Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[K].[CH3:16]C(C)([O-])C.CI>CS(C)=O>[CH3:16][N:13]1[CH:14]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[N:11]=[CH:12]1
Reactant: CC(C)(C)[O-]
Reactant: O=[N+]([O-])c1ccc(-c2c[nH]cn2)cc1
Agent: [K]
Solvent: CS(C)=O
Solvent: CI
Product: Cn1cnc(-c2ccc([N+](=O)[O-])cc2)c1

Procedure:
Prepared by reacting 4-(4-nitro-phenyl)-imidazole in DMSO with potassium-tert.butoxide at 0° C. and then with methyliodide at 20-25° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[C:12]3[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=[C:16]([C:17]4[CH:18]=[N:19][C:20]([N:23]([CH2:33][C:34]5[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=5)[CH2:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)=[N:21][CH:22]=4)[C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].[NH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1.C(N1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2)C(C)C>C1(C)C=CC=CC=1.O>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:23]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:20]2[N:19]=[CH:18][C:17]([C:16]3[C:11]4[CH2:10][CH2:9][N:8]([C:6]5[CH:5]=[CH:4][N:3]=[C:2]([N:54]6[CH2:59][CH2:58][O:57][CH2:56][CH2:55]6)[CH:7]=5)[C:12]=4[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=3)=[CH:22][N:21]=2)=[CH:26][CH:27]=1
Reactant: C1COCCN1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccnc(Cl)c3)cn2)cc1
Agent: CC(C)(C)[O-]
Agent: CC(C)CN1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccnc(N4CCOCC4)c3)cn2)cc1
Temperature: 110 °C
Reaction time: 0.08 h

Procedure:
To a solution of {5-[7-(2-chloro-pyridin-4-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine (50 mg) obtained in Step A, sodium t-butoxide (50 mg) and palladium dibenzylideneacetone complex (6 mg) suspended in toluene (1.5 ml), argon gas was blown for 5 minutes. Morpholine (10 μl) and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane (6.9 mg) were added, followed by stirring at 110° C. for 6 hours. The reaction mixture was cooled to room temperature, and water (5 ml) was added, followed by extraction with dichloromethane (10 ml×2). The combined organic layers were washed with brine, and dried over sodium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane/methanol=50/1), to obtain a yellow amorphous (46 mg, 85%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH2:10].[CH:11](C1C=CC=CC=1C)(C)C.ClCC1C(Cl)=C(C(C)C)C=CC=1>>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([CH3:11])=[CH2:10]
Reactant: C=Cc1ccccc1CCl
Reactant: Cc1ccccc1C(C)C
Agent: CC(C)c1cccc(CCl)c1Cl
Product: C=C(C)c1ccccc1CCl

Procedure:
Finally the art teaches in U.S. Pat. No. 2,780,604 that chloromethyl vinyl benzene can be prepared via a two step liquid phase reaction whereby isopropyl toluene is chlorinated via ultraviolent light and the subsequently distilled chloromethyl chloroisopropyl benzene is dehydrohalogenated with heat to give chloromethylisopropenylbenzene.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]2[C:9](Br)=[CH:10][CH:11]=[CH:12][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[CH2:14]([O:17][C:18]1[C:23]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:22][C:21]([CH2:28][CH3:29])=[CH:20][C:19]=1B(O)O)[CH2:15][CH3:16].C(O)C.C([O-])([O-])=O.[Na+].[Na+]>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>[C:1]([C:4]1[O:8][C:7]2[C:9]([C:19]3[CH:20]=[C:21]([CH2:28][CH3:29])[CH:22]=[C:23]([C:24]([CH3:26])([CH3:25])[CH3:27])[C:18]=3[O:17][CH2:14][CH2:15][CH3:16])=[CH:10][CH:11]=[CH:12][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc2cccc(Br)c2o1
Reactant: CCCOc1c(B(O)O)cc(CC)cc1C(C)(C)C
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: Cc1ccccc1
Solvent: CCO
Product: CCCOc1c(-c2cccc3cc(C(C)=O)oc23)cc(CC)cc1C(C)(C)C
Temperature: 25 °C

Procedure:
To a mixture of 57 mg (0.049 mmol, 5%) of Pd(PPh3)4, 362 mg (1.26 mmol) of 2-acetyl-7-bromobenzo[b]furan and 2.52 mmol of 2-propoxy-3-tert-butyl-5-ethyl phenylboronic acid in 10 mL of toluene, and 5 mL of ethanol was added 1.3 mL of a 2N Na2CO3 aqueous solution. The mixture was heated to reflux for 3 hours and after cooling (room temperature) extracted with ethyl acetate. The organic layer was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was filtrated over a short silica plug (eluent: ethyl acetate/hexane: 10/90) and recrystallized from hexane to afford 2-acetyl-7-(2-propoxy-3-tert-butyl-5-ethylphenyl)benzo[b]furan as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([C:14]1([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:17][CH2:16][CH2:15]1)[NH:7][CH2:6][CH2:5]2.[C:25]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1>C1(C)C=CC=CC=1>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:14]2([CH:8]3[C:9]4[C:4](=[CH:3][C:2]([N:35]5[CH2:34][CH2:33][N:32]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:37][CH2:36]5)=[C:11]([O:12][CH3:13])[CH:10]=4)[CH2:5][CH2:6][NH:7]3)[CH2:15][CH2:16][CH2:17]2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc2c(cc1Br)CCNC2C1(c2ccc(Cl)cc2)CCC1
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1N1CCN(C(=O)OC(C)(C)C)CC1)CCNC2C1(c2ccc(Cl)cc2)CCC1

Procedure:
A solution of 6-bromo-1-[1-(4-chlorophenyl)cyclobutyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline (203 mg, 0.5 mmol), Boc-piperazine (93 mg, 0.5 mmol), tris(benzylideaceton)dipalladium (18 mg, 0.02 mmol), sodium-tert-butylate (48 mg, 0.5 mmol) and 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine 815.7 mg, 0.04 mmol) under nitrogen in toluene (5 ml) was heated in the microwave to 120° C. for 10 minutes. The solvent was removed, the residue dissolved in methylenehloride and extracted with water. The methylenehloride was evaporated and the remaining solid purified by chromatography. Yield: 56 mg (0.1 mmol, 20%)
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][CH:13]=[C:12]([CH3:15])[C:11]=2[CH:16]=1.F[S:18]([C:21]1[N:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)(=[O:20])=[O:19]>C1COCC1>[CH3:28][O:27][C:24]1[N:23]=[N:22][C:21]([S:18]([C:13]2[O:14][C:10]3[CH:9]=[CH:8][C:7]([F:6])=[CH:16][C:11]=3[C:12]=2[CH3:15])(=[O:20])=[O:19])=[CH:26][CH:25]=1
Reactant: Cc1coc2ccc(F)cc12
Reactant: COc1ccc(S(=O)(=O)F)nn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)c2oc3ccc(F)cc3c2C)nn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (2.5 M in hexane, 11 mmol, 4.83 mL) was added dropwise over 15 minutes to a solution of 5-fluoro-3-methyl benzofuran (11 mmol, 1.65 mg) in THF (20 mL) cooled to −78° C. To this was added 3-fluorosulfonyl-6-methoxy-pyridazine (11 mmol, 2.11 g) and stirred for 30 minutes. The reaction mixture was allowed to come to room temperature overnight and was then quenched with EtOAc (40 mL) and H2O (10 mL). The organic portion was collected, dried, filtered and the filtrate was evaporated to dryness to obtain a crude product, which was purified by silica gel chromatography (eluent: hexanes:EtOAc::4:1) to obtain the desired product: 3-methoxy-6-(5-fluoro-3-methyl-benzofuran-2-sulfonyl)-pyridazine (22%, 781 mg).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>C(OCC)(=O)C>[Cl:10][CH2:11][C:12]1[N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:8][CH:14]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1ccccc1
Solvent: CCOC(C)=O
Product: ClCc1coc(-c2ccccc2)n1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
Benzamide (1.21 g, 10 mmol) is mixed with 1,3-dichloroacetone (1.26 g, 10 mmol) and the mixture heated to 130° C. and stirred at this temperature for 1 h. The resulting mixture is then cooled, diluted with ethyl acetate, washed with K2CO3 solution (sat.), then brine, dried over MgSO4 and concentrated to give the title compound as a solid, which is used without further purification. MS (ESI) 194 (M+H, Cl pattern)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]([F:46])([F:45])[C:9]1[CH:10]=[C:11]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:12][NH:13][CH2:14][C:15]1[C:16]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:27][CH2:26]2)=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.Cl[C:48]([O:50][CH2:51][CH3:52])=[O:49].O>C1COCC1>[CH2:51]([O:50][C:48](=[O:49])[N:13]([CH2:12][C:11]1[CH:38]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:40]=[C:9]([C:8]([F:7])([F:45])[F:46])[CH:10]=1)[CH2:14][C:15]1[C:16]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]3)[CH2:27][CH2:26]2)=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:52]
Reactant: FC(F)(F)c1cc(CNCc2cc3ccccc3nc2N2CCN(CC3CCCCC3)CC2)cc(C(F)(F)F)c1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc2ccccc2nc1N1CCN(CC2CCCCC2)CC1
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
Anhydrous potassium carbonate (0.17 g, 1.23 mmol) was added to a solution of (3,5-bis-trifluoromethyl-benzyl)-[2-(4-cyclohexylmethyl-piperazin-1-yl)-quinolin-3-yl-methyl]-amine (0.23 g, 0.4 mmol) in anhydrous THF (5 mL). After stirring 0.5 h, ethyl chloroformate (0.06 mL, 0.6 mmol) was added slowly under a nitrogen atmosphere. After stirring at RT for overnight, water (25 mL) was added, and the mixture was extracted with ethyl acetate (3×25 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a colorless liquid. Purification by silica gel chromatography and eluting with 10-30% ethyl acetate/hexane afforded the desired final product as a viscous liquid (0.206 g), yield: 81%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O[CH:27]1[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(P(CCCC)CCCC)CCC>O1CCCC1>[CH2:35]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH:27]1[O:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: OC1Cc2ccccc2C1
Reactant: COc1ccc(-c2nc(CNC(=O)c3ncccc3C)co2)cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(CNC(=O)c3ncccc3C)co2)cc1OC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 170 mg quantity of the N-[2-(3-hydroxy-4-methoxy phenyl)oxazol-4-ylmethyl]-3-methylpicolinamide obtained in Example 17 was dissolved in 10 ml of tetrahydrofuran. To the obtained solution were added 134 mg of 2-hydroxyindane, 0.5 ml of diisopropyl azodicarboxylate (40% toluene solution) and 202 mg of tri(n-butyl)phosphine, and the mixture was stirred at room temperature overnight, and at 50° C. for 2.5 hours. To the reaction mixture were added 100 mg of 2-hydroxyindane, 0.5 ml of diisopropyl azodicarboxylate (40% toluene solution) and 200 mg of tri(n-butyl)phosphine, and the mixture was stirred at 50° C. for 5 hours, and at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate:methylene chloride=1:1:1) to give 92 mg of N-{2-[3-(indan-2-yloxy)-4-methoxyphenyl]oxazol-4-ylmethyl}-3-methylpicolinamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[C:11]([O:19][CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][CH:23]([C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29])[O:24][CH3:25]>>[CH3:21][O:22][CH:23]([C:26]1[CH:27]=[C:28]([NH:29][C:16](=[O:18])[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[O:19][CH3:20])[CH:30]=[CH:31][CH:32]=1)[O:24][CH3:25]
Reactant: COc1cc(OCc2ccccc2)ccc1CC(=O)O
Reactant: COC(OC)c1cccc(N)c1
Product: COc1cc(OCc2ccccc2)ccc1CC(=O)Nc1cccc(C(OC)OC)c1
Yield: 51 %

Procedure:
Using an analogous procedure to that described in Example 1, 2-(4-benzyloxy-2-methoxyphenyl)acetic acid was reacted with 3-(1,1-dimethoxymethyl)aniline to give N-[3-(1,1-dimethoxymethyl)phenyl]-2-(4-benzyloxy-2-methoxyphenyl)acetamide in 51% yield. The compound was obtained as a mixture of the dimethoxyacetal and the corresponding aldehyde.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16](=[O:31])[CH2:17][NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>CO>[F:29][C:26]([F:27])([F:28])[C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][CH2:17][C:16]([NH:15][CH2:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:31])=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCNCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.7 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (2.29 g, 5.16 mmol) in CH3OH (40 mL) was treated with 1 N HCl-Et2O (55 mL). The reaction mixture was stirred at 25° C. for 15 h and the solvent was removed under reduced pressure. 2 N aqueous NaOH solution (100 mL) was added to the reaction mixture and the mixture was extracted with EtOAc (3×100 mL). The combined extracts were washed with brine and dried (K2CO3). The solvent was removed under reduced pressure to afford a white solid which was purified by column chromatography (SiO2, CH3OH/CH2Cl2/Et3N=7/6/1)) to give 4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine as a white solid (1.27 g, 72%): The purity was determined by RPLC/MS (98%); ESI/MS m/e 344.1 (M++H, C16H20F3N3O2).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C@@H:9]([CH3:17])[CH2:10][CH2:11][CH:12]2[O:14]C2(C)C)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)=O.I([O-])(=O)(=O)=O.[K+]>O>[CH:1]1([CH2:7][CH2:8][C@@H:9]([CH3:17])[CH2:10][CH2:11][CH:12]=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@H](CCC1CCCCC1)CCC1OC1(C)C
Agent: [K+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: C[C@@H](CCC=O)CCC1CCCCC1
Reaction time: 46 h
Yield: 81.1 %

Procedure:
A flask was charged with 10.65 g (44.7 mmol) of 3-((R)-5-cyclohexyl-3-methyl-pentyl)-2,2-dimethyl-oxirane, 70 mL of acetone, 12.3 g (53.6 mmol) of potassium periodate, 70 mL of water, and 0.765 g (4 mmol) of tosic acid-monohydrate. The mixture was stirred for 46 hours. The acetone was removed under reduced pressure, and the mixture was diluted with water. The aqueous layer was extracted with hexanes and dried with sodium sulfate. The drying agent was filtered off and solvent was removed under reduced pressure to get 7.12 g (81% yield) of a clear oil: 1H NMR (400 MHz, CDCl3) ppm 0.87 (m, 5H) 1.13 (m, 3H) 1.25 (m, 5H) 1.66 (m, 8H) 2.40 (m, 2H) 9.75 (s, 1H). MS (APCI) m+1/z is inconclusive.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:4](O)=[N:5][CH:6]=[C:7]([Br:9])[CH:8]=1.C1(P(Cl)([Cl:21])=O)C=CC=CC=1>>[Cl:21][C:4]1[C:3]([C:2]([F:12])([F:11])[F:1])=[CH:8][C:7]([Br:9])=[CH:6][N:5]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: Oc1ncc(Br)cc1C(F)(F)F
Product: FC(F)(F)c1cc(Br)cnc1Cl
Temperature: 135 °C
Reaction time: 4 h

Procedure:
The product of Example 5 (11.5 g, 0.048 mol) and phenylphosphoryl dichloride (45 mL) were heated with stirring at 135° C. for four hours and allowed to cool to room temperature. The reaction mixture was poured onto ice (750 g) and allowed to warm to room temperature. The mixture was extracted with dichloromethane (150 mL) and filtered. The organic phase was separated, washed with water and 10% sodium carbonate solution and dried over anhydrous sodium sulphate. Evaporation of the solvent gave 2-chloro-3-trifluoromethyl-5-bromopyridine (11.6 g) as a yellow oil.
Reaction SMILES: [CH3:1][NH2:2].S(C1C=CC(C)=CC=1)(O[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([F:31])([F:30])[C:14]([F:29])([F:28])[C:15]([F:27])([F:26])[C:16]([F:25])([F:24])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])(=O)=O>O1CCCC1>[CH3:1][NH:2][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([F:31])([F:30])[C:14]([F:29])([F:28])[C:15]([F:27])([F:26])[C:16]([F:25])([F:24])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19]
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Solvent: C1CCOC1
Product: CNCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
3.23 g of methylamine is condensed in a solution of 4.33 g of 7,7,8,8,9,9,10,10,11,11,12,12,12-tridecafluoro-dodecyl tosylate in 10 ml of absolute tetrahydrofuran at −20° C., and it is stirred overnight in a pressure vessel at room temperature. After the pressure vessel was opened at −20° C., it is allowed to come to room temperature to allow excess methylamine to evaporate off. The reaction solution is taken up in dichloromethane, washed with water, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 3.2 g of methyl-(7,7,8,8,9,9,10,10,11,11,12,12,12-tridecafluoro-dodecyl)-amine is obtained as a crude product.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]2[S:11][C:12]([CH:15]=[N:16][OH:17])=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Cl:20]N1C(=O)CCC1=O.O>CN(C)C=O>[OH:17][N:16]=[C:15]([Cl:20])[C:12]1[S:11][C:10]([O:9][C:8]2[CH:18]=[CH:19][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[N:14][CH:13]=1
Reactant: CC(C)Oc1ccc(Oc2ncc(C=NO)s2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(Oc2ncc(C(Cl)=NO)s2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.5 %

Procedure:
To a solution of Example 1D (7.77 g, 0.028 mol) in N,N-dimethylformamide was added N-chlorosuccinimide (4.0 g, 0.029 mol) and the solution was stirred at room temperature for 6 hours. Water was added and the reaction mixture stirred for 30 minutes. The precipitate was filtered and air-dried to give 8.45 g of product as an off-white solid (96% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.28 (d, J=5.88 Hz, 6H) 4.53-4.70 (m, 1 H) 6.95-7.07 (m, 2H) 7.26-7.37 (m, 2H) 7.67 (s, 1H) 12.41 (s, 1H). MS (ESI) m/z 294.0 (M−18)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH3:19])[CH:10]=1.[OH:20][C:21]1[CH:41]=[CH:40][C:24]([C:25]([NH:27][CH2:28][C@H:29]([N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[C:30]([O:32][CH3:33])=[O:31])=[O:26])=[CH:23][CH:22]=1>CC(=O)CC.[I-].[K+]>[CH3:19][C:11]1[CH:10]=[C:9]([CH2:8][O:20][C:21]2[CH:41]=[CH:40][C:24]([C:25]([NH:27][CH2:28][C@H:29]([N:34]3[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]3)[C:30]([O:32][CH3:33])=[O:31])=[O:26])=[CH:23][CH:22]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: Cc1cc(CCl)c2ccccc2n1
Reactant: COC(=O)[C@H](CNC(=O)c1ccc(O)cc1)N1CCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)[C@H](CNC(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1)N1CCCCC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
270 mg (1.9 mmol) of potassium carbonate then 380 mg (1.9 mmol) of 4-chloromethyl-2-methylquinoline and 15 mg of potassium iodide are added to a solution of 500 mg (1.6 mmol) of methyl (S)-3-(4-hydroxybenzoyl-amino)-2-piperidin-1-ylpropanoate in 15 ml of 2-butanone. The reaction medium is stirred at 80° C. for 18 h. After filtration, the filtrate is concentrated under vacuum. The crude product is purified by chromatography over silica gel eluted with a 50/50 heptane/ethyl acetate mixture. 620 mg (83%) of methyl (S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzoylamino]-2-piperidin-1-ylpropanoate are obtained in the form of a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[F:12].[NH2:13][CH2:14][C:15]([O-:17])=[O:16].[Na+:18]>CN(C=O)C.O>[Na+:18].[Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:13][CH2:14][C:15]([O-:17])=[O:16])[CH:7]=1
Reactant: NCC(=O)[O-]
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C([O-])CNc1cc(Br)c(F)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
To a stirred solution of 1-bromo-2,5-difluoro-4-nitrobenzene (1.100 g, 4.622 mmol, as prepared above) in DMF (11.0 mL) at 70° C., was added, dropwise, a solution of sodium glycinate (0.451 g, 4.65 mmol, Aldrich, used as received) in water (5.0 mL). The resulting solution was stirred overnight at 70° C. The solution was cooled to room temperature and the bright orange solid was filtered, washed with cold acetone (10 mL) and dried under vacuum to give 0.469 g (35%) of the title compound as a bright orange powder; 1H NMR (DMSO-d6): δ 3.458 (d, 2H, J=3.9 Hz), 7.148 (d, 1H, J=6.0 Hz), 7.944 (d, 1H, J =9.3 Hz), 8.740 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.Br[C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:16]=1[C:17]([OH:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].O>[N+](C1C=CC=CC=1)([O-])=O.[Cu]=O>[C:17]([C:16]1[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[CH:23][C:15]=1[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)[C:2]([CH3:1])=[N:3]1)([OH:19])=[O:18]
Reactant: Cc1n[nH]c2cc([N+](=O)[O-])ccc12
Reactant: COc1cccc(Br)c1C(=O)O
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1cccc(-n2nc(C)c3ccc([N+](=O)[O-])cc32)c1C(=O)O
Yield: 75.9 %

Procedure:
3-Methyl-6-nitroindazole (5.31 g), 6.93 g of 2-bromo-6-methoxybenzoic acid, 4.71 g of potassium carbonate and 0.218 g of copper (II) oxide were stirred in 60 ml of nitrobenzene at 180° C. for 50 minutes. After cooling, 300 ml of water was added to the reaction mixture, and the insoluble substance was removed by filtration. The resulting solution was washed with chloroform. The aqueous layer was decolored with active charcoal and filtered, and 40 ml of 1 N hydrochloric acid aqueous solution was added to the filtrate. The crystals precipitated were separated by filtration and dried under reduced pressure to obtain 7.45 g (75.9%) of 1-(2-carboxy-3-methoxyphenyl)-3-methyl-6-nitroindazole.