Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH:27]1([CH2:31][C:32](O)=[O:33])[CH2:30][CH2:29][CH2:28]1>>[CH:27]1([CH2:31][C:32]([NH:26][C@H:23]2[CH2:22][CH2:21][C@H:20]([CH2:19][CH2:18][N:15]3[CH2:16][CH2:17][CH:12]([C:11]4[C:6]5[CH2:5][CH2:4][O:3][C:7]=5[CH:8]=[CH:9][CH:10]=4)[CH2:13][CH2:14]3)[CH2:25][CH2:24]2)=[O:33])[CH2:30][CH2:29][CH2:28]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)CC1CCC1
Agent: Cl
Product: O=C(CC1CCC1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (53 mg, 50%), MS (ISP) m/z=425.3 [(M+H)+], mp 196° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydro chloride (intermediate B) (100 mg, 0.25 mmol) and 2-cyclobutyl-acetic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].S(C1C=CC(C)=CC=1)(O[CH2:14][C:15]([F:18])([F:17])[F:16])(=O)=O>>[F:16][C:15]([F:18])([F:17])[CH2:14][NH:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: Cc1ccc(O)cc1N
Product: Cc1ccc(O)cc1NCC(F)(F)F
Reaction time: 5 h

Procedure:
3-Amino-4-methylphenol (9.84 g; 0.08 mole) and trifluoroethyl tosylate (20.32 g; 0.08 mole) were mixed in a 500 ml round-bottomed flask and the flask purged with nitrogen. A short air condenser was added, the nitrogen stream was slowed and located towards the top of the condenser, and the flask was immersed in an oil bath at 200° C. A temperature in the range of 150°-250° C. is acceptable. After the molten reagents had been swirled to complete mixing, the heating was continued for five hours. The flask was allowed to cool and before the mixture had solidified, it was dispersed and dissolved in 200 ml of chloroform. Over four days a light brown precipitate of the tosylate salt of 3-amino-4-methylphenol appeared which was filtered off and recovered. The chloroform was extracted with 10% aqueous sodium hydroxide and the dark brown aqueous phase was extracted with chloroform 50 ml. Ice and concentrated hydrochloric acid (21 ml) were added to the aqueous phase and the brown oil was extracted into chloroform 100 ml plus 50 ml. The chloroform solution was washed with 1N hydrochloric and the chloroform layer was separated, dried with sodium sulfate, filtered and evaporated to give a brown gum that crystallized over a day 8.0 g (49%). Recrystallization from petroleum ether 60/80 gave white, fluffy needles mp. 64°-65°. NMR (deuterodimethylsulfoxide): δ8.86 (s, 1H, OH); 6.8-5.9 (m, 3H, ring protons) resolved as AB quartet at 6.74 (C-5 CH) and 6.01 (C-6 CH), J=8.0 Hz together with 6.13 (d, 1H, J=1.0 Hz, C-2 CH) which in turn coupled with the high-field half of the AB quartet; 5.33 (t, 1H, J=6.8 Hz, N-H); 4.0-3.7 (m, 2H, CH2) resolved as two quadruplets, JCF3, CH2 =9.6 Hz, JCH2, NH =6.8 Hz; 1.99 (s, 3H, CH3). Anal. calc. for C9H10F3NO: C, 52.68; H, 4.91; N, 6.83. Found: C, 52.58; H, 4.99; N, 6.80.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]2[C:16](Cl)=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][O:27][CH2:28][CH2:29][NH2:30]>CS(C)=O.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]2[C:16]([NH:30][CH2:29][CH2:28][O:27][CH3:26])=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCN
Reactant: FC(F)(F)c1ccc(-c2ccnc(OCc3ccccc3)c2)c(Cl)n1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COCCNc1nc(C(F)(F)F)ccc1-c1ccnc(OCc2ccccc2)c1
Temperature: 40 °C
Reaction time: 72 h

Procedure:
-(2-(Benzyloxy)pyridin-4-yl)-N-(2-methoxyethyl)-6-(trifluoromethyl)-pyridin-2-amine. To a 2.5-mL microwave vial was added 3-(2-(benzyloxy)-pyridin-4-yl)-2-chloro-6-(trifluoromethyl)pyridine (0.50 g, 1.37 mmol) and 2-methoxyethylamine (0.59 g, 6.58 mmol, Fluka) in 2 mL of DMSO. The vial was sealed and left to stir at 40° C. for 3 d and then heated at 120° C. for 5 h. The reaction mixture was allowed to cool to room temperature and was diluted with EtOAc (20 mL). The organic layer was washed with saturated NaCl (2×30 mL), dried over Na2SO4, filtered, and concentrated to afford a yellow oil. The crude material was purified by normal phase column chromatography (gradient: 5%-20% EtOAc/Hexanes) to give 3-(2-(benzyloxy)pyridin-4-yl)-N-(2-methoxyethyl)-6-(trifluoromethyl)pyridin-2-amine as a clear oil [MS (ESI, pos. ion) m/z: 404 (M+1)].
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[CH3:16])=[O:5].[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=1.C(O)C>[Pd].O>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([N:6]([C:4](=[O:5])[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=2[F:1])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:8]([CH3:16])[CH:9]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1NC(=O)c1ccccc1F
Reactant: C1=CCCCC1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: Cc1cc(N)ccc1N(C(=O)c1ccccc1F)c1ccccc1
Temperature: 4 °C

Procedure:
A mixture of 2-fluoro-N-(2-methyl-4-nitrophenyl)benzamide (4.55 g), cyclohexene (30 mL), ethanol (70 mL), water (30 mL) and 10% palladium on charcoal (3 g) is heated at reflux for 30 minutes. The mixture is filtered through diatomaceous earth and concentrated under reduced pressure. The resulting oil is dissolved in 50 mL of ethyl acetate and cooled at 4° C. for 12 hours. Filtration provides the product as a tan solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:23]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([CH:10]4[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]4)=[N:7][C:6]=3[CH:23]=2)=[CH:28][CH:27]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(Br)ccc3o2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(C(F)(F)F)cc4)ccc3o2)CC1
Yield: 23 %

Procedure:
Following the General Procedure-1, the titled compound (40 mg) was prepared from Intermediate 7 (150 mg, 0.4 mmol) and 4-(trifluoromethyl)phenylboronic acid (74 mg, 0.39 mmol) as an off-white solid. M.P.: 166-169° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.88 (d, J 1.2, 1H), 7.73-7.67 (m, 4H), 7.59-7.52 (m, 2H), 4.15 (d, J 10, 2H), 3.20-3.10 (m, 1H), 3.00 (t, J 11.6, 2H), 2.21-2.12 (m, 2H), 1.99-1.86 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]=[CH:6][C:5]=2[N:4]=[C:3]1[CH3:15].[OH:17][S:18](O)(=[O:20])=[O:19]>[OH-].[Na+]>[S:18]([C:13]1[CH:12]=[CH:11][C:9]2[C:10]3[C:2]([CH3:16])([CH3:1])[C:3]([CH3:15])=[N:4][C:5]=3[CH:6]=[CH:7][C:8]=2[CH:14]=1)([OH:20])(=[O:19])=[O:17]
Reactant: O=S(=O)(O)O
Reactant: CC1=Nc2ccc3ccccc3c2C1(C)C
Agent: [Na+]
Agent: [OH-]
Product: CC1=Nc2ccc3cc(S(=O)(=O)O)ccc3c2C1(C)C
Temperature: 180 °C

Procedure:
1,1,2-Trimethyl-1H-benz[e]indole, 100 g. was added with stirring to 500 mL of concentrated H2SO4. The mixture was heated at 180° C. for 1/2 h, cooled to 60° C. and poured onto 2 Kg ice. Cautiously 500 ml of 50% aqueous NaOH was added. After 24 hours at room temperature the solid was filtered off, and 500 mL of saturated aqueous Na2SO4 was added. The resulting solid precipitate was collected, added to the previously filtered solid, and recrystallized from 2 L of H2O. Yield 25 g after overnight vacuum drying at 50° C. The location of the sulfo group was determined as being the 7-position by proton nuclear magnetic resonance measurements.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[N:8]=[C:7]3[C:20]4[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][C:21]=4[S:22][C:5]=1[C:6]=23.B(Br)(Br)[Br:30].CO.[BrH:35]>ClC(Cl)C>[BrH:30].[BrH:35].[NH2:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[N:8]=[C:7]3[C:20]4[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:21]=4[S:22][C:5]=1[C:6]=23
Reactant: CCN(CC)CCn1nc2c3c(c(N)ccc31)Sc1cc(OC)ccc1-2
Reactant: BrB(Br)Br
Agent: Br
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: CO
Product: CCN(CC)CCn1nc2c3c(c(N)ccc31)Sc1cc(O)ccc1-2
Temperature: 78 °C
Yield: 96 %

Procedure:
A 25° C. suspension of 75 g (0:17 mol) of 5-amino-N,N-diethyl-8-methoxy-2H-[1]benzothiopyrano[4,3,2-cd]indazole-2-ethanamine, dihydrochloride (1) in 1.35 L of dichloroethane was treated dropwise with 213 g (0.85 mol) of boron tribromide. The mixture was heated at 78° C. for 16 hr, treated cautiously with 1.5 L of methanol, then heated at reflux for 6 hr. After cooling to 25° C., then chilling at -5° C. overnight, the precipitated solids were collected by filtration, washed with cold methanol, and dried at 2 mm/48° C./24 hr to give 84.3 g (96%) of 7 as a salt with 2.0 equivalents of hydrogen bromide, mp 318° C. (dec), 98.3% pure by HPLC.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:6]2[N:5]=[CH:4][N:3]=1.[Br:30]N1C(C)(C)C(=O)N(Br)C1=O>O1CCCC1>[NH2:1][C:2]1[C:7]2=[C:8]([Br:30])[CH:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]4)=[CH:15][CH:16]=3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ccc4c(N)ncnn34)cc2)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cc(Br)c4c(N)ncnn34)cc2)CC1
Temperature: -20 °C
Reaction time: 3 h
Yield: 59.4 %

Procedure:
To a cooled (−20° C.) solution of tert-butyl 4-[4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)phenyl]piperazine-1-carboxylate (1.20 g, 3.04 mmol) in tetrahydrofuran (15 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (435 mg, 1.21 mmol) in four portions over 15 min. The mixture was allowed to stir (−20° C.) for 3 h. The reaction was quenched with the addition saturated aqueous Na2SO3 (20 mL) and was allowed to warm to rt. The mixture was extracted with ethyl acetate (2×25 mL). The combined organics were dried (Na2SO4) and concentrated. The crude material was purified by ISCO® chromatography using a gradient of 25 to 75% ethyl acetate in hexanes. 1H-NMR indicated the presence of residual hydantoin side product, thus the material was partitioned between ethyl acetate (50 mL) and 5% aqueous K2CO3 (50 mL). The layers were separated and the organic layer was further washed with 5% aqueous K2CO3 (2×25 mL). The combined aqueous was back extracted with ethyl acetate (2×25 mL) and the combined organics were washed with brine, dried (Na2SO4) and concentrated to afford 340 mg (23%) of the desired product as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.91-7.83 (m, 3 H), 7.09 (s, 1 H), 7.00 (d, 2H), 3.50-3.42 (m, 4 H), 3.20-3.14 (m, 4 H), 1.42 (s, 9 H); ES-MS m/z 473.0 [M+H]+, HPLC RT (min) 3.25.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[C:19]1([CH:26]=[CH:25][CH:24]=[C:22]([OH:23])[CH:21]=1)[OH:20].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([C:24]1[CH:25]=[CH:26][C:19]([OH:20])=[CH:21][C:22]=1[OH:23])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1cccc(O)c1
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(C)(C)c1cc(C(=O)c2ccc(O)cc2O)cc(C(C)(C)C)c1O
Temperature: 50 °C
Reaction time: 4 h
Yield: 90.8 %

Procedure:
107.5 g of 3,5-di-tert-butyl-4-hydroxybenzoyl chloride and 48.4 g of resorcinol are suspended in 400 ml of nitrobenzene and warmed to 50° C. The brown solution is cooled to 0° C. 58.7 g of aluminium chloride are added in portions over the course of 45 minutes with vigorous stirring. The reaction mixture is slowly warmed to 20° C. over the course of 18 hours. The mixture is subsequently stirred at 50° C. for a further 4 hours, then cooled to room temperature and poured into 500 ml of hydrochloric acid/ice. The thick yellow suspension is extracted with ether, the ether phase is extracted with 500 ml of sodium hydroxide (15%), and the basic solution is washed three times with 250 ml of ether in each case, acidified to a pH of 1-2 using 15% hydrochloric acid and extracted with ether. The ether extracts are combined, dried and evaporated under reduced pressure, giving 124.4 g of 3,5-di-tert-butyl-2',4,4'-trihydroxybenzophenone, which, after recrystallisation from methanol, has a melting point of 192°-193° C.
Reaction SMILES: O.Cl.[N:3]1([C:9]2[C:20]3=[C:21]4[N:16]([CH:17]([CH3:22])[CH2:18][CH2:19]3)[CH:15]=[C:14]([C:23]([OH:25])=[O:24])[C:13](=[O:26])[C:12]4=[CH:11][C:10]=2[Cl:27])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH2:28](Br)[C:29]#[CH:30].C(N(CC)CC)C>CN(C)C=O>[CH2:30]([N:6]1[CH2:7][CH2:8][N:3]([C:9]2[C:20]3=[C:21]4[N:16]([CH:17]([CH3:22])[CH2:18][CH2:19]3)[CH:15]=[C:14]([C:23]([OH:25])=[O:24])[C:13](=[O:26])[C:12]4=[CH:11][C:10]=2[Cl:27])[CH2:4][CH2:5]1)[C:29]#[CH:28]
Reactant: CC1CCc2c(N3CCNCC3)c(Cl)cc3c(=O)c(C(=O)O)cn1c23
Reactant: C#CCBr
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#CCN1CCN(c2c(Cl)cc3c(=O)c(C(=O)O)cn4c3c2CCC4C)CC1
Temperature: 90 °C

Procedure:
A mixture of 0.8 g of 8-(1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]-quinolizine 2-carboxylic acid hydrochloride hydrate, 0.4 ml of propargyl bromide, 0.8 ml of triethylamine and 10 ml of dimethylformamide was allowed to react by heating at 90° C. for 5 hours. After completion of the reaction insoluble substances were removed by filtration. After concentration under reduced pressure the filtrate was purified through a silica gel column chromatography (silica gel: Wako C-200, a trade name for a product of Wako Junyaku Co., Ltd.; eluent: chloroform-methanol (8:1 by volume)) to obtain 0.3 g of 8-[4-(2-propynyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as pale yellow rhombic crystals having a melting point of 211° to 213° C.
Reaction SMILES: [NH:1]1[C:5]([CH:6]([O:8][C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=2)[O:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[NH2:15])[CH3:7])=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.[CH2:30]([O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].Cl>C(Cl)Cl.C1C=CC=CC=1>[NH:4]1[C:5]([CH:6]([O:8][C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=2)[O:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[NH:15][C:41](=[O:42])[C:40]2[CH:39]=[CH:38][C:37]([O:36][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:45][CH:44]=2)[CH3:7])=[N:1][N:2]=[N:3]1
Reactant: CCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: CC(Oc1cccc(Oc2ccccc2N)c1)c1nnn[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCOc1ccc(C(=O)Nc2ccccc2Oc2cccc(OC(C)c3nnn[nH]3)c2)cc1
Temperature: 0 °C
Yield: 62.1 %

Procedure:
In 30 ml of methylene chloride were dissolved 2.1 g of 2-[3-[1-(1H-tetrazol-5-yl)ethoxy]phenoxy]aniline and 2.2 g of triethylamine, followed by dropwise addition of a solution of 1.7 g of 4-hexyloxybenzoyl chloride in benzene with ice-cooling and stirring. The mixture was stirred at room temperature overnight and refluxed for 1 hour. To the reaction mixture was added ice-water and after the mixture was acidified with diluted hydrochloric acid, the methylene chloride layer was separated. The methylene chloride solution was dried over magnesium sulfate and concentrated and the oily residue was subjected to silica gel column chromatography using chloroform-methanol (100:1) as the eluent to give 2.2 g of the title compound as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:28])=[C:4]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([F:27])[CH:26]=2)[C:5]([O:19][CH3:20])=[C:6]([CH:8]([NH:11]C(=O)OC(C)(C)C)[CH2:9][CH3:10])[CH:7]=1>Cl.O1CCOCC1>[Cl:1][C:2]1[C:3]([CH3:28])=[C:4]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([F:27])[CH:26]=2)[C:5]([O:19][CH3:20])=[C:6]([CH:8]([NH2:11])[CH2:9][CH3:10])[CH:7]=1
Reactant: CCC(NC(=O)OC(C)(C)C)c1cc(Cl)c(C)c(-c2cncc(F)c2)c1OC
Agent: Cl
Solvent: C1COCCO1
Product: CCC(N)c1cc(Cl)c(C)c(-c2cncc(F)c2)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
The tert-butyl {1-[5-chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]propyl}carbamate (0.05 g, 0.12 mmol) was diluted with 4 M HCl in dioxane (4 mL) and was stirred at room temperature for 1 hour. The reaction was complete and the reaction mixture was concentrated to give 1-[5-chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]propan-1-amine as a semi-solid (100%). LCMS calculated for C16H16ClFNO (M+H)+: m/z=292.0. found: 292.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13](S(C)=O)=[N:14][CH:15]=2)[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:36][CH2:35][CH2:34][N:33]2C(OC(C)(C)C)=O)=[CH:28][CH:27]=1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[CH:15]=[N:14][C:13]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([CH:32]4[CH2:36][CH2:35][CH2:34][NH:33]4)=[CH:30][CH:31]=3)=[N:12][C:11]=2[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]
Reactant: CS(=O)c1ncc2c(=O)n(-c3ccccc3Cl)c3nccn3c2n1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=c1c2cnc(Nc3ccc(C4CCCN4)cc3)nc2n2ccnc2n1-c1ccccc1Cl
Temperature: 35 °C
Reaction time: 8 h

Procedure:
A mixture of Example 1E (0.048 g, 0.133 mmol) and tert-butyl 2-(4-aminophenyl)pyrrolidine-1-carboxylate (0.056 g, 0.213 mmol) was heated in a capped vial at 130° C. for 30 minutes. The reaction mixture was treated with ethyl acetate and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was dissolved in CH2Cl2 (2 mL) and treated with trifluoroacetic acid (0.103 ml, 1.334 mmol). The mixture was stirred at 35° C. overnight, concentrated, and purified by HPLC (see protocol in Example 1F) to provide the title compound as a trifluoroacetic acid salt. 1H NMR (500 MHz, CD3OD) δ 2.36-2.19 (m, 3H), 2.57-2.47 (m, 1H), 3.53-3.41 (m, 2H), 4.69-4.62 (m, 1H), 7.08 (d, J=1.9 Hz, 1H), 7.62-7.51 (m, 5H), 7.72-7.66 (m, 1H), 7.88 (d, J=1.9 Hz, 1H), 7.97-7.92 (m, 2H), 9.19 (s, 1H). MS (ESI+) m/z 458.2 (M+H)+.
Reaction SMILES: C.[Cl-:2].[Cs+:3].[CH2:4]1[N:43]2[C:44](=[O:45])[N:40]3[CH:41]4[N:73]5[C:74](=[O:75])[N:46]([CH2:47][N:48]6[C:49]([N:51]7[CH2:52][N:53]8[C:54]([N:56]9[CH2:57][N:58]%10[C:59]([N:61]%11[CH2:62][N:63]%12[C:64]([N:66]%13[CH2:67]N%14C(N(C5)C5N([CH2:39]3)C(=O)N(C5%14)C[N:29]3[C:30](=[O:31])[N:26]([CH:27]%12[CH:28]3%13)[CH2:25][N:22]3[C:23](=[O:24])[N:19]([CH:20]%10[CH:21]3%11)[CH2:18][N:15]3[C:16](=[O:17])[N:12]([CH:13]8[CH:14]39)[CH2:11][N:8]3[C:9](=[O:10])[N:5]1[CH:6]6[CH:7]37)=O)=[O:65])=[O:60])=[O:55])=[O:50])[CH:42]42>>[Cl-:2].[Cs+:3].[CH2:52]1[N:53]2[C:54](=[O:55])[N:56]3[CH:14]4[N:15]5[C:16](=[O:17])[N:12]([CH2:11][N:8]6[C:9]([N:5]7[CH2:4][N:43]8[C:44]([N:40]9[CH2:39][N:29]%10[C:30]([N:26]%11[CH2:25][N:22]%12[C:23]([N:19]([CH2:18]5)[CH:20]5[N:58]([CH2:57]3)[C:59](=[O:60])[N:61]([CH:21]5%12)[CH2:62][N:63]3[C:64](=[O:65])[N:66]([CH:28]%10[CH:27]3%11)[CH2:67][N:73]3[C:74](=[O:75])[N:46]([CH:42]8[CH:41]39)[CH2:47][N:48]3[C:49](=[O:50])[N:51]1[CH:7]6[CH:6]37)=[O:24])=[O:31])=[O:45])=[O:10])[CH:13]42
Reactant: O=C1N2CN3C(=O)N4CN5C(=O)N6CN7C(=O)N8CN9C(=O)N%10CN%11C(=O)N%12CN1C1C2N2CN%13C(=O)N(CN%14C(=O)N(CN%15C(=O)N(CN%16C(=O)N(CN%17C(=O)N(CN1C2=O)C%12C%11%17)C%10C9%16)C8C7%15)C6C5%14)C4C3%13
Agent: C
Agent: [Cl-]
Agent: [Cs+]
Product: O=C1N2CN3C(=O)N4CN5C(=O)N6CN7C(=O)N8CN9C(=O)N%10CN1C1C2N2CN%11C(=O)N(CN%12C(=O)N(CN%13C(=O)N(CN%14C(=O)N(CN1C2=O)C%10C9%14)C8C7%13)C6C5%12)C4C3%11
Temperature: 80 °C

Procedure:
A two chamber process where in chamber 1 an aqueous solution of CsCl 0.2M (6 mL) and cucurbit[5]uril (500 mg) was prepared and natural gas passed through (20 mL/min) the solution for 1 to 5 minutes. The majority of methane in the natural gas was retained by the solution in chamber 1. In chamber 2 the exhaust of chamber 1 was passed through an aqueous solution of CsCl 0.2M (1.2 mL) and unsubstituted cucurbit[6]uril (100 mg). The solution of unsubstituted cucurbit[6]uril in chamber 2 was purged with nitrogen (at 20 mL/min) for 30 to 90 seconds to remove any residual methane and ethane (ethane 40 to 60% purity). The propane was then recovered from chamber 2 at 98 to 99% pure by either purging with nitrogen for 20 minutes or heating to 60 to 100° C.
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11](OC)(=[O:14])[CH:12]=[CH2:13].C[Sn](Cl)(Cl)C.C[O-].[Na+].COC1C=CC(O)=CC=1.C1(C=CC(O)=CC=1)O>CCCCCCC>[C:11]([O:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:14])[CH:12]=[CH2:13]
Reactant: C=CC(=O)OC
Reactant: OCCOc1ccccc1
Agent: COc1ccc(O)cc1
Agent: C[O-]
Agent: C[Sn](C)(Cl)Cl
Solvent: CCCCCCC
Product: C=CC(=O)OCCOc1ccccc1
Yield: 91 %

Procedure:
In a similar manner, a mixture of 414.5 parts 2-phenoxyethanol, 388 parts methyl acrylate, 141.6 parts heptane, 4.1 parts dimethyltin dichloride, 1.1 parts sodium methoxide (molar ratio 1.09:1), 1.4 parts 4-methoxyphenol and 0.5 parts hydroquinone yielded 524.8 parts (91 percent yield, based on 2-phenoxyethanol) of 2-phenoxyethyl acrylate with a purity of 98.3 percent, containing no detectable tin.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1([C:18]([NH:20][CH:21]2[CH:28]3[CH2:29][C:24]4([C:31]([OH:33])=O)[CH2:25][CH:26]([CH2:30][CH:22]2[CH2:23]4)[CH2:27]3)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)(=[O:10])=[O:9].Cl.C([N:37]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH4+].[OH-]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1([C:18]([NH:20][CH:21]2[CH:22]3[CH2:23][C:24]4([C:31]([NH2:37])=[O:33])[CH2:25][CH:26]([CH2:27][CH:28]2[CH2:29]4)[CH2:30]3)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)(=[O:9])=[O:10]
Reactant: O=C(O)C12CC3CC(C1)C(NC(=O)C1(NS(=O)(=O)c4ccccc4Br)CCCCC1)C(C3)C2
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: ClCCl
Product: NC(=O)C12CC3CC(C1)C(NC(=O)C1(NS(=O)(=O)c4ccccc4Br)CCCCC1)C(C3)C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 58.7 %

Procedure:
In a 25-mL flask, 4-{[1-(2-bromo-benzenesulfonylamino)-cyclohexanecarbonyl]-amino}-adamantane-1-carboxylic acid (106 mg, 0.196 mmol) and methylenechloride (20 mL) were charged, and then sequentially 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (76 mg, 0.392 mmol) and 1-hydroxybenzotriazol (54 mg, 0.392 mmol) were added thereto, followed by stirring for 5 minutes at room temperature. The resultant solution was added with 35% ammonia aqueous solution (1.1 mL), followed by stirring for 12 hours at room temperature. After the reaction was completed, purified water (10 mL) was added thereto, and the aqueous solution layer was washed with methylenechloride (30 mL) twice. The obtained organic layer was added with magnesium sulfate so as to remove remaining moisture. Through filtering and vacuum evaporation, the residue was obtained. The mixture was purified with column chromatography (MC/MeOH=20:1) so as to obtain 4-{[1-(2-bromo-benzenesulfonylamino)-cyclohexanecarbonyl]-amino}-adamantane-1-carboxylic acid amide (62 mg, 59%).