Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[C:15](Cl)=[CH:14][C:13]([NH2:17])=[C:12]([N+:18]([O-:20])=[O:19])[CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[CH2:1]([O:8][C:15]1[C:10]([Cl:9])=[CH:11][C:12]([N+:18]([O-:20])=[O:19])=[C:13]([NH2:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Nc1cc(OCc2ccccc2)c(Cl)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 36.6 %

Procedure:
Benzyl alcohol (12.5 mL, 0.121 mol), 4,5-dichloro-2-nitro-phenylamine (5.00 g, 24.2 mmol), cesium carbonate (15.7 g, 48.3 mmol), and DMA (110 mL) were combined in a sealable pressure vessel. The vessel was purged with dry nitrogen, sealed, and heated at 80° C. for 17 h. The reaction mixture was poured into brine (400 mL) and cooled to 0° C. The resulting precipitate was collected and dissolved in EtOAc (400 mL). The organic layer was washed with water (50 mL) and brine (50 mL). The organic layers were combined, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (1-50% EtOAc/hexanes, dryloaded) to yield the titled compound (2.47 g, 37% yield). MS (ESI/CI): mass calcd. for C13H11ClN2O3, 278.1; m/z found, 279.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.20 (s, 1H), 7.50-7.30 (m, 5H), 6.23 (s, 1H), 6.19 (br s, 2H), 5.16 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([OH:14])([CH3:13])[C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:15][C@H:16]([C:18]([C:20]1([NH2:40])[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])[C:24]2[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=2[N:22]([CH3:38])[C:21]1=[O:39])=[O:19])[CH3:17]>>[F:8][C:6]1[CH:5]=[C:4]([C:9]([OH:14])([CH3:13])[C:10]([NH:15][C@H:16]([C:18]([C:20]2([NH2:40])[N:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[C:24]3[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=3[N:22]([CH3:38])[C:21]2=[O:39])=[O:19])[CH3:17])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC(O)(C(=O)O)c1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)C1(N)N=C(c2ccccc2F)c2ccccc2N(C)C1=O
Product: C[C@H](NC(=O)C(C)(O)c1cc(F)cc(F)c1)C(=O)C1(N)N=C(c2ccccc2F)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3,5-difluorophenyl-α-hydroxy-α-methylacetic acid (described above in Example 2-18) and 3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-Benzodiazepin-2-one (Example 8-b), the title compound was prepared.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:26][CH:27]=2)=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]([CH:28]3[CH2:33][CH2:32][N:31]([C:8]([NH:7][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][N:1]=4)=[O:15])[CH2:30][CH2:29]3)[S:26][CH:27]=2)=[CH:19][CH:18]=1
Reactant: Fc1ccc(-c2csc(C3CCNCC3)n2)cc1
Reactant: O=C(Nc1cnccn1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1cnccn1)N1CCC(c2nc(-c3ccc(F)cc3)cs2)CC1
Temperature: 70 °C
Reaction time: 6 h
Yield: 69.1 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyrazin-2-ylcarbamate (227 mg, 0.839 mmol), 4-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]piperidine (200 mg, 0.762 mmol) and diisopropylethylamine (0.266 ml, 1.52 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 6 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and ethyl acetate to give the desired product (202 mg, 69.2%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])=[C:8]2[CH3:24])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.O>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH2:19][CH2:20][C:21]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[O:22])=[C:8]2[CH3:24])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(CCCC(=O)O)c(C)n2Cc1ccc(Br)cc1
Reactant: Nc1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(c1)c(CCCC(=O)Nc1ccccn1)c(C)n2Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 21.4 %

Procedure:
To the acid of Example 4, (400 mg, 0.96 mmol) in 30 mL CH2Cl2 at 0° C. was added a few drops of DMF followed by oxalyl chloride (100 μL, 1.15 mmol, dropwise). The reaction was stirred 15 min at 0° C., and then 2-amino pyridine (306 mg, 3.26 mmol) was added. The reaction mixture was stirred overnight at r.t., poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and evaporated in vacuo. Purification by flash chromatography (20%, ethyl acetate in hexane) provided 101 mg of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][NH:2][CH:3]([OH:5])[CH3:4].Cl[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17].C(=O)([O-])O.[Na+].O>C(O)C>[N+:16]([C:8]1[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=1[N:2]([CH:3]([OH:5])[CH3:4])[CH3:1])([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CNC(C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(O)N(C)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
20.3 g of N-methylaminoethanol was dissolved in 100 ml of ethanol and, while stirring, solid 1-chloro-2,4-dinitrobenzene was added to the solution by portions at room temperature. After completion of the addition, 8.4 g of sodium hydrogencarbonate was gradually added to the reaction mixture, followed by stirring for 10-15 minutes at room temperature. Then, the reaction mixture was heated at 60° C. After completion of the reaction, the reaction solution was cooled to room temperature, and poured into 300 ml of water. Continued stirring of the solution yielded a yellowish oily product. Stirring was then discontinued and, after completion of oil formation, the supernatant was removed. After adding water thereto, the solution obtained was stirred and the oil layer formed was collected by separation, and dried to obtain a yellowish oily product. Chemical structure of the product was confirmed by 1H-NMR. Absorptivity coefficient of the product at 365 nm was measured to be 1.79×104 by UV measurement in ethanol. 1H-NMR(CDCl3), TMS standard (400 MHz): 2.22(s,1H), 3.03(s,3H), 3.62(m,2H), 3.92(m,2H), 7.24(d,1H), 8.18(d,1H), 8.63(s,1H).
Reaction SMILES: [CH3:1][Mg]Br.CON(C)[C:7]([C:9]1[N:10]=[C:11]([CH3:18])[O:12][C:13]=1[C:14]([F:17])([F:16])[F:15])=[O:8]>C(OCC)C>[CH3:18][C:11]1[O:12][C:13]([C:14]([F:15])([F:16])[F:17])=[C:9]([C:7](=[O:8])[CH3:1])[N:10]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1nc(C)oc1C(F)(F)F
Solvent: CCOCC
Product: CC(=O)c1nc(C)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.7 %

Procedure:
Under an atmosphere of nitrogen, a solution of methylmagnesium bromide (3M in diethylether; 0.63 ml, 1.89 mmol) was cooled to 0° C. A solution of 2-methyl-5-trifluoromethyl-oxazole-4-carboxylic acid methoxy-methyl-amide (300 mg, 1.26 mmol) in diethylether (3 ml) was added dropwise. The reaction mixture was left to warm to room temperature and stirring was continued for 15 minutes. For the workup, the reaction mixture was cooled to 0° C. and quenched with hydrochloric acid (1N, 3 ml). After 5 minutes of stirring, the mixture was extracted with diethylether. The organic layer was dried over sodium sulphate, then evaporated. The crude product was purified by chromatography on silica gel using a 4:1-mixture of cyclohexane and ethyl acetate as the eluent. The 1-(2-methyl-5-trifluoromethyl-oxazol-4-yl)-ethanone (155 mg, 64% yield) was obtained as a colorless liquid.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[OH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[O:10].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[CH:23]([F:44])[CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[N:31]=[C:32]3[CH2:43][CH2:42][NH:41][CH2:40][C:33]3=[N:34][C:35]=2[NH:36][CH:37]([CH3:39])[CH3:38])[CH2:26][CH2:25]1.N1C=CC=CC=1>C(Cl)Cl>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[CH:23]([F:44])[CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[N:31]=[C:32]3[CH2:43][CH2:42][N:41]([C:5](=[O:7])[CH3:6])[CH2:40][C:33]3=[N:34][C:35]=2[NH:36][CH:37]([CH3:39])[CH3:38])[CH2:26][CH2:25]1.[C:9]([OH:10])([C:11]([F:14])([F:13])[F:12])=[O:8]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(C(F)c3ccc(F)cc3F)CC1)CCNC2
Reactant: CC(=O)OC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCc2nc(N3CCC(C(F)c4ccc(F)cc4F)CC3)c(NC(C)C)nc2C1
Reaction time: 1 h

Procedure:
Acetic anhydride (5 μL, 0.054 mmol) was added to a solution of 2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (14.3 mg, 0.027 mmol) and pyridine (6.5 μL, 0.080 mmol) in DCM (270 μL) at rt. After 1 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (14.3 mg, 93%) as a yellow film. 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.23-1.31 (m, 6H), 1.45 (d, J=12.9 Hz, 1H), 1.53-1.76 (m, 2H), 1.96-2.15 (m, 2H), 2.18 (s, 1.2H), 2.21 (s, 1.8H), 2.67-2.84 (m, 4H), 3.38-3.55 (m, 2H), 3.78-3.83 (m, 1.2H), 3.83-3.87 (m, 0.8H), 4.13 (dq, J=12.6, 6.3 Hz, 1H), 4.56 (s, 0.8H), 4.59 (s, 1.2H), 5.53 (dd, J=46.2, 7.6 Hz, 1H), 6.97-7.09 (m, 2H), 7.47-7.55 (m, 1H); ESI-MS m/z [M+H]+ 462.4.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17](Cl)=[O:18])=[CH:16][C:3]1=2.[CH2:20]([OH:22])[CH3:21]>>[CH2:20]([O:22][C:17]([C:15]1[CH:14]=[CH:13][C:4]2[O:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2](=[O:1])[C:3]=2[CH:16]=1)=[O:18])[CH3:21]
Reactant: CCO
Reactant: O=C(Cl)c1ccc2c(c1)C(=O)c1ccccc1CO2
Product: CCOC(=O)c1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Next, 30.44 g of oxepincarboxylic acid III obtained above was allowed to react with 30 ml of thionyl chloride in 200 ml of toluene by heating under reflux for one hour. Concentration of the reaction mixture to dryness under reduced pressure gave 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-carboxylic acid chloride IV in a quantitative yield. One half of this acid chloride IV was added to 300 ml of ethanol, and the mixture was stirred at room temperature for three hours and concentrated under reduced pressure. The residue was dissolved in chloroform, and the solution was washed with a saturated aqueous solution of sodium bicarbonate, dehydrated and concentrated to dryness to obtain 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-carboxylic acid ethyl ester V in a quantitative yield. Recrystallization from n-hexane gave pure crystals having a melting point of 104°-105° C. IR spectrum (KBr tablet, cm-1): 2980, 1710, 1650, 1610, 1250, 1010.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[C:13]([CH:17]([NH:22][C:23]3[C:32]4[C:27](=[C:28]([C:33]([NH2:35])=[O:34])[CH:29]=[CH:30][CH:31]=4)[N:26]=[CH:25][N:24]=3)[CH2:18][N:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.CC(O)(C)C.CS(C)=O.[NH:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1>O>[CH3:20][N:19]([CH3:21])[CH2:18][CH:17]([NH:22][C:23]1[C:32]2[C:27](=[C:28]([C:33]([NH2:35])=[O:34])[CH:29]=[CH:30][CH:31]=2)[N:26]=[CH:25][N:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([NH:10][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:45]3[CH2:49][CH2:48][CH2:47][CH2:46]3)[CH:7]=2)=[O:9])[CH:12]=1
Reactant: C1CCNC1
Reactant: CN(C)CC(Nc1ncnc2c(C(N)=O)cccc12)c1cccc(NC(=O)c2ccnc(Cl)c2)c1
Solvent: CC(C)(C)O
Solvent: O
Solvent: CS(C)=O
Product: CN(C)CC(Nc1ncnc2c(C(N)=O)cccc12)c1cccc(NC(=O)c2ccnc(N3CCCC3)c2)c1
Temperature: 110 °C
Yield: 35.8 %

Procedure:
To a 10-mL microwave-rated vial with magnetic stir bar at r.t. was added 4-(1-{3-[(2-Chloro-pyridine-4-carbonyl)-amino]-phenyl}-2-dimethylamino-ethylamino)-quinazoline-8-carboxylic acid amide (0.045 g, 0.092 mmol, 1 eq.), t-BuOH (2 mL), DMSO (1 mL), and Pyrrolidine (0.076 mL, 0.92 mmol, 10 eq.). The vial was capped and heated under microwave conditions (50 W, 20 min. ramp, 110° C., STND, 1 hr. hold time) followed by addition of another aliquot of Pyrrolidine (0.1 mL) then microwaved (70 W, 20 min. ramp, 140° C., STND, 1 hr. hold time). Reaction was diluted with water (20 mL) and extracted with EtOAc (3×30 mL). The combined organics were washed with brine, dried (e.g., Na2SO4), filtered and concentrated. The resulting residue was purified via preparative HPLC afforded the desired compound as a white solid (17.3 mg, 36% yield) LCMS (ESI) 525 (M+H).
Reaction SMILES: F[C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[F:12][CH:13]([F:16])[CH2:14][OH:15]>>[F:12][CH:13]([F:16])[CH2:14][O:15][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: Cc1cc(F)ncc1C(=O)O
Reactant: OCC(F)F
Product: Cc1cc(OCC(F)F)ncc1C(=O)O
Yield: 87 %

Procedure:
The title compound is prepared in 87% yield (849 mg, a pale yellow solid) from 6-fluoro-4-methylnicotinic acid (700 mg, 4.51 mmol) and 2,2-difluoroethanol (555 mg, 6.77 mmol) instead of 2,2,2-trifluoroethanol by the similar manner in Step-1 of Amine-1.
Reaction SMILES: [CH3:1][O:2][Si:3]([O:20][CH3:21])([O:18][CH3:19])[CH2:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][CH2:10][Si:11]([O:16][CH3:17])([O:14][CH3:15])[O:12][CH3:13].[CH:22]([N:25]=[C:26]=[N:27][CH:28]([CH3:30])[CH3:29])([CH3:24])[CH3:23]>>[CH3:15][O:14][Si:11]([O:16][CH3:17])([O:12][CH3:13])[CH2:10][CH2:9][CH2:8][N:7]([CH2:6][CH2:5][CH2:4][Si:3]([O:20][CH3:21])([O:18][CH3:19])[O:2][CH3:1])[C:26]([NH:27][CH:28]([CH3:30])[CH3:29])=[N:25][CH:22]([CH3:24])[CH3:23]
Reactant: CO[Si](CCCNCCC[Si](OC)(OC)OC)(OC)OC
Reactant: CC(C)N=C=NC(C)C
Product: CO[Si](CCCN(CCC[Si](OC)(OC)OC)C(=NC(C)C)NC(C)C)(OC)OC
Reaction time: 2 h

Procedure:
A mixture of 30.84 g of bis(3-(trimethoxysilyl)propyl)amine (0.0903 mol) and of 13.68 g of diisopropylcarbodiimide (0.1084 mol, 20% excess) was heated for 31 h at 110° C. (amine conversion of 94%). The final colorless mixture was devolatilized at 100° C. under 2 mbar for 2 h to give 42 g of a colorless, low-viscosity liquid corresponding to the expected guanidine, containing 4% of the initial amine.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[C:28]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH:60]=[CH:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])[CH:27]=1)C(OC(C)(C)C)=O)(C)(C)C.[ClH:71]>C(OCC)(=O)C>[ClH:71].[ClH:71].[ClH:71].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[C:28]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH:60]=[CH:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])[CH:27]=1
Reactant: CCCCCCCCC=CCCCCCCCCOc1ccc(CNCCCCN(CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1OCCCCCCCCC=CCCCCCCCC
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCCCCCC=CCCCCCCCCOc1ccc(CNCCCCNCCCCN)cc1OCCCCCCCCC=CCCCCCCCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A concentrated solution of the amine 18 (0.17 g, 0.17 mmol) in ethyl acetate was added cooled to 0° C. A total of 4 mL of a freshly prepared saturated solution of HCl in ethyl acetate was added dropwise and the solution stirred for 1 h at room temperature during which time a white precipitate formed. The ethyl acetate was removed in vacuo and the residue co-evaporated with ethyl acetate and chloroform to give the product 25 as a white powder (0.151 g, 98%); 1H NMR (CDCl3/CH3OD 9:1) d 7.13 (s, 1H, aryl), 7.02 (d, 1H, aryl), 6.85 (d, 1H, aryl), 5.33 (m, 4H, olefinic), 4.05 (m, 2H, benzylic), 3.97 (t, 2H, OCH2), 3.04 (m, 6H, 3×CH2) 2.93 (m, 2H, CH2), 2.02 (m, 8H, CH2C═C), 1.90 (m, 8H, 4×CH2), 1.81 (m, 4H, CH2CH2O), 1.47 (m, 4H, 2×CH2), 1.40-1.17 (m, 40H, 20×CH2), 0.89 (t, 6H, CH3); 13C NMR (300 MHz, D2O) δ 148.94, 148.33, 129.26, 129.19, 123.64, 122.52, 113.10, 68.50, 68.39, 49.96, 45.98, 45.43, 39.86, 31.28, 29.18, 29.11, 28.93, 28.86, 28.70, 28.62, 26.64, 26.59, 25.68, 25.62, 24.00, 22.54, 22.46, 22.11, 13.89; HRMS (FAB): theory for C51H96N3O2 (M+1), 782.7497; found (M+1), 782.7495; Anal. (C51H95Cl3N3O2.0.6H2O): C, H, N.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][CH2:10][CH2:11][N:12]1[CH2:18][C@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:16][CH2:15][C@@H:14]([NH:25]C(=O)OC(C)(C)C)[C:13]1=[O:33]>ClCCl>[NH2:25][C@@H:14]1[CH2:15][CH2:16][C@@H:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:18][N:12]([CH2:11][CH2:10][O:9][CH3:8])[C:13]1=[O:33]
Reactant: COCCN1C[C@H](c2ccccc2)CC[C@@H](NC(=O)OC(C)(C)C)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCN1C[C@H](c2ccccc2)CC[C@@H](N)C1=O
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (2.5 mL) was added to a solution of tert-butyl (3R,6S)-1-(2-methoxyethyl)-2-oxo-6-phenylazepan-3-ylcarbamate (41 mg, 0.113 mmol) in dichloromethane (5 mL). After 1 h, the solution was concentrated. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 263 (M+1). 1H NMR (500 MHz, CDCl3) δ 7.32 (t, J=7.3 Hz, 2H), 7.25-7.22 (m, 1H), 7.18 (d, J=8.3 Hz, 2H), 3.83-3.76 (m, 3H), 3.56-3.49 (m, 3H), 3.35 (s, 3H), 3.34-3.30 (m, 1H), 2.77-2.72 (m, 1H), 2.13-2.10 (m, 1H), 2.03-1.94 (m, 2H), 1.74-1.68 (m, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](I)[CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN(C=O)C.CNCCNC>[Cu]I>[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Ic1cccc(OCc2ccccc2)c1
Reactant: c1nc[nH]n1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: c1ccc(COc2cccc(-n3cncn3)c2)cc1
Reaction time: 24 h

Procedure:
To a sealable pressure tube, were added CuI (31 mg, 0.16 mmol), 1H-1,2,4-triazole (245 mg, 3.55 mmol), Potassium phosphate (1.37 g, 6.45 mmol), 1-(benzyloxy)-3-iodobenzene (1 g, 3.22 mmol), and a stir bar. The reaction vessel was fitted with a rubber septum, evacuated and back-filled with argon, and this sequence was repeated. DMF (3.22 mmol) and N,N′-dimethylethylene diamine (28 mg, 0.322 mmol) were then added successively under a stream of argon. The reaction tube was crimp sealed with a fresh PTFE septum (caution: build-up of pressure possible; use a safety shield) and immersed in a preheated oil bath at 110° C. for 24 h with magnetic stirring. The reaction mixture was removed from heating, allowed to attain ambient temperature, diluted with ethyl acetate (2-3 mL), filtered through a plug of silica gel, and eluted with additional ethyl acetate (10-20 mL). The filtrate was concentrated and the resulting residue was purified by chromatography on silica gel (80 gram biotage silica gel cartridge, 40-60% EtOAc hexanes) to provide the desired product as white solid. LRMS calc: 251.3; obs: 252.4 (M+1).
Reaction SMILES: [I-].C([N+:9]1(C)[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:10]1)C1C=CC=CC=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])N.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C>[C:17]1([CH3:22])[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH:11]1[C:12](=[O:15])[CH2:13][CH2:14][N:9]([C:28]2[CH:30]=[C:31]([O:35][CH3:36])[C:32]([O:33][CH3:34])=[C:26]([O:25][CH3:24])[CH:27]=2)[CH2:10]1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: Cc1ccccc1C1C[N+](C)(Cc2ccccc2)CCC1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1cc(N2CCC(=O)C(c3ccccc3C)C2)cc(OC)c1OC
Yield: 78.3 %

Procedure:
A slurry of 1-benzyl-1-methyl-4-oxo-3-o-tolyl-piperidinium iodide (1000 mg) in water (5 ml) was added in one portion to a refluxing solution of 3,4,5-trimethoxy aniline (395 mg) and anhydrous potassium carbonate (37 mg) in ethanol (10 ml). The reaction was heated to reflux over night. Water was added and the reaction was extracted four times with DCM. The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated to leave a red-brown oil, which was purified by flash chromatography (diethyl ether) to give the product as a yellow oil (600 mg). MS (ESI): 356.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CCCCCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[CH:14]=[CH:15][C:10]([Br:9])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: Clc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Clc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 90 °C
Yield: 45 %

Procedure:
A mixture of 4-chloro-iodobenzene (0.99 g, 4.15 mmol), (4-bromophenyl)boronic acid (1.0 g, 4.98 mmol), anhydrous potassium carbonate (860 mg, 6.22 mmol) and dichlorobis(triphenylphosphine) palladium (II) (87 mg, 0.12 mmol) in toluene (40 ml) was heated at 90° C. for 4 hours under an argon atmosphere. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane (50 ml). The organic solution was washed successively with 1M hydrochloric acid (2×30 ml), saturated aq. sodium hydrogen carbonate (2×30 ml) and brine, dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure to leave an orange solid, which was purifed by trituration with ethyl acetate-hexane (1:6) to provide 4'-chloro-4-bromo-biphenyl (0.5 g, 45%) as a pale orange solid. 1H-NMR; δ (CDCl3) 7.49 (m).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:37])=[C:11]([N:14]4[CH2:19][CH2:18][CH:17]([CH2:20][O:21][C:22]5[CH:27]=[CH:26][C:25]([N:28]6[CH2:32][C@H:31]([CH2:33][OH:34])[O:30][C:29]6=[O:35])=[CH:24][C:23]=5[F:36])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:38])[C:6]([C:39]([OH:41])=[O:40])=[CH:5]2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[CH:48]1[CH:53]=[CH:52][C:51]([CH2:54]Br)=[CH:50][CH:49]=1>CN(C=O)C>[CH2:54]([O:40][C:39]([C:6]1[C:7](=[O:38])[C:8]2[C:13](=[CH:12][C:11]([N:14]3[CH2:15][CH2:16][CH:17]([CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:32][C@H:31]([CH2:33][OH:34])[O:30][C:29]5=[O:35])=[CH:24][C:23]=4[F:36])[CH2:18][CH2:19]3)=[C:10]([F:37])[CH:9]=2)[N:4]([CH:1]2[CH2:3][CH2:2]2)[CH:5]=1)=[O:41])[C:51]1[CH:52]=[CH:53][CH:48]=[CH:49][CH:50]=1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCC(COc4ccc(N5C[C@H](CO)OC5=O)cc4F)CC3)c(F)cc2c1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cn(C2CC2)c2cc(N3CCC(COc4ccc(N5C[C@H](CO)OC5=O)cc4F)CC3)c(F)cc2c1=O
Temperature: 80 °C
Reaction time: 24 h
Yield: 90.6 %

Procedure:
A solution of the compound of Example 2 (600 mg) in DMF (10 mL) was treated with K2CO3 (155 mg) and BnBr (160 μl) and stirred at 80° C. for 24 h. The solvent was evaporated under reduced pressure and the residue was worked up (DCM). The residue was stirred in ether (100 mL) and the resulting crystals were collected by filtration affording 612 mg (90.6% yield) of an off-white solid.