Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].O.O.O.C([O-])(=O)C.[Na+].[Cl:20][C:21]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:22]=1[CH2:23]Cl.Cl>O.C(#N)C>[Cl:20][C:21]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:22]=1[CH2:23][NH:9][C:6]1[CH:5]=[CH:4][C:3]([S:1]([OH:11])(=[O:10])=[O:2])=[CH:8][CH:7]=1
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=S(=O)(O)c1ccc(NCc2ccc(Cl)cc2Cl)cc1
Yield: 55.3 %

Procedure:
To a mixture of 52.0 g (0.30 mole) of sulfanilic acid in 225 ml of warm water was added 83 g (0.61 mole) of sodium acetate trihydrate and 75 ml of acetonitrile. Then a solution of 37.1 g (0.19 mole) of 2,4-dichlorobenzyl chloride in 75 ml of acetonitrile was added and the resulting solution refluxed for 31/2 hrs, followed by the dropwise addition of 50 ml of conc. HCl while simultaneously removing 75 ml of acetonitrile by distillation. The reaction mixture was filtered while hot (80° C.) and the same purification sequence utilized as described in the previous example, which gave 34.91 g (55.3% yield) of purified 4-(((2,4-dichlorophenyl)methyl)amino)benzenesulfonic acid as a white powder having a melting point greater than 275° C.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:29]([CH2:30][CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:37](=[O:48])[NH:38][C@@H:39]([C:41]4[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=4)[CH3:40])[CH:26]=3)[C:21]2=[O:49])=[CH:16][CH:15]=1.C1CCN2C(=NCCC2)CC1.[CH:61]1([S:64]([NH2:67])(=[O:66])=[O:65])[CH2:63][CH2:62]1>O1CCCC1>[CH:61]1([S:64]([NH:67][C:34](=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][C:29]2[N:20]([C:17]3[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=3)[C:21](=[O:49])[C:22]3[C:27]([CH:28]=2)=[CH:26][C:25]([C:37]([NH:38][C@@H:39]([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)[CH3:40])=[O:48])=[CH:24][CH:23]=3)(=[O:66])=[O:65])[CH2:63][CH2:62]1
Reactant: NS(=O)(=O)C1CC1
Reactant: C[C@@H](NC(=O)c1ccc2c(=O)n(-c3ccc(F)cc3)c(CCCCC(=O)O)cc2c1)c1ccc(F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@@H](NC(=O)c1ccc2c(=O)n(-c3ccc(F)cc3)c(CCCCC(=O)NS(=O)(=O)C3CC3)cc2c1)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
CDI (13.50 mg, 0.083 mmol) was added to a stirred, room temperature mixture of (R)-5-(2-(4-fluorophenyl)-6-((1-(4-fluorophenyl)ethyl)carbamoyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoic acid (28 mg, 0.055 mmol) in tetrahydrofuran (2 mL) and the mixture was stirred at 70° C. for 2 h. DBU (0.017 mL, 0.111 mmol) and cyclopropylsulfonamide (10.09 mg, 0.083 mmol) were added, the resultant mixture was kept stirring at room temperature overnight. The mixture was concentrated, and the residue was purified via PTLC (Emerck 1 mm), eluted with CH2Cl2/MeOH=10:1 to give (R)-3-(5-(cyclopropanesulfonamido)-5-oxopentyl)-2-(4-fluorophenyl)-N-(1-(4-fluorophenyl)ethyl)-1-oxo-1,2-dihydroisoquinoline-6-carboxamide (16 mg) as a white solid. LCMS [M+H]+=608. 1H NMR (500 MHz, DMSO) δ ppm: 9.06 (d, J=7.88 Hz, 1H), 8.20 (d, J=8.20 Hz, 1H), 8.15 (s, 1H), 7.36-7.50 (m, 6H), 7.18 (t, J=8.99 Hz, 2H), 6.69 (s, 1H), 5.22 (t, J=7.25 Hz, 1H), 3.16-3.19 (m, 1H), 2.87-2.94 (m, 1H), 2.26 (br. s, 2H), 2.16 (br. s, 2H), 1.51 (d, J=7.25 Hz, 3H), 1.43 (br. s, 3H), 0.98-1.05 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][O:9]/[N:10]=[C:11](/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)\[C:12]#[N:13])[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].C(=O)([O-])[O-].[K+].[K+]>CC(O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][N:10]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)/[C:12](=[N:21]/[OH:22])/[NH2:13])[CH:5]=[CH:4][CH:3]=1
Reactant: N#C/C(=N\OCc1cccc(N)n1)c1ccccc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: N/C(=N\O)C(=NOCc1cccc(N)n1)c1ccccc1
Temperature: 80 °C
Yield: 110.6 %

Procedure:
To a suspension of (2Z)-{[(6-aminopyridin-2-yl)methoxy]imino}(phenyl)acetonitrile (4 g, 15.85 mmol, 1 eq.) in iPrOH/H2O (10/1, 110 ml) were added hydroxylamine hydrochloride (3.30 g, 47.56 mmol, 3 eq.) and potassium carbonate (6.57 g, 47.56 mmol, 3 eq.). The reaction was heated to 80° C. for 6 h and the solvent was evaporated to ¾th. The residue was extracted with EtOAc (3×50 ml) and washed with aq. sat. NaCl. The organics were combined, dried over MgSO4 and concentrated to give (Z)-2-{[(6-aminopyridin-2-yl)methoxy]imino}-N′-hydroxy-2-phenylethanimidamide (5 g, 99% yield) as a white solid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:12]3=[C:13]4[S:19][CH:18]=[CH:17][C:14]4=[N:15][CH:16]=[C:11]3[N:10]=[C:9]2[C@H:20]([OH:22])[CH3:21])[CH2:4][CH2:3]1.C(N(CC)CC)C.FC(F)(F)S(O[CH2:36][C:37]([F:40])([F:39])[F:38])(=O)=O>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[CH2:36][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:12]3=[C:13]4[S:19][CH:18]=[CH:17][C:14]4=[N:15][CH:16]=[C:11]3[N:10]=[C:9]2[C@H:20]([OH:22])[CH3:21])[CH2:4][CH2:3]1
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1C1CCNCC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1C1CCN(CC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
To a mixture of (1R)-1-(1-piperidin-4-yl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)ethanol hydrochloride (21.6 mg, 0.0637 mmol) and triethylamine (40.0 μL, 0.287 mmol) in methylene chloride (0.78 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (17.8 mg, 0.0765 mmol). The resulting mixture was stirred overnight at room temperature. The solvents were evaporated, and the crude residue purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 6.5 mg (26%) of the desired product. LCMS calculated for C17H20F3N4OS (M+H)+: m/z=385.1. Found: 385.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C1COCC1.[Br:17][C:18]([CH3:23])([CH3:22])[C:19](Br)=[O:20]>CCN(CC)CC>[Br:17][C:18]([CH3:23])([CH3:22])[C:19]([NH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11])=[O:20]
Reactant: CC(C)(Br)C(=O)Br
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(Br)C(=O)Nc1cc([N+](=O)[O-])ccc1O
Reaction time: 0.75 h

Procedure:
2-Amino-4-nitro-phenol (3.08 g, Aldrich) was stirred with THF (30 ml, Aldrich) in an ice bath. 2-Bromo-2-methyl-propionyl bromide (2.47 ml, Aldrich) and Et3N (2.0 g, Aldrich) was slowly added via syringe. The mixture was stirred for 45 min then poured into ice. The aqueous phase was extracted by EtOAc (50 mL×4). The organic layer was dried and concentrated. The desired product was crystallized from EtOAc. (Chem. Pharm. Bull 1996, 44(1) 103-114).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[C:6]=2[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:31])[O:29][CH3:30]>O1CCCC1>[CH3:30][O:29][C:28]([NH:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[C:6]=2[CH:5]=[CH:4][N:3]=1)=[O:31]
Reactant: COC(=O)Cl
Reactant: Nc1nccc2c1ccn2C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Nc1nccc2c1ccn2C(=O)OCc1ccccc1
Temperature: -10 °C
Yield: 49.1 %

Procedure:
A well stirred mixture of a solution of benzyl 4-amino-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (464 mg, 1.74 mmol) and triethylamine (0.49 mL, 3.47 mmol) in tetrahydrofuran was cooled to −10° C. and treated drop wise with methyl carbonochloridate (0.15 mL, 1.92 mmol). The reaction mixture was stirred at room temperature for 30 minutes followed by removal of volatiles under vacuum. The residue was dissolved in ethyl acetate and organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to yield benzyl 4-[(methoxycarbonyl)amino]-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (278 mg, 49.13%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>>[C:12]([O:11][C:9]([N:16]1[CH2:21][CH2:20][CH:19]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:18][CH2:17]1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)CC1
Yield: 100.9 %

Procedure:
Using general procedure A, benzylamine (1.2 mL, 11 mmol) and 1-Boc-4-piperidone (2.0 g, 10 mmol) gave 4-benzylamino-piperidine-1-carboxylic acid tert-butyl ester as a white solid (2.93 g, 100%).
Reaction SMILES: C(OC(=O)[N:7]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=1)[C:8]1[N:13]=[C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:11]=[N:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:27][C:23]1[N:22]=[C:21]([CH2:20][NH:7][C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[CH:11]=[N:10][CH:9]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cccc(CN(C(=O)OC(C)(C)C)c2cncc(N3CCNCC3)n2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(CNc2cncc(N3CCNCC3)n2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (6-methyl-pyridin-2-yl methyl)-(3,4,5,6-tetrahydro-2H-[1,2′]-bipyrazinyl-6′-yl)-carbamic acid tert-butyl ester I-4l (196.9 mg, 0.51 mM) in methylene chloride (2 mL) was treated with trifluoroacetic Acid (0.39 mL, 5.12 mmol). The resulting mixture was stirred at ambient temperature overnight. The reaction mixture was quenched with saturated NaHCO3 solution and the pH of the aqueous layer brought to approximately 10 using 1N NaOH. The reaction mixture was diluted with methylene chloride and separated. The aqueous layer was extracted with methylene chloride and the organic layers were combined, dried (Na2SO4), and concentrated to dryness to afford the desired product I-4m.
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:13]([CH:20](Br)[C:21]([OH:23])=[O:22])[CH2:14][CH:15](Br)[C:16]([OH:18])=[O:17].[OH-].[Li+]>O>[N:1]1([CH:15]([CH2:14][CH2:13][CH:20]([N:1]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[C:21]([OH:23])=[O:22])[C:16]([OH:18])=[O:17])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(Br)CCC(Br)C(=O)O
Reactant: C1CNCCNCCNCCN1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(CCC(C(=O)O)N1CCNCCNCCNCC1)N1CCNCCNCCNCC1
Temperature: 60 °C
Yield: 51.4 %

Procedure:
A mixture of cyclen (60.75 g, 350 mmol), meso-2,5-dibromoadipic acid (10.57 g, 35 mmol), and 1M lithium hydroxide (70 mL, 70 mmol) in water (104 mL) was heated to 60° C. under nitrogen for 170 hours. After cooling to ambient temperature, the reaction mixture was applied to an AG1X8 anion exchange column [400 mL (OH-form)]. The column was washed thoroughly with water (4 L), and the product was eluted with 0.5M acetic acid (2 L). Fractions containing product were combined, chased with water (3×200 mL) and ethanol (3×100 mL) to yield the title product (8.75 g, 51.8%) as a white, hygroscopic foam. Unreacted cyclen was reclaimed by concentration of the first 2 L of eluent and recrystallization from water. 1H NMR: (D2O) δ 2.75-2.90 (br mult, 34H), 1.52 (br, 4H). 13C NMR: (D2O) 24.3, 40.5, 41.1, 41.3, 41.6, 43.1, 44.9, 63.0, 177.1. MS (FAB): m/e 487.4 (MH+).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([C:8]1[CH:31]=[CH:30][C:11]([O:12][CH2:13][CH:14]([OH:29])[CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([OH:28])=[CH:22][C:23](=[O:27])[O:24]3)=[CH:19][CH:18]=2)=[C:10]([CH2:32][CH2:33][CH3:34])[C:9]=1[OH:35])(=[O:7])[CH3:6].Cl>C(Cl)(Cl)Cl>[C:5]([C:8]1[CH:31]=[CH:30][C:11]([O:12][CH2:13][CH:14]([OH:29])[CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([OH:28])=[C:22]([N+:1]([O-:4])=[O:2])[C:23](=[O:27])[O:24]3)=[CH:19][CH:18]=2)=[C:10]([CH2:32][CH2:33][CH3:34])[C:9]=1[OH:35])(=[O:7])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CCCc1c(OCC(O)COc2ccc3c(O)cc(=O)oc3c2)ccc(C(C)=O)c1O
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCc1c(OCC(O)COc2ccc3c(O)c([N+](=O)[O-])c(=O)oc3c2)ccc(C(C)=O)c1O
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Fuming nitric acid (9 ml) was added to a stirred suspension of 7-(3-[4-Acetyl-3-hydroxy-2-n-propylphenoxy]-2-hydroxypropoxy)-4-hydroxycoumarin (2.8 g) in chloroform (300 ml) over 1 hr at 0° and the dark mixture stirred for a further 0.5 hr at this temperature. Dilute hydrochloric acid (150 ml) was added and the chloroform removed in vacuo at 0°. The solid which separated was removed by filtration and recrystallised from ethanol to give 2.42 g, (78%) of yellow solid of mp 201°-203° (dec). νmax (mull) 3350 (br), 1770, 1620, 1610, 1540 cm-1 ; τ(DMSO); 9.17 (3H, t, J 6.9 Hz); 8.55 (2H, m, J ca 7 Hz); 7.43 (3H, S+2H, m); 5.78 (5H, S); 3.20 (3H, m); 2.16 (2H, exchangeable S); 2.16 (2H, near doublet); 1 low field broad exchangeable). (Found; C, 58.49; H, 5.07; N, 3.04; C23H23NO10 requires; C, 58.35; H, 4.90; N, 2.96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[C:13](Cl)(=[O:16])[CH:14]=[CH2:15].C([O-])([O-])=O.[Na+].[Na+].C(N(CC)CC)C>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[CH:14]=[CH2:15])=[CH:5][CH:4]=1
Reactant: COc1ccc(SCCN)cc1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CC(=O)NCCSc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound 1 (1.83 g) in EtOAc (50 mL) was added acryloyl chloride (1.35 g, 1.5 eq.) and Na2CO3 (2.12 g, 2.0 eq.). The reaction mixture was stirred at r.t. overnight and triethylamine was added. After stirring for 20 min, the mixture was washed with H2O (20 mL), 1N HCl (2×20 mL) and sat. NaHCO3 (2×20 mL). The solvents were removed by evaporation under reduced pressure to give product 32 as white solid (one spot on TLC). Yield: 2.2 g, 92.8%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][OH:8])=[CH:2]1.[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:9][S:10]([O:8][CH2:7][CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)(=[O:12])=[O:11]
Reactant: OCCc1ccsc1
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCc1ccsc1
Temperature: 25 °C
Reaction time: 0.29 h
Yield: 65 %

Procedure:
To a solution of 5.0 g (7.8×10-3 mol) of 2-(3-thienyl)-ethanol (Aldrich Chemical) in 10 ml of dry, freshly distilled pyridine was added 3.62 ml (1.2 equiv.) of methanesulfonyl chloride in 20 ml of pyridine at 5°-10° C. The addition was carried out gradually, over a period of about 15-20 min. The reaction mixture was stirred overnight at room temperature and was quenched by pouring into a separatory funnel containing water and ether. The layers were separated and the aqueous layer was extracted three times with ether. The combined organic extracts were extracted once with 10% hydrochloric acid, followed by water and drying over Na2SO4. Evaporation of the solvent afforded 5.3 g of a light brown oil (65% yield), and tlc (CHCl3) showed a single spot. Chromatographic purification on silica gel afforded a light yellow oil. Nmr (CDCl3, δ rel TMS) 2.9s, 3H; 3.1t, 2H; 4.4t, 2H; 7.0-7.4m, 3H. Ir (neat, ν cm-1) 3100w, 2930w, 2920w 1415w, 1355s, 1335s, 1245w, 1173s, 1080w, 1055w, 970s, 955s, 903m, 850m, 825w, 795s, 775s, 740w. MS, 206.0.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:21])([CH3:20])[O:14][SiH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[C:9]([CH:22]([CH3:24])[CH3:23])[CH:8]=1)(=O)=O.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29]>C(N(CC)CC)C.CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:16]([SiH2:15][O:14][C:13]([CH3:21])([CH3:20])[C:10]1[CH:11]=[CH:12][C:7]([C:32]#[C:31][Si:28]([CH3:30])([CH3:29])[CH3:27])=[CH:8][C:9]=1[CH:22]([CH3:24])[CH3:23])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)c1cc(OS(=O)(=O)C(F)(F)F)ccc1C(C)(C)O[SiH2]C(C)(C)C
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1cc(C#C[Si](C)(C)C)ccc1C(C)(C)O[SiH2]C(C)(C)C
Temperature: 95 °C
Yield: 23.6 %

Procedure:
To a solution of 4-(tert-butyl-dimethyl-silanyloxymethyl)-3-isopropyl-phenyl 1,1,1-trifluoro-methansulfonate (Intermediate 150, 970.0 mg, 2.35 mmols) in triethylamine (2 mL) and 6 mL DMF was sparged with argon for 15 minutes. Trimethylsilyl acetylene (1.00 g, 10.6 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (66.0 mg, 0.09 mmol). The resulting reaction mixture was heated to 95° C. for 20 hours. The solution was cooled to room temperature and concentrated under reduced pressure. The title compound (200.0 mg, 78%) was isolated by chromatography (0-25% EtOAc-hexanes) as an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.C(O)C>[Pd].O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH:12]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COc1ccc(C2=Cc3ccc(OC)cc3C3CCCCC23)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(C2Cc3ccc(OC)cc3C3CCCCC23)cc1
Reaction time: 18 h
Yield: 87.7 %

Procedure:
Combine 6-methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,10a-hexahydro-phenanthrene (48.5 mg, 0.15 mmol), 10% Pd—C (5.4 mg, 0.04 mmol), and ethanol (3 mL) and tetrahydrofuran (3 mL), degas, and add H2 at atmospheric pressure and at room temperature. After 18 hours, filter off the Pd catalyst over celite eluting with ethyl acetate. Concentrate and flash chromatograph with 0% to 20% ethyl acetate/hexanes to yield the titled compound (42.4 mg, 87%) as a clear oil. TLC Rf=0.51 in 6:1 hexanes:ethyl acetate. 1H NMR (CDCl3): 7.25 (d, 2H, J=8.4 Hz), 7.11 (d, 1H, J=8.4 Hz), 6.97 (m, 1H), 6.90 (d, 2H, J=7.9 Hz), 6.75 (m, 1H), 3.82 (m, 6H), 3.19 (m, 3H), 2.87 (dd, 1H, J=15.0, 4.0 Hz), 2.49 (m, 1H), 2.04 (m, 1H), 1.65 (m, 2H), 1.45 (m, 1H), 1.29 (m, 1H), 1.15 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5])[CH3:2].[CH2:12]([NH2:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[NH:20][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2]
Reactant: NCCc1ccccc1
Reactant: CCOC(=O)C1CCCC1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1CCCC1NCCc1ccccc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 38.6 %

Procedure:
A solution of 2-oxo-cyclopentanecarboxylic acid ethyl ester (3.00 g, 19.2 mmol) in ethanol (20 mL) was treated with phenethylamine (2.41 mL, 19.2 mmol), sodium cyanoborohydride (2.42 g, 38.4 mmol), and glacial acetic acid (10 drops) and stirred for 16 h at 50° C. After cooling to 25° C. the solvent was removed in vacuo, the crude material was redissolved in ethyl acetate (100 mL and washed with saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was discarded and the organic layer was washed with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was discarded, 1.0 M aqueous sodium hydroxide solution (75 mL) was added and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo to afford the desired product, 2-phenethylamino-cyclopentanecarboxylic acid ethyl ester (1.94 g, 7.42 mmol, 38.6%), as a light yellow solid. LC-MS (ESI) calcd for C16H23NO2 261.17, found 262.2 [M+H+].
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:14])/[CH:9]=[CH:10]\[C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][NH:16][C:17]([NH:19][CH3:20])=[O:18].C1(C)C(O)=CC=CC=1>>[CH3:15][N:16]1[C:10](=[CH:9][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:14])[C:11](=[O:13])[N:19]([CH3:20])[C:17]1=[O:18]
Reactant: CNC(=O)NC
Reactant: O=C(O)/C=C\C(=O)Nc1ccccc1
Agent: Cc1ccccc1O
Product: CN1C(=O)C(=CC(=O)Nc2ccccc2)N(C)C1=O
Temperature: 165 °C
Reaction time: 2.5 h

Procedure:
A mixture of 19.1 parts of N-phenyl maleic acid monoamide 8.8 parts of N,N'-dimethyl urea and 100 parts of cresol is stirred for 2.5 hours at 165° C. The solvent is distilled off in vacuo and the residue fractionated. An oily liquid distills over at a boiling point of from 220° to 223° C./0.1 Torr and solidifies after a while. Recrystallisation from n-propanol gives the compound confirmed by IR- (bands characteristic of hydantoins at 1705 and 1765 cm-1 and of amide at 1690 cm-1) and NMR-spectra.
Reaction SMILES: C([C@H](NC(=O)C1C=C(C2C=CC=CC=2)C=C(N2CCCC2=O)C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[CH:44]([O:47][C:48]1[CH:49]=[C:50]([CH:54]=[C:55]([N:57]2[CH2:61][CH2:60][CH2:59][C:58]2=[O:62])[CH:56]=1)[C:51]([OH:53])=O)([CH3:46])[CH3:45].[CH:63]12[CH2:69][CH:66]([CH2:67][CH2:68]1)[CH2:65][CH:64]2[NH:70][C:71](=[O:86])[C@H:72]([CH3:85])[CH2:73][C@H:74]([OH:84])[C@@H:75]([NH2:83])[CH2:76][C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1>>[CH2:76]([C@H:75]([NH:83][C:51](=[O:53])[C:50]1[CH:54]=[C:55]([N:57]2[CH2:61][CH2:60][CH2:59][C:58]2=[O:62])[CH:56]=[C:48]([O:47][CH:44]([CH3:45])[CH3:46])[CH:49]=1)[C@@H:74]([OH:84])[CH2:73][C@H:72]([C:71](=[O:86])[NH:70][CH:64]1[CH2:65][CH:66]2[CH2:69][CH:63]1[CH2:68][CH2:67]2)[CH3:85])[C:77]1[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=1
Reactant: CC(C)Oc1cc(C(=O)O)cc(N2CCCC2=O)c1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Product: CC(C)Oc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NC2CC3CCC2C3)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to E6 from 3-isopropoxy-5-(2-oxopyrrolidin-1-yl)benzoic acid (D16) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D29).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH2:32])[N:17]=[C:16]([CH:33]3[CH2:35][CH2:34]3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].CC1C=C[C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39]C=1>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH:32][S:43]([CH2:40][CH3:39])(=[O:45])=[O:44])[N:17]=[C:16]([CH:33]3[CH2:34][CH2:35]3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(C2CC2)nc1OCCN
Product: CCS(=O)(=O)NCCOc1nc(C2CC2)nc(NS(=O)(=O)c2ccc(C(C)C)cn2)c1Oc1ccccc1OC

Procedure:
According to the procedure described in Example 4a), 250 mg 5-i-propyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamide was reacted with 4-methylbenzenesulfonylchloride to give 100 mg 5-i-propyl-N-[6-(2-ethanesulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamide. LC-MS: tR=5.32 min, [M−1]−=604.39.