Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][CH:14]([C:21]2[N:22]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[N:23]=[C:24]3[C:29]=2[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[OH-].[Na+]>CO.O>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([N:22]2[C:21]([CH:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:13][S:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:37])=[O:2])=[CH:9][CH:8]=3)(=[O:12])=[O:11])=[C:29]3[C:24]([CH2:25][CH2:26][CH2:27][CH2:28]3)=[N:23]2)=[CH:31][CH:32]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)CC(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(S(=O)(=O)CC(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 44.9 %

Procedure:
To a stirred solution of [rac]-4-{2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-ethanesulfonyl}-benzoic acid methyl ester (40 mg, 0.076 mmol) in MeOH (5 ml) was added NaOH (5.18 mg, 0.129 mmol) in water (2 ml) dropwise at 0° C. The reaction mixture was then stirred at 25° C. for 14 h. After the completion of the reaction (monitored through TLC), MeOH was concentrated in vacuo, diluted with H2O (5 ml) and the aqueous layer was acidified (pH ˜2-3) with 2 N HCl, and then extracted with EtOAc (3×5 ml). Combined organic layers were washed with brine (10 ml) and finally dried over Na2SO4. Organic layer was distilled under reduced pressure to get crude title compound (32 mg). Purification was done by column chromatography over silica gel (230-400 mesh; 2% MeOH/DCM) to give the title compound (18 mg, 47.1%) as an off white solid. MS: m/e=527.2 [M+H+].
Reaction SMILES: [CH:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:12][CH:13]1[S:17](=[O:19])(=[O:18])[O:16][CH2:15][CH2:14]1>CC(=O)CC>[CH:1]1([NH:11][CH2:15][CH2:14][CH:13]([S:17]([OH:19])(=[O:18])=[O:16])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC1CCOS1(=O)=O
Reactant: NC1CCCc2ccccc21
Solvent: CCC(C)=O
Product: CC(CCNC1CCCc2ccccc21)S(=O)(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,2,3,4-tetrahydro-1-naphthylamine (2.01 g, 13.6 mmol) in 2-butanone (15 mL) was added 2,4-butane sultone (1.95 g, 14.3 mmol). The solution was stirred at for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo. 1H NMR (DMSO, 500 MHz) δ ppm 8.56 (s (broad), 1H), 7.49 (dd, 1H, J=8.0 Hz, 11.9 Hz), 7.29 (m, 1H), 7.26 (m, 1H), 7.19 (d, 1H, J=8.0 Hz), 4.40 (d, 1H, J=13.7 Hz), 3.14 (m, 2H), 2.75 (m, 3H), 1.96 (m, 5H), 1.40 (m, 1H), 1.23 (m, 3H). 13C (DMSO, 125 MHz) δ ppm 138.81, 131.81, 130.40, 130.28, 130.16, 129.41, 126.76, 126.73, 54.97, 54.58, 54.08, 44.18, 43.23, 29.50, 28.84, 24.84, 24.76, 18.23, 18.20, 17.79, 17.01. ES-MS 284 (M+1).
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([O:22][CH:23]3[CH2:40][CH:39]4[N:25]([C:26](=[O:46])[N:27]([CH3:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH:33][CH:34]5[C:36]([C:42](O)=[O:43])([NH:37][C:38]4=[O:41])[CH2:35]5)[CH2:24]3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][CH3:21])=[CH:15][CH:14]=3)=[CH:6][CH:5]=1.ClC1N=C(OC2CC3N(C(=O)N(C)CCCCC=CC4C(C([NH:84][S:85]([CH:88]5[CH2:90][CH2:89]5)(=[O:87])=[O:86])=O)(NC3=O)C4)C2)C2C(C=1)=CC(OC)=CC=2>>[F:48][C:2]([F:47])([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([O:22][CH:23]3[CH2:40][CH:39]4[N:25]([C:26](=[O:46])[N:27]([CH3:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH:33][CH:34]5[C:36]([C:42]([NH:84][S:85]([CH:88]6[CH2:90][CH2:89]6)(=[O:87])=[O:86])=[O:43])([NH:37][C:38]4=[O:41])[CH2:35]5)[CH2:24]3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][CH3:21])=[CH:15][CH:14]=3)=[CH:6][CH:5]=1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3ccc(OC(F)(F)F)cc3)cc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nc(Cl)cc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3ccc(OC(F)(F)F)cc3)cc2c1

Procedure:
The title product 58 was prepared from 17-(3-(4-trifluoromethoxyphenyl)-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.0416]octadec-7-ene-4-carboxylic acid (57) following the same procedures described for the preparation of N-[17-(3-chloro-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (43, Example 11): m/z=772 (M+H)+; 1H-NMR (CDC3): 10.63-10.57 (br s, 1H), 8.00 (d, J=8.5 Hz, 2H), 7.94 (d, J=9.0 Hz, 1H), 7.49 (s, 1H), 7.26 (d, J=8.5 Hz, 2H), 7.01 (dd, J=9.0 Hz, 2.4, 1H), 6.98 (d, J=2.4 Hz, 1H), 6.79-6.72 (bs, 1H), 5.98-5.92 (m, 1H), 5.67 (dd, J=7.8 Hz, J=18.9 Hz, 1H), 5.09 (t, J=10.4 Hz, 1H), 4.71 (t, J=8.1 Hz, 1H), 4.03 (dd, J=11.0 Hz, 4.0, 1H), 3.85 (s, 3H), 3.64 (d, J=11.0 Hz, 1H), 3.61-3.53 (m, 1H), 3.15-3.03 (m, 1H), 2.93-2.82 (m, 1H), 2.77 (s, 3H), 2.54-2.38 (m, 3H), 2.25-2.08 (m, 1H), 2.04-1.87 (m, 2H), 1.66-0.86 (m, 9H).
Reaction SMILES: [F-].[Cs+].[CH3:3][C:4]1[S:8][C:7](B(O)O)=[CH:6][CH:5]=1.[Cl:12][C:13]1[CH:29]=[CH:28][C:16]2[CH2:17][CH2:18][N:19]([C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH2:20][CH2:21][C:15]=2[C:14]=1OS(C(F)(F)F)(=O)=O>COCCOC.CCOC(C)=O>[Cl:12][C:13]1[CH:29]=[CH:28][C:16]2[CH2:17][CH2:18][N:19]([C:22](=[O:27])[C:23]([F:25])([F:26])[F:24])[CH2:20][CH2:21][C:15]=2[C:14]=1[C:7]1[S:8][C:4]([CH3:3])=[CH:5][CH:6]=1
Reactant: Cc1ccc(B(O)O)s1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1ccc(-c2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)s1
Temperature: 90 °C
Yield: 70.4 %

Procedure:
Add tetrakistriphenylphosphine palladium(0) (27 mg, 0.024 mmol), cesium fluoride (143 mg, 0.942 mmol) and 5-methyl-thiophen-2-yl-boronic acid (134 mg, 0.942 mmol) to a stirred solution of 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.471 mmol) in anhydrous DME (8 mL) at room temperature. Heat at 90° C. overnight. Cool the reaction mixture to room temperature, dilute with EtOAc and wash with water. Extract the aqueous phase twice with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 19:1) to obtain 7-chloro-6-(5-methyl-thiophen-2-yl)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (124 mg, 70%).
Reaction SMILES: [CH3:1][NH2:2].O.[C:4]([C:6]1[CH:7]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:9]=[CH:10][CH:11]=1)#[N:5]>C(Cl)Cl>[C:4]([C:6]1[CH:7]=[C:8]([S:12]([NH:2][CH3:1])(=[O:14])=[O:13])[CH:9]=[CH:10][CH:11]=1)#[N:5]
Reactant: CN
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Solvent: O
Solvent: ClCCl
Product: CNS(=O)(=O)c1cccc(C#N)c1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A flask containing DCM (90 mL) and methylamine in water (40 wt %, 7.5 mmol) is chilled in an ice water bath with magnetic stirring. 3-Cyano-benzenesulfonyl chloride (5 g, 2.49 mmol) is added along with DCM (10 mL) to wash down the sides of the flask. After 30 min, concentrated HCl in water is added at 0° C., until the reaction is acidic (pH<4). Water (50 mL) is added and DCM is removed in vacuo. The residue is filtered to afford 3-cyano-N-methyl-benzenesulfonamide as a solid (99%). MS: 195 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.76 (d, 3H), 4.48 (broad-s, N—H), 7.7 (t, 1H), 7.9 (d, 1H), 8.13 (d, 1H), 8.19 (s, 1H).
Reaction SMILES: [N:1]([CH2:4][C@H:5]([O:12]C(=O)CCCCC)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N+]=[N-].C([O:23][CH2:24][CH3:25])(=O)C>[Pd]>[C:24]([NH:1][CH2:4][C@H:5]([OH:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:23])[CH2:25][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCOC(C)=O
Reactant: CCCCCC(=O)O[C@@H](CN=[N+]=[N-])CC(=O)OCC
Agent: [Pd]
Product: CCCCCC(=O)NC[C@H](O)CC(=O)OCC
Temperature: 25 °C
Reaction time: 7 h
Yield: 87 %

Procedure:
In a 200 ml autoclave were charged 8.50 g (29.5 mmol) of ethyl (R)-4-azido-3-hexanoyloxybutyrate, 0.20 g of 5% Pd—C, and 16 ml of ethyl acetate, and the mixture was stirred at room temperature under a hydrogen pressure of 1000 KPa. for 7 hours. The catalyst was removed for concentration to give 7.07 g (87%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH2:7][CH2:8][N:9]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:7][CH2:8][N:9]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)c2ccc(Br)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC=C(N2CCOCC2)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a mixture of tert-butyl 7-bromo-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (0.500 g, 1.53 mmol) and morpholine (0.668 mL, 7.66 mmol) in toluene (10 mL) at 0° C. was added titanium(IV) chloride [1M in toluene] (0.843 mL, 0.843 mmol) dropwise. The ice-bath was removed, and the orange, heterogeneous reaction mixture was stirred at room temperature overnight. The heterogeneous, orange reaction mixture was filtered under reduced pressure through a pad of Celite which was then rinsed with toluene (3×10 mL). The pale yellow filtrate was concentrated under reduced pressure to give tert-butyl 7-bromo-4-morpholinoquinoline-1(2H)-carboxylate (0.598 g, 1.513 mmol, 99% yield) as a yellow oil. The product had LC/MS M+1=395.1 and 397.1.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([NH:12][C:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16](=[O:23])[O:15][N:14]=1)([CH:9]([CH3:11])[CH3:10])[C:5]([O:7]C)=O.[O:24]1CCCC1.S(=O)(=O)(O)O>O.C(Cl)Cl>[OH:15][N:14]1[C:5](=[O:7])[C:4]([CH:9]([CH3:11])[CH3:10])([CH3:3])[N:12]=[C:13]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([OH:23])=[O:24]
Reactant: COC(=O)C(C)(Nc1noc(=O)c2ccccc12)C(C)C
Reactant: C1CCOC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)C1(C)N=C(c2ccccc2C(=O)O)N(O)C1=O
Temperature: 45 °C
Reaction time: 36 h
Yield: 76 %

Procedure:
Sodium hydroxide (0.58 g, 0.0145 mol) in water is added to a solution of methyl 2,3-dimethyl-2-[(1-oxo-2,3-benzoxazin-4-yl)amino]butyrate (2.0 g, 0.00689 mol) and tetrahydrofuran under a nitrogen atmosphere. The reaction mixture is stirred at 45° C. for 36 hours then at room temperature for 6 days. The reaction mixture is concentrated in vacuo to give an oil. The oil is dissolved into water. The aqueous solution is cooled with an ice-bath and concentrated sulfuric acid is added until a pH of about 1 is obtained then the solution is extracted with ethyl acetate. The combined ethyl acetate extracts are dried with anhydrous magnesium sulfate and concentrated in vacuo to give a pale yellow solid. The solid is added to boiling methylene chloride and after 2/3 of the methylene chloride has evaporated, the mixture is filtered to give the title compound as a white solid (1.44 g, 76%), mp 186°-188° C., identified by IR and NMR spectral analyses.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][C:6]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].C(N(C(C)C)C(C)C)C.[F:32][C:33]([F:51])([F:50])[C:34]1[CH:35]=[C:36]([C:44]([CH3:49])([CH3:48])[C:45](Cl)=[O:46])[CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1.C(=O)(O)[O-].[Na+]>ClCCl>[F:32][C:33]([F:51])([F:50])[C:34]1[CH:35]=[C:36]([C:44]([CH3:49])([CH3:48])[C:45]([N:2]([CH3:1])[C:3]2[CH:4]=[N:5][C:6]([N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)=[CH:7][C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[O:46])[CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1-c1cc(N2CCN(C)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 37.5 °C
Yield: 80.9 %

Procedure:
A solution of 20 g (67.5 mmol) methyl-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-amine and 17.5 ml (101 mmol) N-ethyldiisopropylamine in 200 ml dichloromethane was cooled in an ice bath and a solution of 24 g (75 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 50 ml dichloromethane was added dropwise. The reaction mixture was warmed to 35-40° C. for 3 h, cooled to room temperature again and was stirred with 250 ml saturated sodium bicarbonate solution. The organic layer was separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 31.6 g (81%) of the title compound as white crystals. M.p. 155-157° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[NH:12]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:13][C:14](O)=[O:15]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:14](=[O:15])[CH2:13][NH:12][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18]
Reactant: Oc1ccc2ccccc2c1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Product: O=C(CNC(=O)OCc1ccccc1)Oc1ccc2ccccc2c1
Yield: 72 %

Procedure:
β-Naphthol and Z-Gly.OH were treated in the same manner as in Example 78 to obtain N-benzyloxycarbonyl glycine β-naphthyl ester (hereinafter represented by ##STR10## in a yield of 72%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12](NC(OCC2C=CC=CC=2)=O)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.CCOC(C)=O.[OH-].[OH-].[Pd+2]>[NH:12]1[CH2:13][CH2:14][CH2:15][CH:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:11]1
Reactant: CC(C)(C)OC(=O)NCC1CCCN(NC(=O)OCc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC1CCCNC1

Procedure:
20% Pd(OH)2 on carbon (1 g) was added to a solution of benzyl 3-(tert-butoxycarbonylamino-methyl)-piperidine-1-carbamate (5 g, 14.3 mmol) in EtOH (50 ml) and EtOAc (50 ml), and hydrogenation was carried out under a hydrogen atmosphere (1 bar). The reaction mixture was filtered and the filtrate was concentrated.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:16])[C:9]([O:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[C:4]([C:17](=[O:19])[NH2:18])[CH:3]=1.CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:71]([CH:73]([CH2:81][CH2:82][CH2:83][CH3:84])[CH2:74][O:75][C:76](=[O:80])[CH2:77][CH2:78][SH:79])[CH3:72]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:71]([CH:73]([CH2:81][CH2:82][CH2:83][CH3:84])[CH2:74][O:75][C:76](=[O:80])[CH2:77][CH2:78][S:79][C:2]1[S:6][C:5]([NH:7][C:8](=[O:16])[C:9]([O:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[C:4]([C:17](=[O:19])[NH2:18])[CH:3]=1)[CH3:72]
Reactant: CC(=O)OC(C)(C)C(=O)Nc1sc(Br)cc1C(N)=O
Reactant: CCCCC(CC)COC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCCCC(CC)COC(=O)CCSc1cc(C(N)=O)c(NC(=O)C(C)(C)OC(C)=O)s1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Intermediate 11 (1.4 g, 4 mmol) is dissolved in toluene (16 mL) and DIEA (1.4 mL, 8 mmol). Next, Pd2dba3 (110 mg, 0.12 mmol), Xantphos (139 mg, 0.24 mmol) and 3-Mercaptopropionic acid 2-ethylhexylester (1.14 mL, 5 mmol) are added, and the resulting solution is flushed with N2. Reaction mixture is stirred at 110° C. overnight. After evaporation, the crude is purified using column chromatography. The resulting product is obtained as an oil, which crystallised overnight. Obtained product is used as such.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[O:5][C:6]1[C:7]([CH2:16][CH3:17])=[N:8][N:9]([CH2:13][CH2:14][NH2:15])[C:10]=1[CH2:11][CH3:12].Cl.CN(C)CCCN=C=NCC.[CH3:34][O:35][CH2:36][C:37](O)=[O:38]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[O:5][C:6]1[C:7]([CH2:16][CH3:17])=[N:8][N:9]([CH2:13][CH2:14][NH:15][C:37](=[O:38])[CH2:36][O:35][CH3:34])[C:10]=1[CH2:11][CH3:12]
Reactant: COCC(=O)O
Reactant: CCc1nn(CCN)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCc1nn(CCNC(=O)COC)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Reaction time: 12 h
Yield: 83.8 %

Procedure:
A solution of the pyrazole of Example 13 (53 mg, 0.161 mmol), 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (34 mg, 0.178 mmol) and 4-(dimethylamino)pyridine (22 mg, 0.178 mmol) in dichloromethane (1 ml) was added to a stirred solution of methoxyacetic acid (14.2 μL, 0.178 mmol) in dichloromethane (1 ml) at room temperature. The reaction was stirred for 12 hours and then concentrated under a stream of nitrogen to leave a yellow solid. The crude product was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol (98:2, by volume) to provide the title compound (54 mg) as a brown solid, m.p. 75–76° C.
Reaction SMILES: [CH2:1]([CH:4]1[C:10](Cl)([Cl:11])[CH2:9][CH2:8][CH:7]2[C:5]1(Cl)[O:6]2)[CH:2]=[CH2:3].Cl>CN(C=O)C>[CH2:1]([C:4]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6])[CH:2]=[CH2:3]
Reactant: C=CCC1C(Cl)(Cl)CCC2OC21Cl
Agent: Cl
Solvent: CN(C)C=O
Product: C=CCc1c(O)cccc1Cl
Reaction time: 0.12 h
Yield: 88.8 %

Procedure:
2 g (8.28 mmol) of epoxide 2j in solution in 5 cm3 of anhydrous DMF were heated to reflux for 5 h. The solution was acidified (pH<1) with 3N HCl, extracted with ether and concentrated, and a 3N sodium hydroxide solution was added to the ether phase (while the mixture was kept stirred for 5 to 10 min), the ether phase was removed and the material washed once with ether. The aqueous phase was acidified using a solution with 3N HCl (pH=1) and extracted with ether (4×30 cm3), dried over MgSO4, filtered and evaporated down. 1.24 g of phenol 4g were obtained as a liquid whose macrobore GC purity was higher than 97%. The yield of phenol 4g was 89%.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[Cl:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([O:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(Oc2cccc(Cl)c2C=O)cc1
Yield: 81.2 %

Procedure:
In a manner similar to the method described in Example 50a, 2,6-dichlorobenzaldehyde (2.7 g, 15 mmol) (Aldrich) was reacted with 4-methoxyphenol (1.8 g, 15 mmol) and K2CO3 in N,N-dimethylacetamide to give 2-chloro-6-(4-methoxy-phenoxy)-benzaldehyde as a yellow oil (Yield 3.2 g, 80%).
Reaction SMILES: [CH2:1]([N:4]([CH2:15][CH2:16][CH3:17])[C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH2:2][CH3:3].[NH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24].[OH-].[Na+].O1CCCC1>O>[CH2:1]([N:4]([CH2:15][CH2:16][CH3:17])[C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: NCCCCC(=O)O
Reactant: CCCN(CCC)c1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCN(CCC)c1ccc(S(=O)(=O)NCCCCC(=O)O)cc1
Reaction time: 2 h
Yield: 71.4 %

Procedure:
6.5 g of 4-dipropylaminobenzenesulphonyl chloride, in solution, are added to a solution comprising 2.76 g of 5-aminovaleric acid and 2.82 g of sodium hydroxide dissolved in 28 cm3 of water, followed by the addition of 28 cm3 of tetrahydrofuran. The mixture is kept stirring for 2 hours, the tetrahydrofuran is evaporated off, the reaction medium is acidified using acetic acid and the solid formed is filtered off, washed with water and dried. 6 g of expected product are obtained. M.p. 95°-98° C. After crystallization in an isopropanol/water mixture (1:1), 5 g of product, melting point 98°-99° C., are obtained.
Reaction SMILES: [OH:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[I-].C[N+]1C=CN([C:19](=[O:28])[N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)C=1.C(N(CC)CC)C>C(#N)C>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([O:1][C:19](=[O:28])[N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]=1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: Oc1cc2ccccc2cn1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C(=O)Oc1cc2ccccc2cn1)c1ccccc1
Yield: 98.2 %

Procedure:
A solution of 3-hydroxyisoquinoline (0.44 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (50:50)) yielding the title compound (0.82 g, 99% yield) as a white solid.
Reaction SMILES: [CH2:1]([CH:8]1[NH:12]C(=O)N[C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:15].[Na+].C.Cl>>[NH2:12][CH:8]([C:9]([OH:14])=[O:15])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)C(Cc2ccccc2)N1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: NC(Cc1ccccc1)C(=O)O
Yield: 72 %

Procedure:
95.1 g (0.5 mole) of 5-benzyl-hydantoin are heated to boiling in 350 ml of a 20% sodium hydroxide solution for 30 hours. The reaction mixture is clarified with activated charcoal and acidified with concentrated hydrochloric acid (pH 2). The precipitate (hydrantoinic acid) is filtered off and the phenyl alanine is precipitated from the filtrate as described in Example 11. Thus 59.5 g of the dry desired compound are obtained, yield 72%. Purity: 97.5% (according to HPLC).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C@H:11]([C:17](O)=[O:18])[CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])(=[O:9])=[O:8])=[CH:4][CH:3]=1>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C@H:11]([CH2:17][OH:18])[CH:12]([CH2:13][CH3:14])[CH2:15][CH3:16])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: CCC(CC)[C@H](NS(=O)(=O)c1ccc(Cl)s1)C(=O)O
Solvent: C1CCOC1
Product: CCC(CC)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To N-[(5-Chloro-2-thienyl)sulfonyl]-3-ethyl-L-norvaline (5.6 g, 17.2 mmol) in THF (150 mL) at 0° C. was added a solution of 1 M borane tetrahydrofuran complex in THF (69 mL, 69 mmol) dropwise via addition funnel. After 15 min, the reaction mixture was warmed to 25° C. and stirred for 18 h. It was then quenched with 90 mL of 10% AcOH in MeOH slowly. Volatiles were removed in vacuo. The residue was then dissolved in EtOAc (300 mL) and washed with saturated aqueous NaHCO3 (3×200 mL), dried (Na2SO4), and concentrated to a white precipitate (5.1 g, 96% yield, 96% chiral purity). The precipitate was recrystallized with heptane/EtOAc, 4:1, to give optically pure 5-chloro-N-[(S)-2-ethyl-1-(hydroxymethyl)butyl]-2-thiophenesulfonamide as white needles (4.4 g, 81% yield). [α]D25=+4.5° (c=1% SOLUTION, DMSO). Mass Spectrum (−ESI): 310 (M−H)−. Anal. Calc'd for C11H18CINO3S2: C, 42.37; H, 5.82; N, 4.49. Found: C, 42.37; H, 5.79; N, 4.38.