Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:14][O:15][C@H:16]1[C@@H:21]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20][CH2:19][NH:18][CH2:17]1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[CH2:25]([O:24][C:23]([NH:22][C@H:21]1[CH2:20][CH2:19][N:18]([C:2]2[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:17][C@H:16]1[O:15][CH3:14])=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)c1cc(I)ccc1OC
Reactant: CO[C@@H]1CNCC[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)ccc1OC
Yield: 5.4 %

Procedure:
The same operation as in Example (42a) was performed using methyl 5-iodo-2-methoxybenzoate (442 mg, 1.51 mmol), benzyl cis(±)-(3-methoxypiperidin-4-yl)-carbamate obtained in Example (40b) (400 mg, 1.51 mmol), palladium acetate (34 mg, 0.15 mmol), (±)-BINAP (188 mg, 0.30 mmol), cesium carbonate (1.08 g, 3.33 mmol), 1,4-dioxane (15 mL) and DMF (4.5 mL), to obtain 35 mg of the title compound as a yellow oily substance (5%).
Reaction SMILES: C1(=O)CCCC(=O)C1.C[C:10]1(C)[CH2:19][C:18]2[NH:17][C:16](=[S:20])[C:15]([C:21]#[N:22])=[CH:14][C:13]=2[C:12](=[O:23])[CH2:11]1>>[O:23]=[C:12]1[CH2:11][CH2:10][CH2:19][C:18]2[NH:17][C:16](=[S:20])[C:15]([C:21]#[N:22])=[CH:14][C:13]1=2
Reactant: CC1(C)CC(=O)c2cc(C#N)c(=S)[nH]c2C1
Agent: O=C1CCCC(=O)C1
Product: N#Cc1cc2c([nH]c1=S)CCCC2=O
Yield: 52 %

Procedure:
Prepared in 52% yield from cyclohexane-1,3-dione in analogy to the procedure described for 7,7-dimethyl-5-oxo-2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile synthesis.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:4]=[N:3]1.[NH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27]>>[OH:27][CH2:26][C:25]([NH:24][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([O:8][CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][C:5]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:10][CH:11]=1)([CH3:29])[CH3:28]
Reactant: CC(C)(N)CO
Reactant: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)O)cn1
Product: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)NC(C)(C)CO)cn1
Yield: 79 %

Procedure:
As described for example 26b, 6-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid (80 mg, 0.26 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of 4-aminotetrahydropyran, to the title compound (78 mg, 79%) which was obtained as a white solid. MS: m/e=383.2 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([CH:10](OCC)[O:11]CC)[N:7]=[C:6]([S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[N:5]=2)[CH2:3][CH2:2]1.Cl.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH:1]1([C:4]2[N:5]=[C:6]([S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[N:7]=[C:8]([CH:10]=[O:11])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: CCCCCCSc1nc(C2CC2)cc(C(OCC)OCC)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCSc1nc(C=O)cc(C2CC2)n1
Yield: 94.6 %

Procedure:
4-Cyclopropyl-6-diethoxymethyl-2-hexylsulfanyl-pyrimidine (2.7 g, 8 mmol) was dissolved in THF (13 mL) and 4 N HCl (13 mL) and stirred at 20° C. for 19 h. The reaction mixture was poured in cold 10% Na2CO3 (100 mL) and extracted twice with AcOEt and once with sat. NaCl solution. The crude product was purified by chromatography on silica gel in heptane/DCM with a gradient of 100:0 to 67:33. One obtained 2 g (94%) of a yellow oil, which solidified upon standing in the fridge. MS: m/z=264 (M).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>O1CCCC1.[Pd]>[C:1]([O:5][C:6]([NH:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NN=Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NNCc1ccccc1

Procedure:
To a solution of N′-benzylidenehydrazinecarboxylic acid tert-butyl ester (2.7 g, 12.3 mmol) in tetrahydrofuran (100 ml) was added 10% palladium on carbon (0.3 g) and the mixture was hydrogenated with 280 ml of hydrogen for 40 min at atmospheric pressure. The mixture was filtered through a plug of celite and the filtrate was concentrated in vacuo to give 2.63 9 of N′-benzylhydrazinecarboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:13].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[S:23][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)=[CH:8][C:7]=1[CH3:13]
Reactant: CCO[C@@H](Cc1ccc(O)cc1C)C(=O)OC
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1ccc(OCc2csc(-c3ccc(Cl)cc3)n2)cc1C)C(=O)OC

Procedure:
In analogy to the procedure described in example 14 b], (2S)-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (example 17 d]) was reacted with 4-chloromethyl-2-(4-chloro-phenyl)-thiazole (example 14 a]) in the presence of cesium carbonate and potassium iodide to yield (2S)-3-{4-[2-(4-chloro-phenyl)-thiazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid methyl ester as light yellow liquid.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:20]([NH:22][C@H:23]([C:30]([NH:32][C@H:33]([CH2:38][OH:39])[CH2:34][CH:35]([CH3:37])[CH3:36])=[O:31])[CH2:24][C:25]1[N:29]=[CH:28][NH:27][CH:26]=1)=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)C1C=CC=CC=1.Br.[N+:41]([C:44]1[C:45]([S:50][S:51][CH2:52][CH2:53][C:54]([OH:56])=O)=[N:46][CH:47]=[CH:48][CH:49]=1)([O-:43])=[O:42].ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>C(OCC)C.C(O)(=O)C>[N+:41]([C:44]1[C:45]([S:50][S:51][CH2:52][CH2:53][C:54]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]([C:30]([NH:32][C@H:33]([CH2:38][OH:39])[CH2:34][CH:35]([CH3:36])[CH3:37])=[O:31])[CH2:24][C:25]2[N:29]=[CH:28][NH:27][CH:26]=2)=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:56])=[N:46][CH:47]=[CH:48][CH:49]=1)([O-:43])=[O:42]
Reactant: O=C(O)CCSSc1ncccc1[N+](=O)[O-]
Reactant: CC(C)C[C@@H](CO)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)C[C@@H](CO)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)CCSSc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 0.16 g. (0.3 mmole) of N-benzyloxycarbonyl-L-phenylalanyl-L-histidyl-L-leucinol were added 3 ml. of a 25% w/v glacial acetic acid solution of hydrogen bromide. The mixture was stirred at room temperature for 30 minutes, and then anhydrous diethyl ether was added thereto. The precipitate thus formed was separated by filtration and dissolved in 5 ml. of dimethylformamide. The solution was cooled with ice, and then there were added 30 mg. of N-methylmorpholine for neutralization. To the neutralized solution were added an active ester prepared from 86 mg. (0.33 mmole) of 3-(3-nitro-2-pyridyldithio)propionic acid, 39 mg. (0.33 mmole) of 1-hydroxybenztriazole and 74 mg. (0.36 mmole) of DCC. The mixture was stirred for 1 hour whilst cooling with ice and then overnight at room temperature, after which it was treated in a conventional manner to give a yellow powder, which was purified by silica gel column chromatography (eluent: chloroform/methanol=8:1 by volume), to afford 47 mg. of the desired compound as a yellow powdery solid, melting at 109°-112° C.; [α]22 -33.8° (C=0.5, methanol).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([NH2:13])=[C:11]([C:14](=O)[NH2:15])[CH:10]=[N:9]2)=[CH:6][CH:7]=1.O.[NH2:18][NH2:19]>CN(C)C=O>[NH:18]([C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([NH2:13])=[C:11]([C:14]#[N:15])[CH:10]=[N:9]2)=[CH:6][CH:7]=1)[NH2:19]
Reactant: NN
Reactant: NC(=O)c1cnn(-c2ccc(Cl)nn2)c1N
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cnn(-c2ccc(NN)nn2)c1N

Procedure:
A mixture of 10 g. of 3-chloro-6-(4-cyano-5-amino-1-pyrazolyl)-pyridazine (prepared according to Example 24), 20 ml. dimethylformamide and 40 ml. of 98% hydrazine hydrate is heated at 90°-95° C. for 5 hours. After cooling the precipitated product is filtered, washed with water and ethanol, triturated with 50 ml. of hot ethanol, filtered and dried. Yield: 9.1 g. (93%); m.p.: 264°-266° C. The hydrochloride melts at 253°-256° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH:19][CH2:20][C:21]1[CH:32]=[CH:31][C:24]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:23][CH:22]=1>>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:31][CH:32]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCOC(=O)c1ccc(CO)cc1
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Product: C=CCOC(=O)c1ccc(COC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1

Procedure:
In a manner similar to Example 1(d), by reaction of 7.7 g (28.6 mmol) of 3,5-di-tert-butyl-4-hydroxybenzoyl chloride with 5.5 g (28.6 mmol) of allyl 4-hydroxymethylbenzoate, 4.1 g (34%) of the expected allyl ester, melting point 100°-1° C., are obtained.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH3:20][NH:21][CH3:22]>>[CH3:20][N:21]([CH3:22])[S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: CNC
Product: CCc1cc(-c2ccc(S(=O)(=O)N(C)C)s2)c(C)[nH]c1=O
Yield: 61 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with dimethylamine as described in Step 5, Example 24 to give the title compound as a solid (61% yield). LC/MS: RT 3.68 min; m/e 327 (M+H); 1H NMR (δ, ppm): 11.84 (1H, s), 7.61 (1H, d), 7.38 (1H, s); 7.28 (1H, d); 2.69 (6H, s), 2.39 (2H, q), 2.33 (3H, s), 1.07 (3H, t).
Reaction SMILES: Cl.[N+:2]([O-:18])([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[O:3].[CH2:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][C:30]([C:33]([O-])=[O:34])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)[CH3:20].[Na+].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.C(Cl)(Cl)Cl>[O:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:33]([C:30]1[CH:31]=[N:32][C:27]([N:24]2[CH2:23][CH2:22][N:21]([CH2:19][CH3:20])[CH2:26][CH2:25]2)=[CH:28][CH:29]=1)=[O:34])[N+:2]([O-:18])=[O:3]
Reactant: CCN1CCN(c2ccc(C(=O)[O-])cn2)CC1
Reactant: NCCCCCCCCCCCCO[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCO[N+](=O)[O-])cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a solution of 5.7 g of 12-aminododecyl nitrate hydrochloride in 80 ml of methylene chloride were added successively under ice-cooling 5.21 g of sodium 6-(4-ethylpiperazinyl)pyridine-3-carboxylate, 3.91 g of 1-hydroxybenzotriazole (HOBt) and 2.76 g of 1-ethyl-3-(3-dimethylaminopropyl )carbodiimide hydrochloride (WSCI) and then the mixture was stirred at room temperature overnight. The reaction solution was diluted with chloroform and washed successively with water, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and then distilled under reduced pressure. The residue thus obtained was chromatographed over a silica gel column to afford 8.56 g of the title compound as a crystal.
Reaction SMILES: C([NH:4][CH2:5][CH:6]([N:8]1[C:12]([SH:13])=[N:11][N:10]=[N:9]1)[CH3:7])(=O)C.[ClH:14]>>[ClH:14].[NH2:4][CH2:5][CH:6]([N:8]1[C:12]([SH:13])=[N:11][N:10]=[N:9]1)[CH3:7]
Reactant: CC(=O)NCC(C)n1nnnc1S
Agent: Cl
Product: CC(CN)n1nnnc1S

Procedure:
A mixture of 1-[1-(acetamidomethyl)ethyl]-1H-tetrazole-5-thiol (23 g) and 6 N aqueous hydrochloric acid (300 ml) was refluxed for 2 hours under stirring and evaporated to dryness. The residue was triturated with diethyl ether to give 1-[1-(aminomethyl)ethyl]-1H-tetrazole-5-thiol hydrochloride (19 g), mp 208° to 210° C.
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:7][F:8])([OH:6])[C:4]#[CH:5].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[H-].[Na+].O>O1CCCC1>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15]([O:6][C:3]([CH2:7][F:8])([C:4]#[CH:5])[CH2:2][F:1])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: C#CC(O)(CF)CF
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C#CC(CF)(CF)OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
An amount (6.6 g) of 1-fluoro-2-fluoromethyl-3-butyn-2-ol and p-toluenesulfonyl chloride (9.5 g) were dissolved in tetrahydrofuran (100 ml); to the solution under cooling with ice, 60% oily sodium hydride (2.4 g) was added under a nitrogen atmosphere. After the end of the addition, the mixture was stirred for 5. hours while its temperature was raised to room temperature. Water was added to the reaction mixture, followed by extraction with ether. The extract was washed with water and a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane/methylene chloride=1/1) to give the titled compound (11.1 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[C:11]([O:22][CH2:23][CH3:24])(=[O:21])[C:12]1[CH:20]=[CH:19][C:17]([OH:18])=[C:14]([O:15][CH3:16])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:16][O:15][C:14]1[CH:13]=[C:12]([CH:20]=[CH:19][C:17]=1[O:18][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[C:11]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCCCN2CCOCC2)c(OC)c1
Temperature: 80 °C
Yield: 99.9 %

Procedure:
N-(3-Chloropropyl)morpholine (90 g, 0.55 mol) was added dropwise, over 30 minutes, to a solution of ethyl vanillate (98 g, 0.50 mol) and powdered potassium carbonate (104 g, 0.75 mol) in dimethylformamide (300 ml) at 80° C. The reaction was heated at 80° C. for 90 minutes, cooled to ambient temperature, filtered and the filtrate concentrated in vacuo. The crude product was taken up in diethyl ether (1000 ml), filtered and washed with water (2×200 ml) and brine (200 ml). Solvent evaporation in vacuo yielded ethyl 3-methoxy-4-(3-morpholinopropoxy)benzoate (161.5 g, 100% yield) as a pale yellow oil which crystallised on standing to afford a pale yellow solid:
Reaction SMILES: [NH2:1][C@@H:2]([C@H:10]([C@@H:12]1[C@@H:16]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C@@H:15]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C@H:14]([N:33]2[CH:38]=[CH:37][C:36](=[O:39])[N:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:34]2=[O:49])[O:13]1)[OH:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH:50]1[C:62]2[CH:61]([CH2:63][O:64][C:65](=[O:84])[NH:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][C:77](=[O:83])[NH:78][CH2:79][CH2:80][CH:81]=O)[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:54]=2[CH:53]=[CH:52][CH:51]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.O1CCCC1>[Si:18]([O:17][C@H:16]1[C@@H:15]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[C@H:14]([N:33]2[CH:38]=[CH:37][C:36](=[O:39])[N:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:34]2=[O:49])[O:13][CH:12]1[C@H:10]([OH:11])[C@@H:2]([C:3]([O:5][C:6]([CH3:7])([CH3:9])[CH3:8])=[O:4])[NH:1][CH2:81][CH2:80][CH2:79][NH:78][C:77](=[O:83])[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72][CH2:71][CH2:70][CH2:69][CH2:68][CH2:67][NH:66][C:65](=[O:84])[O:64][CH2:63][CH:61]1[C:60]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[C:54]2[C:62]1=[CH:50][CH:51]=[CH:52][CH:53]=2)([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19]
Reactant: O=CCCNC(=O)CCCCCCCCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3O[C@H]([C@H](O)[C@H](N)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)CCCCCCCCCCNC(=O)OCC4c5ccccc5-c5ccccc54)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Yield: 64.9 %

Procedure:
By using an analogous procedure to that described for Example 1, a solution of tert-butyl (2S,3R)-2-amino-3-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl-(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-tetrahydro-2-furanyl]-3-hydroxypropanoate (125 mg, 0.173 mmol, obtained from Reference Example 6), 9H-fluoren-9-ylmethyl-11-oxo-11-[(3-oxopropyl)amino]undecyl-carbamate (99 mg, 0.208 mmol, obtained from Reference Example 30), acetic acid (2 drops) and sodium triacetoxyborohydride (73 mg, 0.346 mmol) in anhydrous tetrahydrofuran (4 ml) was stirred at room temperature under nitrogen for 5.5 hours. The product was purified by chromatography (flash column, silica gel, ethyl acetate) to provide tert-butyl (21S)-21-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-1-(9H-fluoren-9-yl)-3,15-dioxo-2-oxa-4,16,20-triazadocosan-22-oate (133 mg, 65%) as a white solid.
Reaction SMILES: [CH:1]1[C:6]([C:7]2[CH:13]=[C:12]([NH2:14])[C:10](=[O:11])[NH:9][CH:8]=2)=[CH:5][CH:4]=[N:3][CH:2]=1.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[O:11]=[C:10]1[NH:9][CH:8]=[C:7]([C:6]2[CH:1]=[CH:2][N:3]=[CH:4][CH:5]=2)[CH:13]=[C:12]1[NH:14][S:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:23])=[O:22]
Reactant: Nc1cc(-c2ccncc2)c[nH]c1=O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=c1[nH]cc(-c2ccncc2)cc1NS(=O)(=O)c1ccccc1
Reaction time: 2 h
Yield: 57.6 %

Procedure:
Amrinone (100 mg, 0.53 mmol) was suspended in pyridine (2 mL) and benzenesulfonyl chloride (75 μL, 0.59 mmol) was added dropwise at 0° C. The reaction mixture was stirred for 2 hours. The pyridine was removed in vacuo. MeOH was added to the crude mixture and the solid was filtered and rinsed with more MeOH to give the title compound as a light yellow solid (100 mg, 57% yield). MS (ES+) m/e=328. 1H NMR (DMSO-d6) δH 7.51 (2H, dd), 7.54-7.58 (2H, m), 7.61-7.65 (1H, m), 7.75 (2H, dd), 7.90 (2H, dd), 8.56 (2H, dd), 9.78 (1H, br s), 12.33 (1H, br s).
Reaction SMILES: [CH:1]1[CH:9]=[C:8]2[C:4]([CH:5]=[CH:6][S:7]2)=[C:3]([CH2:10][C:11]([OH:13])=O)[CH:2]=1.[CH3:14][NH:15][C@@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][C@H:17]1[N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1>[N:25]1([C@@H:17]2[CH2:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@H:16]2[N:15]([CH3:14])[C:11](=[O:13])[CH2:10][C:3]2[C:4]3[CH:5]=[CH:6][S:7][C:8]=3[CH:9]=[CH:1][CH:2]=2)[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: O=C(O)Cc1cccc2sccc12
Reactant: CN[C@@H]1c2ccccc2C[C@H]1N1CCCC1
Solvent: C1CCOC1
Product: CN(C(=O)Cc1cccc2sccc12)[C@@H]1c2ccccc2C[C@H]1N1CCCC1
Reaction time: 1 h
Yield: 78.2 %

Procedure:
A mixture of 0.5 g of 4-thianaphthene-acetic acid, 0.422 g of carbonyldimmidazole and 20 ml of tetrahydrofuran was stirred for one hour and then a solution of 0.432 g of the product of Step B in 5 ml of tetrahydrofuran was slowly added thereto. The mixture was stirred for 31/2 hours and the tetrahydrofuran was distilled off under reduced pressure. The residue was taken up in 100 ml of ether and the solution was washed with aqueous saturated sodium bicarbonate solution, then with aqueous saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure to obtain 0.61 g of trans (±)- N-[2,3-dihydro-2-(pyrrolidin-1-yl)-1H-inden-1-yl]-N-methyl-4-benzo[b]thiophene-acetamide in the form of an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:22]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][C:32]=2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[NH:29][CH:28]=[C:27]3[CH3:41])=O)=[CH:18][N:19](C)C)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:42]N>CCO>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[C:22]([C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][C:32]=3[O:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:29][CH:28]=[C:27]4[CH3:41])=[N:42][NH:19][CH:18]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: Cc1c[nH]c2cc(OCc3ccccc3)c(C(=O)C(=CN(C)C)N3CCN(C(=O)OCc4ccccc4)CC3)cc12
Solvent: CCO
Product: Cc1c[nH]c2cc(OCc3ccccc3)c(-c3n[nH]cc3N3CCN(C(=O)OCc4ccccc4)CC3)cc12
Yield: 29.4 %

Procedure:
A solution of 4-[1-(6-benzyloxy-3-methyl-1H-indole-5-carbonyl)-2-dimethylamino-vinyl]-piperazine-1-carboxylic acid benzyl ester (0.158 g, 0.29 mmol) and hydrazine (0.75 ml, 15.5 mmol) in EtOH was refluxed for 1 hour, after which time the reaction had gone to completion. The solvent was removed in vacuo and the product purified by column chromatography in hexane/EtOAc (1:1) to afford an off-white solid (0.0445 g, 30%). LC/MS: RT=2.713 min. 522 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([N+:9]#[C-:10])[CH2:7][CH3:8].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[CH2:16]Cl>>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[CH2:16][C:6]([N+:9]#[C-:10])([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:7][CH3:8]
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: [C-]#[N+]C(CC)c1cccs1
Product: [C-]#[N+]C(CC)(Cc1cc(OC)c(OC)c(OC)c1)c1cccs1
Yield: 67.5 %

Procedure:
2.5 g of 1-(2-thienyl)propyl isocyanide and 4.4 g of 3,4,5-trimethoxybenzyl chloride are treated in the same manner as described in Example 1-(1) to give 3.7 g of 1-(3,4,5-trimethoxybenzyl)-1-(2-thienyl)propyl isocyanide as a colorless oil. yield; 67.5%
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14](=[O:21])OCC(Cl)(Cl)Cl)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:22]1([C:28]2[N:32]=[C:31]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[S:30][N:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]([N:36]3[CH2:37][CH2:38][N:33]([C:31]4[S:30][N:29]=[C:28]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:32]=4)[CH2:34][CH2:35]3)=[O:21])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: CC(=O)N1CCc2cc(NC(=O)OCC(Cl)(Cl)Cl)ccc21
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCc2cc(NC(=O)N3CCN(c4nc(-c5ccccc5)ns4)CC3)ccc21

Procedure:
A solution of 2,2,2-trichloroethyl (1-acetyl-2,3-dihydro-1H-indol-5-yl)carbamate (200 mg, 0.569 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (140 mg, 0.569 mmol), diisopropylethylamine (0.198 ml, 1.14 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 48 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product. This was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to obtain the desired product (110.0 mg, 43.1%) as a solid.