Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)N.C(=O)([O-])[O-].[K+].[K+].[CH3:12][O:13][C:14](=[O:44])[NH:15][CH:16]([C:20]([N:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[C:27]1[NH:28][C:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38]#[C:39][Si](C)(C)C)=[CH:34][CH:33]=2)=[CH:30][N:31]=1)=[O:21])[CH:17]([CH3:19])[CH3:18]>CO>[CH3:12][O:13][C:14](=[O:44])[NH:15][CH:16]([C:20]([N:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[C:27]1[NH:28][C:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38]#[CH:39])=[CH:34][CH:33]=2)=[CH:30][N:31]=1)=[O:21])[CH:17]([CH3:19])[CH3:18]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(C#C[Si](C)(C)C)cc2)[nH]1)C(C)C
Agent: COC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(-c2cnc(C3CCCN3C(=O)C(NC(=O)OC)C(C)C)[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
A mixture of (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (364 mg, 0.81 mmol), Ethynyl-trimethyl-silane (0.68 mL, 4.9 mmol), Copper(I) iodide (154 mg, 0.81 mmol), tetrakis(triphenylphosphine)palladium (94 mg, 0.08 mmol) and triethylamine (0.67 mL, 4.9 mmol) in 5 ml DMF was heated to 70° C. overnight. The reaction mixture was cooled and dissolved in ethyl acetate and washed with 5% lithium chloride aqueous solution. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) and followed by preparative reverse phase HPLC (GEMINI, 5 to 100% ACN/H2O+0.1% TFA) to give (2-Methyl-1-{2-[5-(4-trimethylsilanylethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester (324 mg). LCMS-ESI−: calc'd for C25H34BN4O3Si: 466.65. Found: 467.1 (M+H+). (1-{2-[5-(4-Ethyny]-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: Potassium carbonate (192 mg) was added to (2-Methyl-1-{2-[5-(4-trimethylsilanylethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester (324 mg) in 7 mL MeOH solution. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated down and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give (1-{2-[5-(4-Ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (234 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.ClC1C=CC=CC=1.[C:16]([CH:19]1[CH2:24][CH2:23][O:22][C:20]1=[O:21])(=O)[CH3:17]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[OH:8][C:7]1[C:2]2=[N:1][C:16]([CH3:17])=[C:19]([CH2:24][CH2:23][OH:22])[C:20](=[O:21])[N:3]2[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1O
Reactant: CC(=O)C1CCOC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Clc1ccccc1
Product: Cc1nc2c(O)cccn2c(=O)c1CCO
Temperature: 125 °C
Reaction time: 18 h
Yield: 74.6 %

Procedure:
In a reaction vessel equipped with a dropping funnel and a reverse water-separator, 2-amino-3-hydroxypyridine (110.12 g; 1 mol) was added to chlorobenzene (1500 ml) at room temperature. 2-Acetylbutyrolactone (134.53 g; 1.05 mol) was added dropwise to this mixture from the dropping funnel while stirring. The dropping funnel was rinsed with chlorobenzene (250 ml) and the resulting solution was added dropwise to the previously obtained mixture. Next, p-toluenesulfonic acid monohydrate (5.7 g; 0.03 mol) was added, and the resulting mixture was heated to reflux temperature (refluxing starting at 125° C.). The reaction mixture was refluxed for 19 hours, while the water liberated during the course of the reaction was collected in the reverse water-separator. The mixture was allowed to cool to about 80° C. and then there were added 2-propanol (250 ml), activated carbon (Norit A™ supra, 25 g) and filter agent (dicalite speed plus; 2.5 g). The mixture was heated to reflux (100° C.) during 30 minutes. The reaction mixture was filtered at a temperature of 90 to 95° C. and the filter cake was washed with chlorobenzene (100 ml; 80° C.). The combined filtrate was allowed to cool to room temperature. Crystallization of the reaction product started at about 40-45° C. and was left to continue for 18 hours at room temperature. The crystals were collected and washed with chlorobenzene (100 ml) and dried in vacuo at 50-60° C. for 24 hours, yielding 164.2 g (73.6%) 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one; mp 150° C.; purity >97% (LC % w/w); residual 2-amino-3-hydropyridine: 0.85%; sum of other impurities <0.52%; residual 2-acetylbutyrolactone was 0% (GC % w/w).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])=[CH:11][C:10]=1[Cl:24])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[Cl:24][C:10]1[CH:11]=[C:12]([CH2:15][CH2:16][C:17]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: O=C(CCc1ccc(OCc2ccccc2)c(Cl)c1)C1CCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(CCc1ccc(O)c(Cl)c1)C1CCCC1
Reaction time: 4 h
Yield: 62.2 %

Procedure:
A mixture of 3-[4-(benzyloxy)-3-chlorophenyl]-1-cyclopentylpropan-1-one (48 g, 0.140 mole), from Step 1, and 10% palladium-on-carbon (11.52 g of 50 wt % wet, 0.005 mol, 3.5 mole %) in ethyl acetate (500 mL) was degassed and purged with hydrogen three times. The reaction was stirred with 1 atm H2 for 4 h, resulting in complete conversion. The mixture was filtered through a fine fritted glass funnel and the filtrate concentrated in vacuo, affording a yellow oil which crystallized on cooling. This material was recrystallized from two parts of isopropyl ether, affording 22 g (62%) of the title product. mp 88-90° C.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([NH2:18])[CH2:14][CH:15]([CH3:17])[CH3:16]>CN(C=O)C>[CH3:16][CH:15]([CH3:17])[CH2:14][CH2:13][NH:18][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: CC(C)CCN
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: CC(C)CCNc1ccc(C#N)cc1[N+](=O)[O-]
Yield: 90 %

Procedure:
A solution of 4-chloro-3-nitrobenzonitrile (18.3 g, 0.10 mol) and isoamylamine (19.2 g, 0.22 mol) in DMF (250 mL) was heated to 90° C. for 4 h under nitrogen then cooled and the solvent evaporated. The residue is triturated with EtOAc (300 mL) and solids removed by filtration. The filtrate was washed with water and brine. The organic layer was dried over MgSO4 and evaporated. The residue was recrystallized from MeOH to give 21.0 g (90%) of 4-(3-methyl-butylamino)-3-nitro-benzonitrile as a yellow crystalline solid.
Reaction SMILES: [CH2:1]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:28]N1C(=O)CCC1=O>O1CCOCC1>[CH2:1]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[C:17]([OH:20])[C:18]([Cl:28])=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CCCc2cc(O)ccc2C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CCCc2cc(O)c(Cl)cc2C1
Temperature: 25 °C
Yield: 76.6 %

Procedure:
A solution of N-benzyl-N-(6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (166 mg) and N-chlorosuccinimide (66.4 mg) in 1,4-dioxane (2 ml) was refluxed for 28 hours, cooled to room temperature, and partitioned between ethyl acetate and brine. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed (toluene-ethyl acetate) over silica gel (3.6 g) to afford N-benzyl-N-(3-chloro-6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (139 mg) as a colorless gum.
Reaction SMILES: [OH-:1].[Na+].BrBr.[Cl:5][C:6]1[C:11]([Cl:12])=[C:10]([Cl:13])[CH:9]=[CH:8][C:7]=1[C:14](=[O:16])C.Cl>O.O1CCOCC1>[Cl:5][C:6]1[C:11]([Cl:12])=[C:10]([Cl:13])[CH:9]=[CH:8][C:7]=1[C:14]([OH:16])=[O:1]
Reactant: [OH-]
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1Cl
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(Cl)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 90.9 %

Procedure:
Sodium hydroxide (45.42 g, 1.090 mol) was dissolved in water (220 ml), and while cooling with ice, bromine (16.85 ml, 0.327 mol) was dripped therein over a period of 5 minutes. After stirring the reaction solution at 0° C. for 15 minutes, a dioxane (220 ml) solution of 2′,3′,4′-trichloroacetophenone (24.40 g, 0.109 mol) was dripped therein at 0° C. over a period of 30 minutes. After stirring at room temperature for 14 hours, water (350 ml) was added and then washed with dichloromethane (350 ml). The aqueous layer obtained was gradually made acidic with concentrated hydrochloric acid while cooling with ice and the resulting crystals were filtered out. After washing the filtered-out crystals with water, the water was removed by azeotropic distillation with toluene. 22.33 g (91%) of the title compound was thereby obtained as a pale yellow powder.
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].[Cl:32]C1C=CC(CCI)=CC=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[Cl:32][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][N:16]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][C:2]([CH3:1])([CH3:6])[C:3]([OH:5])=[O:4])=[CH:9][N:10]=2)=[CH:20][CH:21]=1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: Clc1ccc(CCI)cc1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCc2ccc(Cl)cc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-Methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-propionic acid using 1-chloro-4-(2-iodo-ethyl)-benzene (J. Med. Chem. 1998, 41, 3, 358-378) and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([NH:20][C:21]([CH3:29])([CH3:28])[CH2:22]/[CH:23]=[CH:24]/[C:25]([OH:27])=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].ON1C2N=CC=CC=2N=N1.[CH2:40]([C@@H:47]([N:60]([CH3:77])[C:61](=[O:76])[C@H:62]([NH:74][CH3:75])[CH2:63][C:64]1[CH:73]=[CH:72][C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH:65]=1)[C:48]([N:50]1[CH2:55][CH2:54][CH:53]([CH2:56][N:57]([CH3:59])[CH3:58])[CH2:52][CH2:51]1)=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(C(C)C)C(C)C)C>ClCCl.CN(C)C=O.C(OCC)(=O)C>[C:13]([O:17][C:18](=[O:19])[NH:20][C:21]([CH3:29])([CH3:28])[CH2:22]/[CH:23]=[CH:24]/[C:25](=[O:27])[N:74]([C@@H:62]([C:61](=[O:76])[N:60]([C@H:47]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:48]([N:50]1[CH2:55][CH2:54][CH:53]([CH2:56][N:57]([CH3:58])[CH3:59])[CH2:52][CH2:51]1)=[O:49])[CH3:77])[CH2:63][C:64]1[CH:73]=[CH:72][C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH:65]=1)[CH3:75])([CH3:14])([CH3:15])[CH3:16]
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N1CCC(CN(C)C)CC1
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)CC1CCN(C(=O)[C@@H](Cc2ccccc2)N(C)C(=O)[C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 72927.8 %

Procedure:
At 0° C., N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (112 mg, 0.58 mmol) was added to a solution of (2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid (142 mg, 0.58 mmol) and 1-hydroxy-7-azabenzotriazole (79 mg, 0.58 mmol) in dichloromethane (10 ml) and N,N-dimethylformamide (5 ml). The reaction mixture was stirred for 20 min at 0° C. A solution of (2R)—N-[(1R)-1-benzyl-2-(4-((dimethylamino)methyl)piperidin-1-yl)-2-oxoethyl]-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide (300 mg, 0.58 mmol) in dichloromethane (5 ml) and N,N-dimethylformamide (5 ml) and ethyldiisopropylamine 0.10 ml, 0.58 mmol) were added successively. The reaction mixture was stirred for 3 days, while it was warming up to room temperature. It was diluted with ethyl acetate (70 ml) and washed with a saturated aqueous solution of sodium hydrogen carbonate (70 ml). The aqueous phase was extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (70 g), using dichloromethane/methanol/25% aqueous ammonia (200:10:1) as eluent, to give 313 g of {(3E)-4-[N-((1R)-1-{N-[(1R)-1-benzyl-2-(4-((dimethylamino)methyl)piperidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylcarbamoyl]-1,1-dimethylbut-3-enyl}carbamic acid tert-butyl ester.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1>>[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)=[CH:23][CH:22]=1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: Cc1ccc(S)cc1
Product: Cc1ccc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-methyl-thiophenol.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: OB(O)c1ccccc1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccccc2)c2ncnn12
Reaction time: 16 h
Yield: 80.2 %

Procedure:
To a suspension (20 mL) of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.6 g), phenylboronic acid (0.4 g), triethylamine (0.5 mL), pyridine (1 mL) and molecular sieves 4A (1 g) in dichloromethane was added copper(II) acetate (0.59 g), and the mixture was stirred for 16 hr. The reaction mixture was diluted with ethyl acetate, insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.58 g, 80%).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:28])=[CH:22][CH:21]=1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(4-chlorophenyl)acetic acid were treated using a method similar to that described in Example 10C to give the title compound. 1H NMR (400 MHz, DMSO-d6, Temp=90° C.) δ ppm 11.09-11.16 (m, 1H), 8.30 (d, J=7.1 Hz, 1H), 7.99 (d, J=1.3 Hz, 1H), 7.92-7.96 (m, 1H), 7.84-7.88 (m, 1H), 7.26-7.46 (m, 4H), 3.80-3.83 (m, 4H), 3.64-3.65 (m, 1H), 3.65 (d, J=5.0 Hz, 1H), 3.09-3.13 (m, 4H); MS (APCI+) M/Z 399 (M+H)+.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:14][CH3:15])=[C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:8]=1)[NH2:2].[CH:16]([O-])=[O:17].[Na+].C(O)=O>C(O)C>[CH:16]([NH:2][NH:1][C:3]1[CH:4]=[CH:5][C:6]([O:14][CH3:15])=[C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:8]=1)=[O:17]
Reactant: COc1ccc(NN)cc1CCC(=O)O
Reactant: O=C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O=CO
Product: COc1ccc(NNC=O)cc1CCC(=O)O

Procedure:
3-(5-Amino-2-methoxyphenyl)propionic acid (4 g, 0.02 mole), concentrated hydrochloric acid (30 ml) and water (45 ml) were stirred together at 0°. The mixture was treated with sodium nitrite (1.38 g, 0.02 mole) in water (10 ml) at 0°. The solution was then stirred for a further one-half hour. The excess of nitrous acid was destroyed with urea. The above reaction mixture was added to a solution of stannous chloride (7.6 g) in concentrated hydrochloric acid (10 ml). The precipitate (5 g) was collected by filtration. Free hydrazine was obtained from a concentrated aqueous solution of the crude hydrochloride by addition of saturated aqueous solution of sodium acetate. A mixture of 3-(5-hydrazino-2-methoxyphenyl)propionic acid (8.8 g, 0.025 mole), sodium formate (2.8 g, 0.04 mole), formic acid (18 ml) and ethanol (60 ml) was heated under reflux for one hour. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate (1 liter). The organic layer was then washed with water and dilute aqueous hydrochloric acid (1 percent). The organic layer was dried with sodium sulphate, the solvent was removed under reduced pressure and the residue crystallized from water (5 g).
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[C:10]([S:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:9]=[C:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[OH:23])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH2:31]([O:33][C:34]([C:36]1[NH:37][C:38]([CH3:46])=[C:39]([S:42](Cl)(=[O:44])=[O:43])[C:40]=1[CH3:41])=[O:35])[CH3:32]>ClCCl>[CH2:31]([O:33][C:34]([C:36]1[NH:37][C:38]([CH3:46])=[C:39]([S:42]([N:16]2[CH2:17][CH2:18][CH:13]([S:12][C:10]3[CH:9]=[C:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]([OH:23])=[C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[CH:11]=3)[CH2:14][CH2:15]2)(=[O:43])=[O:44])[C:40]=1[CH3:41])=[O:35])[CH3:32]
Reactant: CCOC(=O)c1[nH]c(C)c(S(=O)(=O)Cl)c1C
Reactant: CC(C)(C)c1cc(SC2CCNCC2)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c(C)c(S(=O)(=O)N2CCC(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)c1C
Reaction time: 0.05 h
Yield: 80.4 %

Procedure:
To 2,6-di-tert-butyl-4-(piperidin-4-ylsulfanyl)-phenol hydrochloride (Ex. 3c, 500 mg, 1.4 mmol) in 5 mL of dichloromethane was added triethylamine (495 mg, 4.9 mmol). The mixture was stirred for 3 min followed by the addition of 4-chlorosulfonyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (446 mg, 1.68 mmol). The stirring was continued for 3 h at room temperature. The reaction mixture was diluted with Ethyl acetate/hexanes (15 mL, 1:1 v/v), and washed with water (2×20 mL), 0.5 M HCl (2×20 mL) and water (40 mL). It was dried over Na2SO4 and concentrated under reduced pressure to give a brown oil. Chromatography (5-40% Ethyl acetate/hexanes) gave 4-[4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidine-1-sulfonyl]-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester as a light-pink foamy solid (620 mg, 80%). ESI/CI-MS m/z 551 ([M+H]+), 549 ([M−H]−).
Reaction SMILES: Cl[CH2:2][CH2:3][Si:4]([O:9][CH3:10])([O:7][CH3:8])[O:5][CH3:6].[N-:11]=[N+:12]=[N-:13].[Na+]>C(#N)C>[N:11]([CH2:2][CH2:3][Si:4]([O:9][CH3:10])([O:7][CH3:8])[O:5][CH3:6])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: CO[Si](CCCl)(OC)OC
Agent: [Na+]
Solvent: CC#N
Product: CO[Si](CCN=[N+]=[N-])(OC)OC

Procedure:
1.0 mole of 2-chloroethyltrimethoxysilane and 1.1 moles of sodium azide in 500 ml of acetonitrile were heated in the presence of 3 mole percent of the catalyst described in Example 1 (a) for ten hours under stirring and reflux. After separation of the salt the subsequent distillation under reduced pressure gave the 2-azidoethyltrimethoxysilane in a yield of 61 weight percent with the following characteristics:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1([CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=[O:23])C.[Na+].ClC1C=C(C=CC=1)C(OO)=O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1([CH3:20])[O:23][C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH2:18]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)[O-]
Reactant: CC1(CCCCOCc2ccccc2)CCCCC1=O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC1(CCCCOCc2ccccc2)CCCCC(=O)O1
Yield: 90.6 %

Procedure:
A solution of 2-(4'-benzyloxybutyl)-2-methylcyclohexanone (25.2 g, 0.092 mol), sodium acetate (8.2 g, 0.1 mol), m-chloroperoxybenzoic acid 85% (24.2 g, 0.12 mol) and distilled methylene chloride (1200 ml) is heated at reflux under a nitrogen atmosphere for 7 hours. The solution is cooled and filtered and the filtrate is washed with satd. NaHCO3, satd. NaCl, and dried (MgSO4). The solvent is removed under reduced pressure and the crude product (30.6 g) is chromatographed on SilicAR CC-7 (600 g) in hexane. Elution with 20% ethyl acetate/hexane gives 7-(4'-benzyloxybutyl)-7-methyl-1-oxa-cycloheptan-2-one (6) as a clear light yellow oil (24.2 g, 91%): ir (neat) 1720 cm-1 (lactone); nmr (CDCl3) δ1.42 (s, 3H, CH3), 2.64 (m, 2H, OC--CH2 --CH2), 3.50 (m, 2H, O--CH2 --CH2), 4.50 (s, 2H, O--CH2 --Ph), 7.32 (s, 5H, aromatic).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[C:21]([CH3:30])=[N:22][C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:31][CH3:32])C1C=CC=CC=1>CN(C)C=O.[OH-].[Pd+2].[OH-]>[CH3:32][O:31][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[OH:8])[N:16]=[CH:15][CH:14]=[C:13]2[O:19][C:20]1[C:21]([CH3:30])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
7-Benzyloxy-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 351) (1 g) was dissolved in N,N-dimethylformamide (15 ml) to prepare a solution. 20% Palladium hydroxide (100 mg) was added to the solution, and the mixture was stirred at room temperature under a hydrogen stream overnight. The reaction solution was filtered through Celite, and the solvent was removed from the filtrate by distillation under the reduced pressure. The residue was purified by column chromatography using chloroform-methanol to give the title compound (647 mg, yield 85%).