:22])[CH:13]=1>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][C:3]=2[NH:9][CH3:10])=[C:14]([O:21][CH3:22])[CH:13]=1
Reactant: COc1cc(F)ccc1B(O)O
Reactant: CNc1cnc(C)cc1I
Product: CNc1cnc(C)cc1-c1ccc(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-6-methyl-pyridin-3-yl)-methyl-amine and 4-fluoro-2-methoxyphenylboronic acid after a reaction time of 14.5 hours at reflux. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown solid (84%). MS (ESI): m/z=247.12 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[C:8]1[C:7]2[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=2[C:5]2[C:4]3[CH:3]=[C:2]([OH:1])[CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Reactant: OB(O)c1cccc(Cl)c1Cl
Product: O=C1NC(=O)c2c1c(-c1cccc(Cl)c1Cl)cc1[nH]c3ccc(O)cc3c21
Yield: 27 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 2,3-dichlorobenzeneboronic acid according to the procedure described in example 8 gave 4-(2,3-dichlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (18) (I, Ar=2,3-dichlorophenyl) in a yield 27%; mp 233–235° C. 1H NMR δ [(CD3)2SO] 11.87 (br, 1H), 11.05 (br, 1H), 9.29 (br, 1H), 8.31 (d, J=2.5 Hz, 1H), 7.74–7.70 (m, 1H), 7.55 (s, 1H), 7.48–7.45 (m, 3H), 7.09 (dd, J=8.7, 2.5 Hz, 1H). Found: C, 59.19; H, 3.04; N, 6.56, C20H10Cl2N2O3.1/2H2O requires C, 59.13; H, 2.73; N, 6.89.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N+:13]([O-])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:14]1[CH:15]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)[CH:11]=[CH:12][N:13]=1
Reactant: CC(C)c1ccc(-c2cc[n+]([O-])cc2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)c1ccc(-c2ccnc(Cl)c2)cc1
Yield: 81 %

Procedure:
Part C. A mixture of 4-(4-isopropyl-phenyl)-pyridine-N-oxide (126 mg, 0.59 mmol) and phosphorus oxychloride (5 mL) is heated to reflux for 12 h. The mixture is cooled and evaporated, and the residue is dissolved in water, neutralized with satd. aq. Na2CO3 and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue is separated by column chromatography to afford 2-chloro-4-(4-isopropyl-phenyl)-pyridine (110 mg, 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1B(O)O.Br[C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:15]1[CH:21]=[CH:20][CH:19]=[C:17]([NH2:18])[CH:16]=1
Reactant: Nc1cccc(Br)c1
Reactant: COc1ccc(B(O)O)c(OC)c1
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
Product: COc1ccc(-c2cccc(N)c2)c(OC)c1
Temperature: 25 °C
Yield: 74 %

Procedure:
2,4-dimethoxyphenyl boronic acid (0.126 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in H20 and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (5-20% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.078 g in 74% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:23][C:24]1[CH:52]=[CH:51][C:27]([CH2:28][N:29]2[CH2:33][CH:32]([CH2:34][CH2:35]OS(C3C=CC(C)=CC=3)(=O)=O)[N:31]([CH2:47][CH2:48][CH3:49])[C:30]2=[O:50])=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:35][CH2:34][CH:32]2[CH2:33][N:29]([CH2:28][C:27]3[CH:51]=[CH:52][C:24]([CH3:23])=[CH:25][CH:26]=3)[C:30](=[O:50])[N:31]2[CH2:47][CH2:48][CH3:49])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: CCCN1C(=O)N(Cc2ccc(C)cc2)CC1CCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCN1C(=O)N(Cc2ccc(C)cc2)CC1CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)OCC)cc1
Temperature: 55 °C
Yield: 68.6 %

Procedure:
A mixture of 3-(4-hydroxy-phenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (0.80 g, 2.66 mmol), toluene-4-sulfonic acid 2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethyl ester (1.26 g, 2.93 mmol) and Cs2CO3 (1.04 g, 3.19 mmol) in DMF (40 mL) is heated to 55° C. under N2 for 17 h. The reaction is cooled and quenched with 1 N HCl (20 mL) and worked up extractively with Et2O and water. The organic layer is dried and the solvent removed to afford crude product that is purified by flash chromatography using 7:1 hexanes:acetone to afford 1.02 g (68%) 2-methyl-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid ethyl ester. The diasteriomeric products were separated by chiral HPLC (90:10 heptane:IPA, 280 mL/min, 220 nm,) to give products in >99% de. Rf=0.49 (1:1 acetone:hexanes). 1H NMR. MS (ES+) Calc'd for C34H43N2O5 (M+1) 559. Found m/z 559 (100%).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2.[CH3:17][C:18]1[C:19](=O)[CH2:20][CH2:21][C:22]=1[CH3:23].Cl.N>C1COCC1>[N:15]1[C:16]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[C:19]2[CH2:20][CH:21]=[C:22]([CH3:23])[C:18]=2[CH3:17])[CH:12]=[CH:13][CH:14]=1
Reactant: CC1=C(C)C(=O)CC1
Reactant: Brc1cccc2cccnc12
Agent: Cl
Agent: N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=CCC(c2cccc3cccnc23)=C1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.4 %

Procedure:
5 ml of n-BuLi (2.5 M in hexane, 12.5 mmol) were added at −95° C. dropwise to a solution of 2.5 g of 8-bromoquinoline (12 mmol) in 120 ml of THF; this was stirred for 15 minutes, and then 1.3 g of 2,3-dimethylcyclopent-2-enone (12 mmol), dissolved in 10 ml of THF, was added. After warming to room temperature, the solution was heated for one hour in ref lux. The cooled reaction mixture was hydrolized with ice, acidified with hydrochloric acid, and then neutralized with ammonia solution. The aqueous phase was extracted with diethyl ether, and the combined organic phases were dried. Distillation at 150° C. and 0.05 mbar yielded 1.1 g of 1-(8-quinolyl)-2,3-dimethylcyclopentadiene (40%) in the form of a yellow, viscous oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.Cl[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH2:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:4][CH2:5]1)=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Clc1cccnc1Cl
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncccc2Cl)CC1
Temperature: 100 °C

Procedure:
A mixture of benzyl 4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, Step 1) (1 g, 4.03 mmol) and 2,3-dichloropyridine (0.25 g) was heated to 100° C. for 12 h. The reaction mixture was cooled and partitioned between EtOAc and pH5.2 citrate buffer. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent evaporated to give a crude product. Purification by flash column chromatography (5–50% EtOAc hexane) afforded the title compound. M.S (M+1): 360.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)=[C:4]([CH3:16])[CH:3]=1.[I:17]I.N(OCCC(C)C)=O>C1(C)C=CC=CC=1>[I:17][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)=[C:4]([CH3:16])[CH:3]=1
Reactant: COc1cccc(-c2ccc(N)cc2C)c1
Reactant: II
Agent: CC(C)CCON=O
Solvent: Cc1ccccc1
Product: COc1cccc(-c2ccc(I)cc2C)c1
Temperature: 90 °C
Yield: 74.2 %

Procedure:
A stirred solution of 4-amino-1-(3-methoxyphenyl)-2-methylbenzene (5.0 gm 23.4 mmol) and iodine (2.97 gm, 25.8 mmol) in toluene (120 mL) was heated to 50° C. and a solution of iso-amyl nitrite (3.46 mL, 25.8 mmol) in toluene (50 mL) was added. The mixture was heated at 90° C. for 2 h and cooled. The toluene was removed under reduced pressure and the residue was dissolved in dichloromethane and washed with excess 5% aqueous sodium metabisulphite to remove iodine. The organic solution was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by repeated flash chromatography (first column gradient elution with hexane:ethyl acetate starting with neat hexane; second column eluted with hexane) to give 4-iodo-1-(3-methoxyphenyl)-2-methylbenzene as a pale orange oil (5.63 gm, 74%).