Azzindani/Open_Reaction_Data huggingface dataset:
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].CCOCC.[C:17](O)(=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].CS(O)(=O)=O>>[C:17]([O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: Oc1ccc2ccccc2c1
Agent: CS(=O)(=O)O
Solvent: CCOCC
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Oc1ccc2ccccc2c1
Temperature: 220 °C

Procedure:
To a four neck round bottom flask fitted with nitrogen inlet, mechanical stirrer, temperature probe and condenser is charged 1102.84 g (1.85 moles) of the Alkoxylate from example 15 and 497.16 g (1.76 moles) of Oleic Acid. A catalytic amount of Methanesulfonic Acid (1.6 g) is charged and the reaction mixture is heated to 220° C. under nitrogen sparge. The reaction is monitored by measuring the acid value to an AV of preferably less than 5. Once the AV is reached, the temperature is cooled to 85° C. and the catalyst is neutralized with an equivalent molar amount of 45% KOH and washed once with water. The reaction is dried under vacuum yielding the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:37]
Reactant: COCCC1(C(=O)N[C@@H](Cc2ccc([N+](=O)[O-])cc2)C(=O)OC)CCCC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COCCC1(C(=S)N[C@@H](Cc2ccc([N+](=O)[O-])cc2)C(=O)OC)CCCC1
Reaction time: 18 h
Yield: 98.6 %

Procedure:
To a solution of [[1-(2-methoxyethyl)cyclopentyl]carbonyl]-4-nitro-L-phenylalanine methyl ester (4.30 g, 11.4 mmol) in toluene (20 mL) was added Lawesson's reagent (2.60 g, 6.27 mmol). The resultant mixture was warmed to 50° C. and stirred for 18 h. The reaction mixture was filtered through a sintered glass funnel and the filtrate was concentrated in vacuo. The residue was by flash column chromatography over silica gel (hexane-ethyl acetate, 9:1 then 8:1) to afford N-[[1-(2-methoxyethyl)cyclopentyl]thioxomethyl]-4-nitro-L-phenylalanine methyl ester (2.44 g, 54%; 70% based on recovered starting material) as a light yellow oil. HR MS: Obs. mass, 395.1639. Calcd. mass, 395.1640 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9]/[CH:10]=[C:11]2\[C:12](=[O:23])[NH:13][C:14](=[O:22])[C:15]3[C:20]\2=[CH:19][C:18](I)=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]=1[NH:24][C:25](=[O:32])[C:26]1C=CC=C[CH:27]=1.NC1C=CC(CN/C=C2\C(=O)NC(=O)C3C\2=CC([Br:51])=CC=3)=CC=1O[Si](C(C)C)(C(C)C)C(C)C.C(Cl)(=O)C=C>>[Br:51][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:22])[NH:13][C:12](=[O:23])/[C:11]/2=[CH:10]\[NH:9][CH2:8][C:6]1[CH:5]=[CH:4][C:3]([NH:24][C:25](=[O:32])[CH:26]=[CH2:27])=[C:2]([OH:1])[CH:7]=1
Reactant: CC(C)[Si](Oc1cc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)ccc1N)(C(C)C)C(C)C
Reactant: O=C1NC(=O)c2ccc(I)cc2/C1=C/NCc1ccc(NC(=O)c2ccccc2)c(O)c1
Agent: C=CC(=O)Cl
Product: C=CC(=O)Nc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1O

Procedure:
Following the acetylation and desilylation procedure employed for the preparation of N-[2-hydroxy-4-({[(Z)-(6-iodo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)phenyl]benzamide, (4Z)-4-[({4-amino-3-[(triisopropylsilyl)oxy]benzyl}-amino)methylene]-6-bromoisoquinoline-1,3(2H,4H)-dione (54 mg, 0.10 mmol) is reacted with acryloyl chloride (41 μL, 0.50 mmol). Following desilylation, precipitation, and washing with methanol and diethyl ether, N-[4-({[(Z)-(6-bromo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)-2-hydroxyphenyl]acrylamide is obtained (8 mg, 18
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])[CH:5]=[CH:6][C:7]=1[Cl:8].C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][S:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])=[O:26])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [O-][n+]1ccccc1SCc1ccc(Cl)c(Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=S(Cc1ccc(Cl)c(Cl)c1)c1cccc[n+]1[O-]

Procedure:
The procedure employed is identical to that of Example 68 using 8 gm (0.028 mol) B 2-(3,4-dichlorophenylmethylthio)pyridine N-oxide in 50 ml of chloroform and 5.6 gm (0.028 mol) MCPBA in 100 ml chloroform.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.CN(C)[CH:12]=[O:13].P(Cl)(Cl)(Cl)=O.O>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:12]=[O:13])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCO2
Reactant: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1ccc2c(c1)CCO2
Temperature: 85 °C
Reaction time: 2 h
Yield: 275.8 %

Procedure:
2,3-Dihydrobenzofuran (100 g, 832 mmol) and N,N-dimethylformamide (134 g, 1830 mmol) were mixed and heated, and phosphorus oxychloride (255 g, 1643 mmol) were added thereto at an inner temperature of 70 to 80° C. over 2 hrs. The reaction mixture was heated at an inner temperature of 80 to 90° C. and stirred for 7.5 hrs. Then, the resulting mixture was added dropwise to water (1000 g) under cooling, and stirred at room temperature for 5 hrs. The resulting mixture was extracted with toluene, and the extract was washed sequentially with water, saturated sodium bicarbonate aqueous solution and water, and the organic layer was concentrated under vacuum to give a toluene solution of the title compound (amount 340 g, apparent yield 100%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]([CH2:8][NH:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][CH3:13])[CH2:6][CH3:7].[Br:18][CH:19]([CH3:23])[C:20](Cl)=[O:21]>>[Br:18][CH:19]([CH3:23])[C:20]([N:9]([CH2:8][CH:5]([CH2:6][CH3:7])[CH2:4][CH2:3][CH2:2][CH3:1])[CH2:10][CH:11]([CH2:12][CH3:13])[CH2:14][CH2:15][CH2:16][CH3:17])=[O:21]
Reactant: CC(Br)C(=O)Cl
Reactant: CCCCC(CC)CNCC(CC)CCCC
Product: CCCCC(CC)CN(CC(CC)CCCC)C(=O)C(C)Br
Yield: 98 %

Procedure:
Step A is conducted starting with 2,2′-diethylhexylamine and 2-bromopropionyl chloride and leads to 2-bromo-N,N-bis(2-ethylhexyl)propanamide (Yield: 98%) for which the 1H and 13C NMR characterisations are the following:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]([NH:22][NH:23][C:24]([NH2:26])=S)=[O:21])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1>ClCCCl>[NH2:1][C:2]1[C:3]([C:20]2[O:21][C:24]([NH2:26])=[N:23][N:22]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C(=O)NNC(N)=S)n2)cc1
Solvent: ClCCCl
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(N)o3)n2)cc1
Yield: 86.1 %

Procedure:
EDC (109.3 mg, 0.5704 mmol) was added to a stirred suspension of [[3-amino-6-(4-isopropylsulfonylphenyl)pyrazine-2-carbonyl]amino]thiourea (150 mg, 0.3803 mmol) in DCE (3.000 mL) and the reaction mixture heated at reflux for 22 h. The solvent was removed in vacuo and the residue partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3×10 mL) and the combined organic extracts dried MgSO4, filtered and concentrated in vacuo to give the sub-title compound as a yellow solid (118 mg, 86%) 1H NMR (400 MHz, DMSO) d 1.19 (d, 6H), 3.45 (dt, 1H), 7.65-7.80 (m, 4H), 7.95 (d, 2H), 8.26 (d, 2H) and 8.89 (s, 1H) ppm; MS (ES+) 361.0
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:31]([NH:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH3:23])=[O:32])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Cc1ccccc1N=C=O
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4C)cc3)c2cc1OC
Yield: 82 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (51 mg) was dissolved in toluene (5 ml) with heat, 2-methylphenyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 15 minutes. The resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 61 mg of the title compound (yield: 82%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=1.[B:18]([O:27][CH:28]([CH3:30])[CH3:29])([O:23][CH:24]([CH3:26])[CH3:25])OC(C)C.C([Li])CCC>C1COCC1>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:6]2[CH:5]=[N:4][CH:3]=[C:2]([B:18]3[O:23][C:24]([CH3:25])([CH3:26])[C:28]([CH3:29])([CH3:30])[O:27]3)[CH:7]=2)=[CH:11][CH:12]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(COc2cncc(Br)c2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(COc2cncc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Temperature: -78 °C

Procedure:
To a solution of 3-bromo-5-(4-methoxy-benzyloxy)-pyridine (300 mg) in THF (10 mL) was added triisopropyl borate (0.28 mL) and the mixture cooled to −78° C. Then n-butyllithium (0.49 mL of a 2.5 M solution in hexanes) was added maintaining the temperature below −65° C. The reaction mixture was then allowed to warm to −20° C. over 1 h and then quenched with 2 M aqueous hydrochloric acid (2 mL). The mixture was allowed to warm to room temperature over 1 h and then diluted with water (25 mL), the pH was adjusted to 7 and then extracted into ethyl acetate (3×25 mL). The combined organics were washed with brine (20 mL), dried (MgSO4) and reduced in vacuo. A mixture of the crude product and pinacol (236 mg) in toluene (15 mL) was then heated at reflux for 4 h. The mixture was then reduced in vacuo, dissolved in ethyl acetate (30 mL) and washed with water (2×30 mL) and brine (30 mL). The combined organics were dried (MgSO4) and reduced in vacuo to give 3-(4-methoxy-benzyloxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine as an off-white solid (162 mg).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>ClCCl.FC(F)(F)C(O)=O>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[C:20]([OH:22])=[O:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)C(=O)CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 68.5 %

Procedure:
tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(dimethylamino)-5-oxopentanoate (Compound SP447) (15.2 g, crude product) was dissolved in a mixture of dichloromethane (200 ml) and trifluoroacetic acid (200 ml), followed by stirring at room temperature for 2.5 hours. The solvent was evaporated under reduced pressure, and the resulting solid was washed with a mixed solution of hexane and tert-butyl methyl ether and then dried in vacuo to afford (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(dimethylamino)-5-oxopentanoic acid (Compound SP448) (9.12 g, 85%, two steps).
Reaction SMILES: [Cl:1][C:2]1[N:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([CH:6](C(OCC)=O)C(OCC)=O)=[O:5]>CS(C)=O.O>[Cl:1][C:2]1[C:3]([C:4](=[O:5])[CH3:6])=[CH:17][CH:18]=[CH:19][N:20]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cccnc1Cl
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)c1cccnc1Cl
Temperature: 130 °C
Yield: 52 %

Procedure:
A solution of diethyl 2-(2-chloronicotinoyl)malonate (267 mmol) in dimethylsulfoxide (100 ml) was added dropwise over 1.5 h to a 130° C. solution of water (10 mL) in dimethylsulfoxide (260 mL). The reaction mixture was maintained at 130° C. for an additional 2 h and was allowed to cool to rt. The reaction mixture was diluted with cold (0° C.) water (500 mL) and was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (5×200 mL), dried (sodium sulfate), and concentrated. The residue was purified by chromatography (10/1 petroleum ether/ethyl acetate) to provide 1-(2-chloropyridin-3-yl)ethanone 52% yield as yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[H-].[Na+].[OH2:17]>ClCCl>[C:3]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][S:11]([CH3:14])(=[O:12])=[O:13])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)(=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O
Reactant: CS(=O)(=O)Nc1ccc2c(c1)CCN2
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc2c(c1)CCN2C(=O)c1ccccc1
Reaction time: 1 h
Yield: 50 %

Procedure:
N-(2,3-dihydro-1H-indole-5-yl)-methanesulfonamide (20 mg, 0.095 mmol) was dissolved in anhydrous dichloromethane (3 ml), sodium hydride (0.010 g, 50% in oil) was added and then, benzolychloride (0.011 ml, 0.095 mmol) was added at a temperature under −20° C. The resulting solution was stirred at the same temperature for 1 hour, stirred again at room temperature for 24 hours to complete the reaction. After pouring water (3 ml), dichloromethane layer was separated, washed with brine, dried over anhydrous magnesium sulfate and then, concentrated under reduced pressure. Afterward, the residue was purified through flash column chromatography (an eluent: ethyl acetate/n-hexane=1/1, v/v) and triturated with isooctane. As a result, the present compound (15 mg, productive yield 50%) was obtained as a solid.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][O:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][CH2:21][C:22]2=O)=[CH:18][CH:17]=1.O>C1COCC1>[CH3:14][O:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][CH2:21][C:22]2=[CH:5][C:3]#[N:4])=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=CC#N)CC2
Reaction time: 15 h
Yield: 52.5 %

Procedure:
To a solution of 60% sodium hydride (2.71 g, 67.9 mmol) in THF (150 ml) was added dropwise, under ice-cooling, diethyl cyanomethylphosphonate (11.5 g, 64.8 mmol). The mixture was stirred for 15 hours, to which was then added dropwise a solution of 6-methoxy-1-indanone (10.0 g, 61.7 mmol) in THF (30 ml). The reaction mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into water, and the organic layer was subjected to extraction with ethyl acetate. The extract solution was washed with brine and water, followed by drying over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (hexane:ethyl acetate=8:2). Recrystallization of the product-from ethyl acetate/hexane afforded the above-titled compound (6.00 g, yield 53%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9](Cl)[CH:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])[N:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[C-:23]#[N:24].[K+].C1(C)C=CC=CC=1S([O-])=O.[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:23]#[N:24])[CH:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])[N:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: Fc1cccc(F)c1C1N=CC=C(c2ccc(Br)cc2)N1Cl
Agent: Cc1ccccc1S(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CN1C(c2ccc(Br)cc2)=CC=NC1c1c(F)cccc1F
Temperature: 80 °C
Reaction time: 3 h

Procedure:
6 g of 4-(4-bromophenyl)-2-(2,6-difluorophenyl)-3-chloropyrimidine, 80 ml of dimethylformamide, 1.53 g of KCN and 0.93 g of sodium tolylsulfinate are mixed together, stirred for 3 hours at 80° C., mixed with ice water and filtered. After dissolving the precipitate in ethyl acetate, drying with magnesium sulfate, filtering and concentrating, the title compound is obtained with a melting point 146-148° C. (compound 3.355).
Reaction SMILES: [CH:1]1([N:4]([CH2:12][C:13]2[CH:18]=[C:17](/[CH:19]=[CH:20]/[CH2:21][O:22][CH3:23])[CH:16]=[CH:15][C:14]=2[CH3:24])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1.C>CCOC(C)=O.[Pd]>[CH:1]1([N:4]([CH2:12][C:13]2[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])[CH:16]=[CH:15][C:14]=2[CH3:24])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1
Reactant: COC/C=C/c1ccc(C)c(CN(C(=O)OC(C)(C)C)C2CC2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCCc1ccc(C)c(CN(C(=O)OC(C)(C)C)C2CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1-Dimethylethyl cyclopropyl({2-methyl-5-[(1E)-3-(methyloxy)-1-propen-1-yl]phenyl}methyl)carbamate (1 eq.) from the previous step and 10% w/w palladium over charcoal (0.1 eq.) were suspended in EtOAc (0.08 M). The vessel was then evacuated and purged with H2. Under a balloon-filled H2 atmosphere, the reaction suspension was stirred at RT for 2 h. The reaction was then quenched with CH2Cl2, filtered through a bed of celite and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH:34]1[C:46]2[CH:45]([CH2:47][O:48][C:49]([NH:51][C@H:52]([C:58](O)=[O:59])[CH2:53][CH2:54][C:55](=[O:57])[NH2:56])=[O:50])[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38]=2[CH:37]=[CH:36][CH:35]=1.[C:61]([O:65][C:66](=[O:82])[NH:67][CH2:68][CH2:69][CH2:70][C@H:71]([NH:74][C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[CH2:72][NH2:73])([CH3:64])([CH3:63])[CH3:62]>CN(C=O)C>[CH:43]1[C:44]2[CH:45]([CH2:47][O:48][C:49](=[O:50])[NH:51][C@H:52]([C:58]([NH:73][CH2:72][C@@H:71]([NH:74][C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[CH2:70][CH2:69][CH2:68][NH:67][C:66]([O:65][C:61]([CH3:63])([CH3:64])[CH3:62])=[O:82])=[O:59])[CH2:53][CH2:54][C:55]([NH2:56])=[O:57])[C:46]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:39]=2[CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CN)NC(=O)OC(C)(C)C
Reactant: NC(=O)CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)[C@H](CCC(N)=O)NC(=O)OCC1c2ccccc2-c2ccccc21)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
129 mg (0.34 mmol) of HATU and 133 mg (0.95 mmol) of N,N-diisopropylethylamine are added to a solution of 100 mg (0.27 mmol) of N2-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-glutamine and 112 mg (0.35 mmol) of tert-butyl{(4S)-5-amino-4-[(tert-butoxycarbonyl)amino]pentyl}carbamate (Example 86A) in 5 ml of anhydrous DMF at 0° C. The reaction mixture is stirred at RT for 15 h. The solvent is then evaporated and the residue is stirred with water, collected by filtration and dried under high vacuum.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:50])[CH2:4][N:5]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:22][CH:21]([N:23](CC3C=CC=CC=3)[CH2:24][CH:25]([OH:42])[CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([O:34]CC4C=CC=CC=4)=[CH:30][CH:29]=3)[CH2:20]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1)[CH2:6][CH2:7][CH2:8][CH3:9].C([O-])=O.[NH4+]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:50])[CH2:4][N:5]([CH2:6][CH2:7][CH2:8][CH3:9])[C:10]1[CH:11]=[CH:12][C:13]([S:16]([N:19]2[CH2:22][CH:21]([NH:23][CH2:24][CH:25]([OH:42])[CH2:26][O:27][C:28]3[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=3)[CH2:20]2)(=[O:18])=[O:17])=[CH:14][CH:15]=1
Reactant: CCCCN(CC(=O)OC)c1ccc(S(=O)(=O)N2CC(N(Cc3ccccc3)CC(O)COc3ccc(OCc4ccccc4)cc3)C2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCCCN(CC(=O)OC)c1ccc(S(=O)(=O)N2CC(NCC(O)COc3ccc(O)cc3)C2)cc1
Temperature: 25 °C
Yield: 115 %

Procedure:
To a solution of {[4-(3-{Benzyl-[3-(4-benzyloxy-phenoxy)-2-hydroxy-propyl]-amino}-azetidine-1-sulfonyl)-phenyl]-butyl-amino}-acetic acid methyl ester (35 mg, 0.05 mmol) in methanol (2 ml) was added ammonium formate (49 mg, 0.75 mmol), and 8 mg of 10% Pd/C. The mixture was stirred at reflux for 18 h. After cooling to room temperature, it was filtered through Celite. The solvent was evaporated and the residue triturated with ether-hexanes to give 30 mg of an off-white foam; MS (ES) m/z 522.0 (MH+); HRMS (FAB) Calcd. for C25H36N3O7S (MH+): 522.2274, Found: 522.2293.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]3[C:21]4([CH2:37]CC[CH:34]4I)[O:22][CH:23]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)[C:12]3=[C:11]([CH:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Si]([SiH]([Si](C)(C)C)[Si](C)(C)C)(C)C.N(C(C)(C)C#N)=NC(C)(C)C#N.CO>C1(C)C=CC=CC=1>[C:4]([Si:1]([CH3:3])([CH3:2])[O:8][CH:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]3[C:21]([CH3:34])([CH3:37])[O:22][CH:23]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=4)[C:12]3=[C:11]([CH:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[C:10]1=2)([CH3:5])([CH3:6])[CH3:7]
Reactant: CC1(C)Cc2nc3c(c(C4CCCC4)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1)C(c1ccc(C(F)(F)F)cc1)OC31CCCC1I
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[Si](C)(C)[SiH]([Si](C)(C)C)[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: CC1(C)Cc2nc3c(c(C4CCCC4)c2C(O[Si](C)(C)C(C)(C)C)C1)C(c1ccc(C(F)(F)F)cc1)OC3(C)C
Temperature: 25 °C

Procedure:
10 mg 8-(tert-Butyl-dimethyl-silanyloxy)-9-cyclopentyl-3-iodomethyl-3,6,6-trimethyl-1-(4-trifluoromethyl-phenyl)-1,3,5,6,7,8-hexahydro-furo[3,4-b]quinoline (example XXI) are dissolved in 1 ml toluene and mixed successively under argon with 300 μl tris-trimethylsilyl-silane and 1 mg azo-bis-isobutyro-nitrile. The reaction mixture is heated for 4 hours to 110° C. and for 12 hours at room temperature. After addition of 1 ml methanol the solvents are evaporated in vacuo and the residue is partitioned between water and ethylacetate. The aqueous phase is extracted twice with ethylacetate and the combined organic phases are washed with brine. After drying with magnesium sulphate the solvents are evaporated in vacuo. The crude product thus obtained is directly submitted to the next step (example 1 (4)).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH2:7][S:8]([O:11]CC)(=[O:10])=[O:9])=[CH:4][CH:3]=1>Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][S:8]([OH:11])(=[O:9])=[O:10])=[CH:14][CH:15]=1
Reactant: CCOS(=O)(=O)CCc1ccc(O)cc1
Agent: Cl
Product: O=S(=O)(O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of ethyl 4-hydroxyphenethyl sulfonate (0.42 g) in 12% aqueous hydrochloric acid (8 ml) is stirred at room temperature for about 18 hours and then heated at 100° C. for 5 hours, the concentrated in vacuo to give 4-hydroxyphenyethyl sulfonic acid.
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][CH:6]=1)=[O:4].[NH2:22][CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[O:26]1[CH2:27][CH2:28][CH:23]([NH:22][C:3]([C:5]2[S:9][C:8]([CH2:10][CH2:11][C:12]3[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=3[CH3:17])=[N:7][CH:6]=2)=[O:4])[CH2:24][CH2:25]1
Reactant: NC1CCOCC1
Reactant: CCCCc1noc(C)c1CCc1ncc(C(=O)OC)s1
Product: CCCCc1noc(C)c1CCc1ncc(C(=O)NC2CCOCC2)s1
Yield: 76 %

Procedure:
As described for example 57b, 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid methyl ester (90 mg, 0.29 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (50 mg, 76%) which was obtained as a light yellow solid. MS: m/e=378.4 [M+H]+.