Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][Si:7]([OH:9])=[O:8].[NH2:10][C:11]([NH2:13])=[O:12]>>[Si:7]([OH:12])([OH:9])([OH:6])[OH:8].[NH2:10][C:11]([NH2:13])=[O:12].[NH2:10][C:11]([NH2:13])=[O:12]
Reactant: O=[Si](O)O
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Product: O[Si](O)(O)O

Procedure:
Clay is reacted with sulfuric acid, thereby producing metasilicic acid, which is recovered by filtration. About one mol of said metasilicic acid is mixed with 2 mols of urea, heated to 90° to 150° C. for 20 to 30 minutes, thereby producing white granules of diurea silicate. The said diurea silicate is added to an aqueous solution of hexamethylene tetramine in the ratio of 1:1.5 mols, heated to 70° to 110° C. for 20 to 90 minutes, thereby producing a clear thick solution of poly (formaldehyde diurea silicate) resin, and upon further heating, a white resin is produced. The said white resin is soluble in acetic acid and produces a clear solution; the unreacted silicic acid is precipitated. The solution of poly (formaldehyde diurea silicate) resin forms a clear tough coating on wood.
Reaction SMILES: I[C:2]1[N:9]2[C:5]([S:6][C:7]([C:10]3[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=3)=[N:8]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]([C:32]([F:35])([F:34])[F:33])[C:28]([NH2:31])=[N:29][CH:30]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:16][C:13]1[N:12]=[CH:11][C:10]([C:7]2[S:6][C:5]3=[N:4][CH:3]=[C:2]([C:25]4[CH:26]=[C:27]([C:32]([F:35])([F:34])[F:33])[C:28]([NH2:31])=[N:29][CH:30]=4)[N:9]3[N:8]=2)=[CH:15][CH:14]=1
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Reactant: Cc1ccc(-c2nn3c(I)cnc3s2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)cnc3s2)cn1
Temperature: 110 °C
Yield: 1.9 %

Procedure:
A mixture of 5-Iodo-2-(6-methyl-pyridin-3-yl)-imidazo[2,1-b][1,3,4]thiadiazole (226 mg, 0.661 mmol, 1 eq), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (228 mg, 0.793 mmol, 1.2 eq), PdCl2(PPh3)2 (95 mg, 0.132 mmol, 0.2 eq) and 2M aq Na2CO3 (1.6 mL) in dioxane (7 mL) was heated at 110° C. for 90 min. The solvent was removed under reduced pressure and the residue was suspended in water and filtered. The solid was washed with diethylether, methanol and acetone. The residue was purified by HPLC to afford the desired product (4.7 mg, 2%). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=5.23 min, [M+H]+ m/z 377.0; 1H NMR (300 MHz, DMSO) δ 9.02 (s, 1H), 8.87 (s, 1H), 8.36 (s, 1H), 8.25 (dd, J=8.1, 2.2 Hz, 1H), 7.81 (s, 1H), 7.52 (d, J=8.2 Hz, 1H), 6.75 (s, 2H), 2.59 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[C:20]([CH:24]=2)[C:21](O)=[O:22])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1.[C:34]([O:38][C:39](=[O:46])[C@H:40]([CH2:42][CH2:43][S:44][CH3:45])[NH2:41])([CH3:37])([CH3:36])[CH3:35]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[C:20]([CH:24]=2)[C:21]([NH:41][C@@H:40]([CH2:42][CH2:43][S:44][CH3:45])[C:39]([O:38][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:46])=[O:22])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:6][CH:7]=1
Reactant: CSCC[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(O)c1cc(OC(Cn2ccnc2)c2ccc(F)cc2)ccc1CCc1ccc(F)cc1
Product: CSCC[C@H](NC(=O)c1cc(OC(Cn2ccnc2)c2ccc(F)cc2)ccc1CCc1ccc(F)cc1)C(=O)OC(C)(C)C
Yield: 80 %

Procedure:
The title compound was prepared in 80% yield from 5-(1-(4-fluorophenyl)-2-(imidazol-1-yl)ethoxy)-2-(4-fluorophenethyl)benzoic acid and L-methionine tert-butyl ester by a similar method to that used for Example 34. 1H NMR (DMSO-d6, 300 MHz) δ: 1.38 (9H,s); 1.88-2.0 (2H,m); 2.02 (3H,d); 2.62-2.75 (2H,m); 2.75-2.9 (2H,m); 4.32-4.42 (1H, m); 4.68 (2H,d); 5.83 (1H,m); 6.79-6.83 (2H,md); 6.95-7.1 (3H,m); 7.1-7.28 (4H,m); 7.45-7.52 (2H,dd); 7.61 (1H,s); 7.68 (1H,s); 8.62 (1H,t); 9.08 (1H,s). MS (ES+) m/z 636.4 (MH+); Anal.calculated for C35H39F2N3O4S.2.7H2O C, 61.4; H, 6.5; N, 6.1%; Found: C, 61.1; H, 6.2; N, 5.7%.
Reaction SMILES: [CH:1]([C@:4]1([C:17]([N:19]2[CH2:24][CH:23]=[C:22]([C:25]3[CH:26]=[N:27][CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5]1)([CH3:3])[CH3:2]>Cl.O1CCOCC1>[CH:1]([C@:4]1([C:17]([N:19]2[CH2:20][CH:21]=[C:22]([C:25]3[CH:26]=[N:27][CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=3)[CH2:23][CH2:24]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)N2CC=C(c3cncc(C(F)(F)F)c3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)[C@]1(C(=O)N2CC=C(c3cncc(C(F)(F)F)c3)CC2)CC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 147.4 %

Procedure:
tert-Butyl ((1 R,3S)-3-isopropyl-3- {[5-(trifluoromethyl)-3′,6′-dihydro-3 ,4′-bipyridin-1′-(2′H)-yl]carbonyl}cyclopentyl)carbamate (24.0 mg, 0.0498 mmol) was dissolved in a 4 M solution of HCl in 1,4-dioxane (2.0 mL) to form a light yellow clear solution. After being stirred at room temperature for 1 h, the reaction mixture was concentrated in vacuo. The residue was treated with a 1 M solution of NaOH and the solution was extracted with methylene chloride three times. The extracts were dried, filtered and concentrated to provide 28 mg of product as a light yellow solid. LC-MS calculated for C20H26F3N3O:(M+H) 382; found 382.1.
Reaction SMILES: [C:1]1(=[O:7])[CH2:5][CH2:4][C:3](=[O:6])[CH2:2]1.[Cl:8][C:9]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:10]=1[C:11](C#N)=[O:12].C(N(CC)CC)C.Cl>C(Cl)Cl.CCOCC.[Cl-].[Zn+2].[Cl-].C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:8][C:9]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:10]=1[C:11]([CH:2]1[C:3](=[O:6])[CH2:4][CH2:5][C:1]1=[O:7])=[O:12]
Reactant: O=C1CCC(=O)C1
Reactant: N#CC(=O)c1ccc(Cl)cc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1CCC(=O)C1C(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 21.8 %

Procedure:
1,3-Cyclopentanedione [9.8 grams (g), 0.1 mole], 20.0 g (0.1 mole) 2,4-dichlorobenzoyl cyanide and 13.6 g (0.11 mole) anhydrous, powdered zinc chloride were combined in 100 milliliters (ml) methylene chloride. Triethylamine (10.1 g, 0.12 mole) was slowly added with cooling. The reaction mixture was stirred at room temperature for 5 hours and then poured into 2N hydrochloric acid. The aqueous phase was discarded and the organic phase was washed with 150 ml 5% Na2CO3 four times. The aqueous washings were combined and acidified with HCl, extracted with methylene chloride, dried and concentrated to yield 25.3 g of crude product. The crude product was dissolved in ether and stirred with 250 ml of 5% copper (II) acetate. The resulting copper salt was filtered, washed with ether and stirred with 6N hydrochloric acid to destroy the salt. The extract was washed with ether to yield 5.9 g of the desired product m.p. 109°- 113° C. (21.7% yield). The structure was confirmed by instrumental analysis.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[NH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.O>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([CH2:11][NH:10][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=C(O)c1ccccn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2ccccn2)CC1
Reaction time: 6 h
Yield: 36.1 %

Procedure:
A mixture of pyridine-2-carboxylic acid (2.7 g) and 4-(aminomethyl)-1-tert-butoxycarbonylpiperidine (5.0 g) in dry xylene (50 ml) was heated under reflux under a Dean and Stark water separator for six hours. The cooled solution was diluted with ethyl acetate (150 ml), washed with aqueous oxalic acid solution (2M; 2×100 ml) then aqueous sodium hydrogen carbonate soultion (5M; 2×100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo to give N-[(1-tert-butoxycarbonyl-4-piperidyl)methyl]pyridine-2-carboxamide (2.53 g) as an oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=S)[NH:16][NH:17][C:18](=O)[C:19]2[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[C:22]([O:28][CH2:29][O:30][CH3:31])=[CH:21][C:20]=2[O:32][CH2:33][O:34][CH3:35])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:38].[Na+]>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]([C:19]3[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[C:22]([O:28][CH2:29][O:30][CH3:31])=[CH:21][C:20]=3[O:32][CH2:33][O:34][CH3:35])=[N:17][NH:16][C:15]2=[O:38])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1C(=O)NNC(=S)NC1CCN(Cc2ccccc2)CC1
Agent: [Na+]
Product: COCOc1cc(OCOC)c(C(C)C)cc1-c1n[nH]c(=O)n1C1CCN(Cc2ccccc2)CC1

Procedure:
4-(1-benzyl-piperidin-4-yl)-1-(5-isopropyl-2,4-bismethoxymethoxy-benzoyl)thiosemicarbazide (the crude product F66-02 of the previous step) and 5% aqueous sodium hydroxide were placed in a 10 mL eggplant shaped flask and heated under reflux for 3 hours. After completing the reaction, the reaction mixture was extracted with methylene chloride, and the extract was dried over anhydrous sodium sulfate. After filtration and evaporation, the residue thus obtained was subjected to the next reaction without further purification.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][C@H:11]1[CH2:16][O:15][CH2:14][CH2:13][NH:12]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[CH3:10][C@@H:11]1[N:12]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:13][CH2:14][O:15][CH2:16]1
Reactant: N#Cc1ccc(F)cc1
Reactant: C[C@H]1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H]1COCCN1c1ccc(C#N)cc1
Temperature: 110 °C
Reaction time: 70 h
Yield: 43.4 %

Procedure:
4-Fluorobenzonitrile (359 mg, 2.97 mmol), (S)-3-methylmorpholine (150 mg, 1.48 mmol) and K2CO3 were suspended in DMSO (1.5 ml). The mixture was stirred for 70 hours at 110° C. in a closed high-pressure flask. The reaction was cooled, diluted with water (50 ml) and extracted with EtOAc (3*20 ml). Combined organics were washed with water (20 ml), dried over MgSO4 and evaporated. The product was purified by flash chromatography using pet.ether/EtOAc (3:1) as eluent to give 130 mg (43%) of the title compound as pale solids.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[N:7]=1)[CH3:4].Cl[CH2:27][C:28]1[N:29]=[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:37][CH3:38])[N:31]2[CH:39]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:27][C:28]3[N:29]=[C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:37][CH3:38])[N:31]4[CH:39]=3)=[CH:23][CH:24]=2)[N:7]=1)[CH3:4]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1OCC
Reactant: CCOc1cccc2nc(CCl)cn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cn4c(OCC)cccc4n3)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (478 mg) and 2-chloromethyl-5-ethoxyimidazo[1,2-a]pyridine (316 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[4-(5-ethoxyimidazo[1,2-a]pyridin-2-ylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (442 mg, yield: 60%) as a colorless oily substance from the fraction eluted with ethyl acetate.
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]([OH:10])[CH3:9])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH2:11]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1(C)C=CC=CC=1>N1C=CC=CC=1>[C:1]([O:6][CH2:7][CH:8]([O:10][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([C:22]2[CH:23]=[CH:24][C:19]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:20][CH:21]=2)=[CH:33][CH:32]=1)[CH3:9])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Reactant: CCCC(=O)OCC(C)O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCc1ccc(-c2ccc(C(=O)OC(C)COC(=O)CCC)cc2)cc1

Procedure:
0,75 g of optically active 1-butyryloxy-2-propanol [obtainable by esterification of (S)-1,2-propanediol], 1,7 g of p-(p-n-octylphenyl)-benzoic acid chloride, 20 ml of toluene and 2,1 ml of pyridine are boiled under reflux for 6 hours. The pyridinium chloride is filtered off hot with suction and the filtrate is worked up in the customary manner. Optically active 1-butyryloxy-2-[p-(p-n-octylphenyl)-benzoyloxy]-propane is obtained.
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.[CH3:11][C:12]1[CH:13]=[C:14]([NH:19][NH2:20])[CH:15]=[CH:16][C:17]=1[CH3:18].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:2]([C:1]1[CH:7]=[C:8]([NH2:9])[N:19]([C:14]2[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([CH3:11])[CH:13]=2)[N:20]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1ccc(NN)cc1C
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1C
Yield: 66.9 %

Procedure:
To a solution of pivaloylacetonitrile (400 mg) in toluene (10 mL) were added 3,4-dimethylphenylhydrazine hydrochloride (520 mg) and triethylamine (0.4 mL) and refluxed with heating for 5 hours. The reaction mixture was added with a saturated sodium hydrogen carbonate aqueous solution. The obtained organic layer was washed with a saturated sodium chloride aqueous solution. The obtained organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified on silica gel column chromatography (hexane:ethyl acetate=4:1) to give the titled compound (490 mg) having the following physical data.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:28])[C:5]([C:8](=[N:23][O:24][CH:25]([CH3:27])[CH3:26])[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])=[N:6][CH:7]=1.[CH3:29][C:30]([CH3:34])([CH3:33])[C:31]#[CH:32].O>C(N(CC)CC)C.[Cu]I>[Cl:28][C:4]1[C:5]([C:8](=[N:23][O:24][CH:25]([CH3:27])[CH3:26])[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])=[N:6][CH:7]=[C:2]([C:32]#[C:31][C:30]([CH3:34])([CH3:33])[CH3:29])[CH:3]=1
Reactant: C#CC(C)(C)C
Reactant: CC(C)ON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Br)cc1Cl
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)ON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(C#CC(C)(C)C)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To a solution of 0.15 g of N-[2-(5-bromo-3-chloropyridin-2-yl)-2-(isopropoxyimino)ethyl]-2-(trifluoromethyl)benzamide and 0.05 g of 3,3-dimethyl-1-butyne in 3 ml of triethylamine, 0.04 g of copper(I) iodide and 0.02 g of dichlorobistriphenylphosphine palladium(II) were added, and the mixture was stirred at 80° C. for 3 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, mixed with 10 ml of water and extracted with ethyl acetate (20 ml×1). The resulting organic layer was washed with water (10 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:5 to 2:4) as the eluent to obtain 0.15 g of the desired product as a yellow resinous substance.
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[C:16]([C:29](O)=[O:30])=[CH:15]2.[NH2:32][C:33]1[CH:34]=[N:35][C:36]([N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:37][CH:38]=1.C(N(CC)CC)C>CN(C)C=O>[N:39]1([C:36]2[N:35]=[CH:34][C:33]([NH:32][C:29]([C:16]3[N:17]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[C:18]4[C:14]([CH:15]=3)=[CH:13][C:12]([F:11])=[CH:20][CH:19]=4)=[O:30])=[CH:38][CH:37]=2)[CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: Nc1ccc(N2CCCC2)nc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(N2CCCC2)nc1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Yield: 87 %

Procedure:
0.28 ml (1.68 mmol) of diethyl cyanophosphonate is added, dropwise, at 20° C. under argon, to a solution of 0.402 g (1.4 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (example 1.1) and of 0.274 g (1.68 mmol) of 3-amino-6-(pyrrolidin-1-yl)pyridine (WO 02/48152) in 10 ml of dry dimethylformamide. The mixture is stirred for ten minutes and then 0.43 ml (3.08 mmol) of triethylamine is added dropwise. The mixture is stirred at ambient temperature for 18 hours, concentrated under reduced pressure, and then taken up with 50 ml of ethyl acetate. This solution is then successfully washed with three times 20 ml of a saturated sodium hydrogen carbonate solution, 50 ml of water and 20 ml of a saturated sodium chloride solution, and then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The solid obtained is triturated in isopropylether under hot conditions. 0.527 g of a solid is obtained, which solid is dried under reduced pressure.
Reaction SMILES: [Si](OC[C@@H]1C=C(C(OC)=O)[C@H](O)CN1C(OC(C)(C)C)=O)(C(C)(C)C)(C)C.[C:28]([O:32][C:33]([N:35]([C@@H:45]([CH:49]=C)[CH2:46][O:47][CH3:48])[CH2:36][CH:37]([OH:44])[C:38](=C)[C:39]([O:41][CH3:42])=[O:40])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[OH:44][C@@H:37]1[CH2:36][N:35]([C:33]([O:32][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:34])[C@H:45]([CH2:46][O:47][CH3:48])[CH:49]=[C:38]1[C:39]([O:41][CH3:42])=[O:40]
Reactant: C=C[C@@H](COC)N(CC(O)C(=C)C(=O)OC)C(=O)OC(C)(C)C
Agent: COC(=O)C1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O
Product: COC[C@@H]1C=C(C(=O)OC)[C@H](O)CN1C(=O)OC(C)(C)C
Yield: 40.3 %

Procedure:
The title compound (0.45 g, 40%) was prepared according to the procedure described for Intermediate 101 starting from methyl 4-(tert-butoxycarbonyl((S)-1-methoxybut-3-en-2-yl)amino)-3-hydroxy-2-methylenebutanoate (Intermediate 253, 1.22 g).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[O:27][C:28]([CH3:31])=[N:29][N:30]=3)=[CH:22][CH:21]=2)[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[O:27][C:28]([CH3:31])=[N:29][N:30]=3)=[CH:24][CH:25]=2)[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: [H][H]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(Oc2ccc(-c3nnc(C)o3)cc2)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)c1cc(O)cc(Oc2ccc(-c3nnc(C)o3)cc2)c1
Yield: 82 %

Procedure:
To a solution of Methyl 3-(benzyloxy)-5-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]benzoate (28 g) (Intermediate 8) in glacial acetic acid, suspension of 10% Pd/C in glacial acetic acid was added in Parr hydrogenation apparatus. The reaction was subjected under 60 PSI of hydrogen for 6 h. After completion, the reaction mixture was filtered to remove catalyst. Filtrate was poured into ice, the solid obtained was filtered, washed with water, saturated sodium bicarbonate solution, water, petroleum ether, air dried to obtain desired product (18 g, 70%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:8]=2[NH2:9])[CH2:3][CH2:2]1.[C:18](Cl)(Cl)=[S:19]>O1CCOCC1.O>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:10][C:8]=2[N:9]=[C:18]=[S:19])[CH2:5][CH2:6]1
Reactant: S=C(Cl)Cl
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCOCC1
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1ccc(N2CCOCC2)c(N=C=S)c1

Procedure:
Reaction of 2-morpholino-5-trifluoromethylaniline (12 g) with thiophosgene (8.6 g) in dioxan (30 ml) and water (100 ml) at 0° C. for 30 minutes and then at room temperature for 2 hours yielded a residue which was extracted with dichloromethane to give 2-morpholino-5-trifluoromethylphenyl isothiocyanate as a yellow oil.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[C:22]1([N:28]=[C:29]=[S:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C.O>[C:1]([NH:4][NH:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:29]([NH:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[S:30])=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: S=C=Nc1ccccc1
Reactant: COc1ccc(CNc2ccc(NNC(C)=O)cc2)cc1
Solvent: CCO
Solvent: O
Product: COc1ccc(CN(C(=S)Nc2ccccc2)c2ccc(NNC(C)=O)cc2)cc1

Procedure:
1-Acetyl-2-[4-(4-methoxybenzyl)aminophenyl]hydrazine (3.1 g, 0.011 mole) and phenylisothiocyanate (1.35 g, 0.01 mole) were mixed in ethanol (25 ml) and the resulting mixture was refluxed for 10 minutes. The mixture was chilled in ice and diluted with water. The product oiled out of solution, but upon standing and scratching the substance solidified. The solid material was filtered off, washed with water and allowed to dry. The material was stirred twice in a large volume of ether, then was filtered and washed with fresh ether. The product was a white powder. Yield 2.75 g (66%), m.p. 126°-128° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][C@@H:9]1[C@@H:17]([OH:40])[C@H:18]([N:26]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][C@@H:9]1[C@@H:17]([OH:40])[C@H:18]([NH2:26])[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](Cc2ccccc2)N=C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@H](N)Cc2ccccc2)C1

Procedure:
Dissolve 4-acetyl-2-(R)-[2-(R)-(benzhydrylidene-amino)-1-(S)-hydroxy-3-phenylpropyl]-piperazine-1-carboxylic acid tert-butyl ester (66 mg, 0.12 mmol) in methanol (1 mL) and add 10% palladium on carbon (12 mg). Stir under 1 atmosphere of hydrogen gas overnight, filter through a filtering agent, wash with methanol and concentrate to give the title compound that may be used without further purification.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][C:13]=1[C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(Cl)(=O)C([Cl:28])=O>C(Cl)Cl.CN(C)C=O>[CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([Cl:28])=[O:17])=[CH:14][C:13]=1[C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1ccc(C(=O)O)cc1C(C)(C)C
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1ccc(C(=O)Cl)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 3.0 g of product from Example 131 in 30 ml of methylene chloride plus 2 drops of dimethylformamide is added 2.0 ml of oxalyl chloride via syringe. The reaction is stirred at room temperature for 18 hours, concentrated in vacuo, dissolved in diethyl ether and filtered through a pad of diatomaceous earth. The diethyl ether is concentrated in vacuo to give 3.15 g of the desired product as a yellow oil.