Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH:28]3[S:32][C:31](=[O:33])[NH:30][C:29]3=[O:34])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)[N:53]([CH3:55])[CH3:54])C2C=CC=CC=2N=N1.CNC>C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10](=[O:11])[N:53]([CH3:55])[CH3:54])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH:28]3[S:32][C:31](=[O:33])[NH:30][C:29]3=[O:34])=[CH:23][CH:22]=2)=[CH:18][CH:19]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1)C(=O)O
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)C(Cc1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 13.8 %

Procedure:
The compound, 2-tert-butoxycarbonylamino-3-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-propionic acid (4.2 g, 8.63 mmol) was dissolved in CH2Cl2 (30 mL) and stirred at room temperature under an atmosphere of argon. Triethylamine (1.44 mL, 0.014 mmol) and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 4.19 g, 9.5 mmol) were added and the reaction mixture was stirred for 15 min. Dimethylamine (2.0 M solution in THF, 5.6 mL, 11.2 mmol) was added and the resulting solution was stirred at room temperature for about 1 h. The solvent was removed under reduced pressure and the resulting oil was taken up in EtOAc (100 mL). The organic layer was extracted with 0.5 N NaOH (1×50 mL), water (1×100 mL) and brine (1×100 mL). Silica gel chromatography of the crude product with CHCl3-MeOH (19:1) yielded pure amide, (1-dimethylcarbamoyl-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-ethyl)-carbamic acid tert-butyl ester (0.61 g, 13.8%). 1H NMR (400 MHz, CDCl3): 7.17 (overlapped d, J=8.4 Hz, 2H), 7.16 (overlapped d, J=8.4 Hz, 2H), 6.92 (overlapped d, J=8.4 Hz, 2H), 6.90 (overlapped d, J=8.4 Hz, 2H), 5.51 (d, J=8.4 Hz, 1H), 4.81 (m, 1H), 3.02-3.13 (m, 2H), 2.83-2.95 (m, 5H), 2.76 (s, 3H), 1.46 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]([CH3:17])([CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14]O)=[CH:9][CH:8]=1)=[O:4].C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]([CH3:17])([CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][Br:19])=[CH:9][CH:8]=1)=[O:4]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)C(C)(C)Cc1ccc(CCO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(C)(C)Cc1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of lithium diisopropylamide (0.1 mol/l solution in tetrahydrofuran, 15 ml) was added a solution of 1-(2-t-butyldimethylsiloxyethyl)-4-(2-methoxycarbonylpropyl)benzene (0.62 g) in tetrahydrofuran (2 ml) at -78° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added a solution of iodomethane (0.20 g) in tetrahydrofuran (2 ml), and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The extract was washed with water, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on a silica gel column using a mixture of n-hexane and methylene chloride (3:1) as eluent to give 1-(2-t-butyldimethylsiloxyethyl)-4-(2-methoxycarbonyl-2-methylpropyl)benzene (0.49 g) as an oily liquid. To a solution of 1-(2-t-butyldimethylsiloxyethyl)-4-(2-methoxycarbonyl-2-methylpropyl)benzene (0.49 g) in tetrahydrofuran (1.5 ml) was added tetra-n-butylammonium fluoride (1 mol/l solution in tetrahydrofuran, 1.34 ml), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The extract was washed with water, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on a silica gel column using a mixture of methylene chloride and diethyl ether (7:1) as eluent to give 2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl alcohol (0.300 g) as an oily liquid. To a solution of 2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl alcohol (0.300 g) in methylene chloride (3 ml) were added carbon tetrabromide (0.48 g) and triphenylphosphine (0.38 g), and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on a silica gel column using a mixture of n-hexane and methylene chloride (3:1) as eluent to give 2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl bromide (0.323 g) as an oily liquid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[F:8][C:9]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]2[N:30]3[CH:31]=[CH:32][CH:33]=[C:29]3[C:28](=[O:34])[NH:27][CH:26]=2)=[CH:20][C:10]=1[C:11]([N:13]1[CH2:19][CH2:18][CH2:17][NH2+:16][CH2:15][CH2:14]1)=[O:12].C=O.[CH3:37]C([O-])=O.[Na+]>CO.O.CC#N>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[F:8][C:9]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]2[N:30]3[CH:31]=[CH:32][CH:33]=[C:29]3[C:28](=[O:34])[NH:27][CH:26]=2)=[CH:20][C:10]=1[C:11]([N:13]1[CH2:19][CH2:18][CH2:17][NH+:16]([CH3:37])[CH2:15][CH2:14]1)=[O:12]
Reactant: CC(=O)[O-]
Reactant: O=C(c1cc(Cc2c[nH]c(=O)c3cccn23)ccc1F)N1CCC[NH2+]CC1
Agent: C=O
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC#N
Product: C[NH+]1CCCN(C(=O)c2cc(Cc3c[nH]c(=O)c4cccn34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 1 in MeOH (0.1 M) was added TEA (2 eq), formaldehyde (5 eq), NaBH3(CN) (1.6 eq) and NaOAc (2.8 eq). The mixture was stirred overnight at RT and then the solvent was removed under reduced pressure and the product was isolated by purification at prep RP-HPLC using H2O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C18 column). The desired fractions were lyophilized to afford the title compound. 1H NMR (600 MHz, DMSO-d6+TFA) (one major rotamer described) δ: 10.56-10.49 (1H, m), 9.78 (1H, br. S), 7.54-7.47 (1H, m), 7.44-7.37 (1H, m), 7.33-7.21 (2H, m), 6.88-6.93 (1H, m), 6.57-6.46 (2H, m), 4.08 (2H, s), 3.78-3.28 (6H, m, partially overlapped with D2O signal), 3.26-3.17 (2H, m), 2.85 (3H, s), 1.91-1.99 (2H, m). MS (ES) C21H23FN4O2 requires: 382, found: 383 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].FC1C=CC=C(F)C=1C[C@@H](C(O)=O)N.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@H:18]([CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[CH2:31][C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[F:39])=[O:15])[S:10][C:11]=1[CH3:12]
Reactant: N[C@@H](Cc1cc(F)ccc1F)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: N[C@@H](Cc1c(F)cccc1F)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1sc(C(=O)N[C@@H](Cc2cc(F)ccc2F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (219 mg, 0.85 mmol) [prepared according to the procedure of Example 158], 2-[(2S)-2-amino-3-(2,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (290 mg, 0.82 mmol) [prepared according to the procedure of Preparation 18 except substituting 2,5-difluoro-L-phenylalanine (3.02 g, 15.0 mmol) for 2,6-difluoro-L-phenylalanine] and PyBrop (481 mg, 1.03 mmol) in chloroform (8.5 mL). DIEA (750 μL, 4.29 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (246 mg, 0.44 mmol, 52%): LC-MS (ES) m/z=555 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=5)[S:20][C:13]=34)[CH:9]=[CH:10][C:4]=2[C:3]=1[C:27]([OH:29])=O.C([N:33](CC)[CH:34]([CH3:36])[CH3:35])(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:34]1([NH:33][C:27]([C:3]2[C:4]3[CH:10]=[CH:9][C:8]([O:11][C:12]4[CH:17]=[CH:16][N:15]=[C:14]5[CH:18]=[C:19]([C:21]6[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=6)[S:20][C:13]=45)=[CH:7][C:5]=3[S:6][C:2]=2[CH3:1])=[O:29])[CH2:36][CH2:35]1
Reactant: Cc1sc2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc2c1C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1sc2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc2c1C(=O)NC1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of 2-methyl-6-{[2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yl]oxy}benzo[b]thiophene-3-carboxylic acid 117b (75 mg, 0.18 mmole) in DMF (1.5 mL) at 0° C. were added N,N-diisopropylethylamine (68 μL, 0.39 mmole) and HBTU (100 mg, 0.27 mmole). The reaction mixture was stirred 30 min at 0° C. then warmed to room temperature and stirred 18 hr. The mixture was poured onto H2O (25 mL) and the precipitate was collected by vacuum filtration. The filter paper was extracted with a mixture of CH2Cl2 (10 mL) and MeOH (10 mL). The solution was concentrated and the crude mixture was purified by silica gel chromatography (5% MeOH/EtOAc) to afford a pale yellow solid (58 mg, 71%). 1H NMR (DMSO-d6, 300 MHz) δ 8.52 (1H, d, J=5.46 Hz), 8.46 (1H, d, J=4.33 Hz), 7.95 (1H, d, J=2.26 Hz), 7.88 (1H, s), 7.80 (1H, d, J=8.67 Hz), 7.40 (1H, s), 7.32 (1H, dd, J=2.26, 8.85 Hz), 7.02 (1H, s), 6.70 (1H, d, J=5.46 Hz), 3.98 (3H, s), 2.90 (1H, m), 2.57 (3H, s); 0.73 (2H, m), 0.57 (2H, m);
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:22])[C:8]=1[O:23][CH3:24])(=O)=O.[C-:25]#[N:26].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:15]=1[CH2:14][O:13][C:9]1[C:8]([O:23][CH3:24])=[C:7]([CH2:6][C:25]#[N:26])[CH:12]=[CH:11][CH:10]=1
Reactant: COc1c(COS(C)(=O)=O)cccc1OCc1c(C)cccc1C
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c(CC#N)cccc1OCc1c(C)cccc1C

Procedure:
The solution of 3-(2,6-dimethylbenzyloxy)-2-methoxybenzyl methanesulfonate (Step C, 8.8 g, 30.26 mmol) and NaCN (1.60 g, 32.6 mmol) in dry DMF (40 ml) was heated at 85° C. for 18 hours then cooled and diluted with EtOAc (50 ml). The organic layer was washed with water (30 ml), concentrated, and passed through short silica gel column using methylene chloride to give the title compound as a yellow solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].O.Cl>CO>[CH:8]1[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15](=[O:16])[N:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[CH:13]2
Reactant: CCOC(=O)c1ccc2ccccn2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2ccccn2c1=O
Reaction time: 0.33 h
Yield: 92.6 %

Procedure:
To a solution of 3-ethoxycarbonyl-4H-quinolizin-4-one (2.17 g) in methanol (65.2 ml) was added dropwise 6 N aqueous sodium hydroxide (6.5 ml) at room temperature. After stirring for 20 minutes, water (10 ml) was added. After stirring for 20 minutes, water (30 ml) was also added. After stirring for an hour, the reaction mixture was acidified to pH 3 with 4N aqueous hydrochloric acid. The precipitate was filtered and washed with water to give 4H-quinolizin-4-one-3-carboxylic acid (1.75 g) as pale yellow crystal. mp 233° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=2[CH3:29])[CH2:17][C:16]1([CH3:31])[CH3:30])=O)(C)(C)C>C(Cl)Cl>[CH3:30][C:16]1([CH3:31])[CH2:17][N:18]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=2[CH3:29])[C:19](=[O:21])[CH2:20][NH:15]1
Reactant: Cc1c(F)cccc1N1CC(C)(C)N(C(=O)OC(C)(C)C)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(F)cccc1N1CC(C)(C)NCC1=O
Reaction time: 0.5 h
Yield: 102.9 %

Procedure:
2.8 ml of trifluoroacetic acid (37 mmol) was added to a solution of 1.25 g of 2,2-dimethyl-4-(3-fluoro-2-methylphenyl)-5-oxopiperazine-1-carboxylic acid t-butyl ester obtained in Example (67c) (3.7 mmol) in methylene chloride (5.6 ml) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. A saturated sodium bicarbonate aqueous solution was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=10/1) to obtain 0.9 g of the title compound (yield: quant.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5](O)=[O:6].[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH2:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[NH:33][CH2:32][CH2:31][N:30]([CH3:34])[CH3:29])[CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(C(=O)O)cc1Cl
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1

Procedure:
3-Chloro-4-(N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoic acid and N1,N1-dimethylethane-1,2-diamine were reacted by a procedure similar to that to prepare 137 in Example 47 to give 248. MS: (ESI+) 484.3
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([NH2:18])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)(O)[O-].[Na+].O.Cl[CH2:26][C:27](Cl)=[O:28].[CH3:30][C:31](CC(C)C)=[O:32]>>[O:8]1[C:7]2[CH:6]=[CH:5][C:4]([CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]4[O:17][CH2:30][C:31](=[O:32])[NH:18][C:13]=4[CH:12]=3)=[CH:3][C:2]=2[NH:1][C:27](=[O:28])[CH2:26]1
Reactant: O=C(Cl)CCl
Reactant: Nc1cc(CCc2ccc(O)c(N)c2)ccc1O
Reactant: CC(=O)CC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C1COc2ccc(CCc3ccc4c(c3)NC(=O)CO4)cc2N1

Procedure:
To 3.0 g (0.0123 mole) of 1,2 bis(3-amino-4-hydroxyphenyl)ethane in 25 ml of isobutyl methyl ketone was added 5.0 g (0.06 mole) sodium bicarbonate and 25 ml of water. The mixture was cooled in an ice-bath and 1.4 g (0.012 mole) of chloroacetyl chloride was added dropwise over 15 minutes. After coming to room temperature, the mixture was refluxed for 4 hours. On cooling, the solid was filtered off and washed with acetone. The precipitate was suspended in acetone, refluxed for 15 minutes and cooled. On filtration, there was obtained 2.3 g of a beige solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C:17]([C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([OH:33])=O)=[O:28])[CH:23]=[CH:24][CH:25]=1)([F:19])[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C:17]([C:20]1[CH:21]=[C:22]([N:26]2[C:31](=[O:33])[CH2:30][NH:29][C:27]2=[O:28])[CH:23]=[CH:24][CH:25]=1)([F:19])[F:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)Nc1cccc(C(F)(F)COCCCCCCOCc2ccccc2)c1
Agent: Cl
Solvent: O
Product: O=C1CNC(=O)N1c1cccc(C(F)(F)COCCCCCCOCc2ccccc2)c1

Procedure:
A solution of Intermediate 60 (3.42 g, 7.4 mmol), water (20 mL) and concentrated HCl (5.5 mL) was heated at 140° C. for 12 hours. The reaction was cooled. The crude was extracted with ethyl acetate (50 mL) and washed with saturated solution of sodium bicarbonate (2×20 mL), water (2×20 mL) and brine (1×20 mL), dried (Na2SO4) and concentrated. The titled compound was obtained (2.52 g, 76%) as oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[C:19](Cl)[N:18]=[C:17]([NH:22]C)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.CN.C([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])C>C(O)C>[CH2:19]([NH:18][C:17]1[N:16]=[C:15]([NH:14][S:11]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:10][CH:9]=2)(=[O:13])=[O:12])[CH:33]=[C:32]([NH:29][CH2:30][CH3:31])[N:22]=1)[CH3:20]
Reactant: CNc1nc(Cl)cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: CCO
Product: CCNc1cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(NCC)n1
Temperature: 140 °C
Reaction time: 18 h
Yield: 30.6 %

Procedure:
0.47 g (0.0013 mol) of 4-tert-butyl-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide was dissolved in 10 ml of ethanol, treated with 1.3 g (0.019 mol) of methylamine hydrochloride and 4.7 ml (0.034 mol) of triethylamine and stirred in an autoclave at 140° C. for 18 hours. The mixture was freed completely from solvent, the residue was partitioned in ethyl acetate/water and the insoluble constituents were filtered off under suction. The filtered cake was recrystallized in methanol/diethyl ether. There was obtained 0.15 g (33%) of N-(2,6-bis-ethylamino-pyrimidin-4-yl)-4-tert-butyl-benzenesulfonamide as white crystals; m.p. 316-318° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]([CH:25]=[O:26])=[C:11]([C:27]3[CH2:28][CH2:29][O:30][CH2:31][CH:32]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:34]1[CH:35]=[CH:36][C:37]([C:40]([F:43])([F:42])[F:41])=[N:38][CH:39]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]([C@H:25]([C:34]3[CH:39]=[N:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=3)[OH:26])=[C:11]([C:27]3[CH2:28][CH2:29][O:30][CH2:31][CH:32]=3)[C:10]1=2)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: CC(C)c1nc2c(c(C3=CCOCC3)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2
Product: CC(C)c1nc2c(c(C3=CCOCC3)c1[C@@H](O)c1ccc(C(F)(F)F)nc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2

Procedure:
Obtained by starting from (S)-5′-(tert-butyldimethylsilyloxy)-4′-(3,6-dihydro-2H-pyran-4-yl)-2′-isopropyl-6′,8′-dihydro-5′H-spiro[cyclobutane-1,7′-quinoline]-3′-carbaldehyde and 5-bromo-2-(trifluoromethyl)pyridine.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@H:14]([NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH2:13][C@H:12]([CH2:24][OH:25])[C@H:11]1[O:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.Cl[S:47]([NH2:50])(=[O:49])=[O:48]>C(#N)C>[C:1]([O:9][C@H:10]1[C@H:14]([NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH2:13][C@H:12]([CH2:24][O:25][S:47]([NH2:50])(=[O:49])=[O:48])[C@H:11]1[O:26][C:27](=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)Cl
Reactant: O=C(N[C@@H]1C[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: NS(=O)(=O)OC[C@H]1C[C@@H](NC(=O)c2ccncc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.5 %

Procedure:
To a solution of (1S,2R,3R,5R)-3-(hydroxymethyl)-5-(isonicotinoylamino)cyclopentane-1,2-diyl dibenzoate (160. mg, 0.350 mmol) in ACN (10.0 mL) at 0° C. was added DBU (0.0600 mL, 0.401 mmol) and the mixture was stirred for 15 min. A freshly prepared 1.40 M solution of chlorosulfonamide (0.500 mL, 0.700 mmol, as prepared in Example 1d) was then added dropwise via syringe and the mixture was stirred for 2.5 h at 0° C. before being allowed to warm to rt. The mixture was concentrated in vacuo and the residue was purified via silica gel chromatography eluting with a gradient of 0 to 10% MeOH in E)CM to afford the title compound (50.0 mg, 27%). LC/MS: Rt=1.57 min, ES+ 540. (FA standard).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1.[C:18](O)(=[O:22])[C:19]([CH3:21])=[CH2:20]>>[C:18]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)(=[O:22])[C:19]([CH3:21])=[CH2:20]
Reactant: O=C(O)c1ccc(OCCCCCCO)cc1
Reactant: C=C(C)C(=O)O
Product: C=C(C)C(=O)CCCCCCOc1ccc(C(=O)O)cc1

Procedure:
A solution of 4-(6-hydroxyhexyloxy)benzoic acid (24.0 g, 0.10 mol, prepared as described in Example 10) was treated with methacrylic acid as described in Example 8 to give 4-(6-methacryloylhexyloxy)benzoic acid after recrystallization from tetrahydrofuran-hexane (1:2) (19.9 g, 67%): mp 81°-94° C., nematic mesophase; NMR (CDCl3) 9.82(bs, 1H), 8.0(d, 2H), 6.87(d, 2H), 6.05(s, 1H), 4.15(t, 2H), 4.0(t, 2H), 1.9(s, 3H), 1.85(m, 8H).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:8]1[CH:9]=[C:2]([C:13]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=2[F:11])[C:3]([C:4]#[N:5])=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(F)cc1Br
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Product: N#Cc1ccc(F)cc1-c1cc([N+](=O)[O-])ccc1F

Procedure:
2-Bromo-4-fluorobenzonitrile was coupled to 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane as described in Example 7 part c) to give 5,2′-difluoro-5′-nitrobiphenyl-2-carbonitrile as a black solid: δH (360 MHz, CDCl3) 7.25-7.33 (2H, m), 7.40-7.44 (1H, m), 7.86 (1H, dd, J 9 and 6), 8.35-8.42 (2H, m).
Reaction SMILES: Cl.[CH:2]1([O:7][C:8]2[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[NH2:11])[CH2:6][CH2:5][CH2:4][CH2:3]1.[N:17]([O-])=O.[Na+].[F:21][B-:22]([F:25])([F:24])[F:23].[Na+]>O>[F:21][B-:22]([F:25])([F:24])[F:23].[CH:2]1([O:7][C:8]2[CH:9]=[C:10]([N+:11]#[N:17])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=N[O-]
Reactant: COc1ccc(N)cc1OC1CCCC1
Agent: Cl
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: O
Product: COc1ccc([N+]#N)cc1OC1CCCC1
Reaction time: 0.17 h
Yield: 101.2 %

Procedure:
A stirred solution of concentrated hydrochloric acid (1.7 mL) in water (5 mL) from 0° C. and 5° C. is treated with 3-cyclopentyloxy-4-methoxyaniline (0.83 g), followed by a solution of sodium nitrite (0.29 g) in water (0.6 mL), at such a rate that the temperature remains from 0° C. and 5° C. The resulting solution is stirred for a further 10 minutes, while keeping the temperature below 5° C. The stirred solution, while still maintained at below 5° C., is then treated dropwise with a solution of sodium tetrafluoroborate (0.88 g) in water (1.8 mL). The resulting precipitate is filtered off, washed with cold water (3 mL) and dried in vacuo, to give 3-cyclopentyloxy-4-methoxyphenyldiazonium tetrafluoroborate (1.24 g) in the form of a gray solid, m.p. 120° C.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[N+:12]([C:15]1[O:19][C:18](/[CH:20]=[CH:21]/[C:22](O)=[O:23])=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:22](=[O:23])/[CH:21]=[CH:20]/[C:18]1[O:19][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1)[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)/C=C/c1ccc([N+](=O)[O-])o1
Agent: Cl
Product: O=C(/C=C/c1ccc([N+](=O)[O-])o1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(5-nitro-2-furyl)propenoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent; MS (ES+) 293 (MH+).