Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[CH:6][N:7]=1.[Li]CCCC.[CH2:13]([Sn:17]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:19][CH2:20][CH2:21][CH3:22])Cl)[CH2:14][CH2:15][CH3:16]>O1CCCC1>[CH3:1][O:2][C:3]1[S:4][C:5]([Sn:17]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][N:7]=1
Reactant: COc1nccs1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(OC)s1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 22.8 %

Procedure:
To a stirred solution of 2-methoxythiazole (5 g, 43.4 mmol) in tetrahydrofuran (THF) (50 mL) was added n-BuLi (35.3 mL, 56.4 mmol) and the contents stirred at −78° C. After 15 min, tributylchlorostannane (14.13 mL, 52.1 mmol) was added and the mixture stirred with warming to room temperature over a 3 h period. The reaction mixture was quenched with water (20 mL) and the contents extracted with ether (25 mL). The organic layer was separated and dried over anhydrous sodium sulphate, filtered, and the filtrate concentrated in vacuo to afford the crude product (6 g). The crude product was purified by silica gel column chromatography (eluent: 2% EtOAc/Hexane) to afford 2-methoxy-5-(tributylstannyl)thiazole (4 g, 22%) as yellow liquid. 1H NMR (400 MHz, CDCl3-d3) δ ppm 0.90-0.98 (m, 9H), 1.05-1.15 (m, 6H), 1.30-1.40 (m, 6H), 1.50-1.65 (m, 6H), 4.04 (s, 3H), 7.03 (s, 1H). LCMS (ES) [M+H]+ 405.99.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH:18]1(Br)[CH2:22][CH2:21][CH2:20][CH2:19]1.C1(C)C=CC=CC=1>CN(C)C=O.[I-].[K+]>[CH:18]1([O:6][C:5]2[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=2[O:8][CH3:9])[CH:2]=[O:1])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(C=O)cc1OC1CCCC1
Temperature: 65 °C
Reaction time: 24 h
Yield: 80.5 %

Procedure:
A solution of 100 g (0.66 mol) of isovanillin, 136.2 g (0.99 mol) of anhydrous potassium carbonate, and 3 g of potassium iodide in 650 ml of anhydrous dimethylformamide was stirred at 65° C. 127.3 g (0.85 mol) of cyclopentyl bromide was slowly added dropwise for 1 hour to the solution. This solution was stirred at 65° C. for 1 day and, then, its temperature was lowered to a room temperature. It was diluted by 2.0 L of toluene and was washed with 1M sodium hydroxide (2×1.5 L). The aqueous layer was extracted with 0.5 L of toluene, and the organic layer was washed with distilled water (2×1.5 L). The organic layer was dried and concentrated to obtain 117 g of light brown oily title compound. 1H NMR(CDCl3,d): 9.84(s, 1H) 7.42(m, 2H) 6.95(d, 1H, J=9 Hz) 4.87(m, 1H) 3.93(s, 3H) 2.1-6(m, 8H)
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.[F:66][C:67]1([F:122])[C:79]2[CH:78]=[C:77]([C:80]3[CH:81]=[CH:82][C:83]4[N:87]=[C:86]([C@@H:88]5[CH2:96][C:91]6([O:95][CH2:94][CH2:93][O:92]6)[CH2:90][N:89]5[C:97](=[O:110])[C@@H:98]([NH:105][C:106](=[O:109])[O:107][CH3:108])[CH:99]5[CH2:104][CH2:103][O:102][CH2:101][CH2:100]5)[NH:85][C:84]=4[CH:111]=3)[CH:76]=[CH:75][C:74]=2[C:73]2[C:68]1=[CH:69][C:70]([C:112]1[NH:116][C:115]([C@@H:117]3[CH2:121][CH2:120][CH2:119][NH:118]3)=[N:114][CH:113]=1)=[CH:71][CH:72]=2.Cl>>[CH3:108][O:107][C:106](=[O:109])[NH:105][C@@H:98]([CH:99]1[CH2:104][CH2:103][O:102][CH2:101][CH2:100]1)[C:97]([N:89]1[C@H:88]([C:86]2[NH:85][C:84]3[CH:111]=[C:80]([C:77]4[CH:76]=[CH:75][C:74]5[C:73]6[C:68](=[CH:69][C:70]([C:112]7[NH:116][C:115]([C@@H:117]8[CH2:121][CH2:120][CH2:119][N:118]8[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]8[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=8)=[N:114][CH:113]=7)=[CH:71][CH:72]=6)[C:67]([F:66])([F:122])[C:79]=5[CH:78]=4)[CH:81]=[CH:82][C:83]=3[N:87]=2)[CH2:96][C:91]2([O:95][CH2:94][CH2:93][O:92]2)[CH2:90]1)=[O:110]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1nc3ccc(-c4ccc5c(c4)C(F)(F)c4cc(-c6cnc([C@@H]7CCCN7)[nH]6)ccc4-5)cc3[nH]1)OCCO2)C1CCOCC1
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1nc3ccc(-c4ccc5c(c4)C(F)(F)c4cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc4-5)cc3[nH]1)OCCO2)C1CCOCC1

Procedure:
Title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (S)-2-((S)-8-(6-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate 3× HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3HCl salt. MS (ESI) m/z 972.54 [M+H]+. (30 mg, 43%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[C:8]2[C:4]=1[CH2:5][CH:6]([CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=1)[CH2:7]2.[N:31]1([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.[ClH:43].C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C1COCC1.O.C(N(CC)CC)C>[ClH:43].[CH3:17][O:16][C:9]1[C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:3]([O:2][CH3:1])=[C:4]2[C:8]=1[CH2:7][CH:6]([CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:40]3[CH2:41][CH2:42][CH:37]([N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[CH2:38][CH2:39]3)=[O:28])=[CH:24][CH:23]=1)[CH2:5]2
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCOc1ccc(C(=O)O)cc1)C2
Reactant: C1CCN(C2CCNCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCOc1ccc(C(=O)N3CCC(N4CCCCC4)CC3)cc1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.4 %

Procedure:
The mixture of 4-[3-(4,5,6,7-tetramethoxyindan-2-yl)propoxy]benzoic acid (2.00 g), 4-piperidinopiperidine (1.62 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.84 g), 1-hydroxybenzotriazole monohydrate (1.47 g), and triethylamine (2.01 ml) in THF (40 ml) was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by alumina column chromatography (hexane to hexane:ethyl acetate=1:2) and converted into its hydrochloride, which was further recrystallized from ethanol-diisopropylether to yield the entitled compound (2.85 g) as crystals.
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[C:5]1[N:10]=[C:9]([C:11]([O:13]C)=[O:12])[CH:8]=[C:7]([CH3:15])[N:6]=1)[CH2:2][CH3:3].C1COCC1.O.[OH-].[Li+]>CO.O>[CH2:16]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]1[N:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[C:7]([CH3:15])[N:6]=1)[CH2:17][CH3:18]
Reactant: CCCN(CCC)c1nc(C)cc(C(=O)OC)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCN(CCC)c1nc(C)cc(C(=O)O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To methyl 2-(dipropylamino)-6-methylpyrimidine-4-carboxylate (0.450 g, 1.79 mmol) in MeOH (2 mL), water (1 mL), and THF (1 mL) was added lithium hydroxide monohydrate (0.113 g, 2.68 mmol). The mixture was stirred at room temperature for 1 h and then MeOH and THF were removed under reduced pressure. The pH of the residue was adjusted to approximately 5 and the resulting mixture was extracted with dichloromethane, dried over sodium sulfate, and concentrated to give 2-(dipropylamino)-6-methylpyrimidine-4-carboxylic acid (0.351 g) as a yellow solid.
Reaction SMILES: Cl[CH:2]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22].Cl>CN(C=O)C.O>[CH:8]1([CH:2]([C:19]2[CH:18]=[CH:17][C:16]([N+:21]([O-:23])=[O:22])=[C:15]([F:14])[CH:20]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCOC(=O)C(Cl)C1CCCCC1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(c1ccc([N+](=O)[O-])c(F)c1)C1CCCCC1
Temperature: -45 °C
Reaction time: 0.33 h
Yield: 48.6 %

Procedure:
8.2 g of potassium tert.butylate were dissolved in 70 ml of DMF and cooled to −45° C. For this purpose, a mix of ethyl 2-chloro-2-cyclohexylacetate (36.6 mmol, 7.5 g) and 1-fluoro-2-nitrobenzene (36.6 mmol, 3.9 ml) was carefully added dropwise and stirred for a further 20 minutes. The reaction mix was set to pH 4 using 16% HCl, diluted with 25 ml of water and extracted with EE (3×50 ml). Once combined, the organic phases were washed with water and sat. aq. NaCl sol., dried over MgSO4 and concentrated under vacuum. The residue obtained was purified by column chromatography (silica gel: mesh 100-200, eluent: 10% EE in cyclohexane) and produced 5.5 g (49%) of product.
Reaction SMILES: O[Li].O.C([O:6][C:7](=[O:25])[CH2:8][C:9]([N:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[CH3:12])=[O:10])C.C1COCC1.Cl>CO.O>[C:16]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:17]=[CH:18][C:13]([N:11]([CH3:12])[C:9](=[O:10])[CH2:8][C:7]([OH:25])=[O:6])=[CH:14][CH:15]=1
Reactant: CCOC(=O)CC(=O)N(C)c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN(C(=O)CC(=O)O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
LiOH.H2O (25 mg, 0.58 mmol) was added to a solution of N-biphenyl-4-yl-N-methyl-malonamic acid ethyl ester (116 mg, 0.39 mmol) in a mixture of Methanol (0.6 mL), THF (1.5 mL) and H2O (0.4 mL). The resulting mixture was stirred at ambient temperature for 2 hrs. The reaction mixture was concentrated to get a residue. The residue was diluted with water, acidified with conc. HCl. The precipitate was collected and dried to afford 100 mg (95.24%) of N-biphenyl-4-yl-N-methyl-malonamic acid
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([C:9]1[CH:17]=[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]2[N:10]=1)([CH3:8])[CH3:7].[OH-].[Na+].CN([CH:23]=[O:24])C>>[CH:6]([C:9]1[C:17]([CH:23]=[O:24])=[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]2[N:10]=1)([CH3:8])[CH3:7]
Reactant: CN(C)C=O
Reactant: CC(C)c1cc2ccccn2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1nn2ccccc2c1C=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
Upon stirring 3 mL of DMF at room temperature, neat phosphorous oxychloride (0.8 mL 1.3 equivalents) was added dropwise. The resulting mixture was stirred at room temperature for 10 minutes, followed by dropwise addition of neat 2-isopropylpyrazolo[1,5-a]pyridine (1 g, 1 equivalent). The solution was stirred at room temperature for 19 hours and poured into 100 mL of ice water. The pH of the aqueous solution was adjusted to 8 using solid NaOH. The precipitate formed was collected by filtration and dried under reduced pressure to furnish 2-isopropylpyrazolo[1,5-a]pyridine-3-carbaldehyde (0.97 g, 82% yield) as a white solid. Compound 1073.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH3:5].[CH3:6][O:7][C:8](=[O:19])[C:9]1[CH:17]=[C:16]([Br:18])[CH:15]=[C:11]([C:12]([OH:14])=O)[CH:10]=1.BrC1C=C(C(O)=O)C=C(C=1)C(O)=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl-].[NH4+].Cl>ClCCl>[CH3:6][O:7][C:8](=[O:19])[C:9]1[CH:17]=[C:16]([Br:18])[CH:15]=[C:11]([C:12]([N:2]([CH3:1])[CH2:3][CH2:4][CH3:5])=[O:14])[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc(C(=O)O)c1
Reactant: CCCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)c1cc(Br)cc(C(=O)O)c1
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(Br)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
Add N-methylpropylamine (5.14 g, 70.4 mmol) to a mixture of 5-bromo-isophthalic acid monomethyl ester and 5-bromo-isophthalic acid (18.2 g), 1-hydroxybenzotriazole (9.5 g, 70.4 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.5 g, 70.4 mmol) in dichloromethane (200 mL). Stir the solution for 2 h at room temperature. Add saturated aqueous ammonium chloride (100 mL) and acidify the mixture with 1 N HCl. Filter away the precipitate, extract the filtrate with dichloromethane, wash the organic extracts with 1 N HCl, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 30:70 ethyl acetate:hexanes) to give the title compound as an oil (10.1 g, 46%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].Br[C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:34]3[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[CH:36][CH:35]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reactant: O=C(O)CCc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3ccc(CCC(=O)O)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution of 6-(((2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (for a preparation see Intermediate 5) (382 mg, 0.884 mmol) and 3-(4-bromophenyl)propanoic acid (243 mg, 1.060 mmol) in toluene (6 mL) and ethanol (6 mL) were successively added tetrakis(triphenylphosphine)palladium(0) (102 mg, 0.088 mmol) and potassium carbonate (366 mg, 2.65 mmol). The resulting mixture was stirred at 80° C. for 2 h, then partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (25 g), eluting with EtOAc in cyclohexane (10-70%). The appropriate fractions were combined and concentrated under reduced pressure to give 3-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)propanoic acid (209 mg, 52%) as a white solid. LCMS (Formate, 2 min), Rt=0.91 min, MH+=455.
Reaction SMILES: C[O:2][C:3](=[O:35])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:34])=[O:26])=[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:7].[OH-].[Na+]>C(O)C.O1CCCC1>[Cl:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:34])[C:27]=1[C:25]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C@@H:4]([C:3]([OH:35])=[O:2])[NH:5][C:6]([C:8]2([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:19][CH:20]=1)=[O:26]
Reactant: COCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)OC)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)CCCC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-(2-methoxyethyl)-cyclopentyl]carbonyl]-L-phenylalanine methyl ester (20.17 mmol, 10.52 g) in ethanol (80 mL) and tetrahydrofuran (10 mL) was added aqueous 1.0 N sodium hydroxide (80 mL) at room temperature. The mixture was heated to 50° C. and the resulting clear solution was stirred overnight. Then, the ethanol solution was concentrated and diluted with 50 mL of water and was extracted with 200 mL of ether to remove neutral impurities. The aqueous layer was acidified with 1N HCl and the precipitated white solid was collected by filtration and washed with 200 mL of water and 200 mL of hexane. After air-drying, 8.4 g (82%) of as a white solid: mp 136-140° C. was obtained. 1H NMR, DMSO-d6 (400 MHz) δ 10.64 (s, 1H), 7.73 (d, 1H, J=22 Hz), 7.46-7.59 (m, 5H), 7.22 (d, 2H, J=22 Hz), 4.43-4.48 (m, 1H), 2.87-3.11 (m, 7H), 1.76-2.01 (m, 4H), 1.23-1.47 (m, 6H). HR MS (C25H28Cl2N2O5): Obs. mass, 507.1464. Calcd. mass, 507.1454 (M+H).
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH2:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:17]#[CH:18]>>[C:28]1([CH2:27][NH:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:19][CH2:16][C:17]#[C:18][C:2]2[CH:15]=[CH:14][C:5]([C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[O:7])=[CH:4][CH:3]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C#CCOCCCCCCNCc1ccccc1
Reactant: O=C(c1ccc(I)cc1)N1CCOCC1
Product: O=C(c1ccc(C#CCOCCCCCCNCc2ccccc2)cc1)N1CCOCC1
Yield: 40.4 %

Procedure:
4-(4-Iodobenzoyl)morpholine (4.0 g) and N-[6-[(2-propynyl)oxy]- hexyl]benzenemethanamine (3.09 g) were reacted according to the method of Intermediate 31. FCC purification eluting with ethyl acetate-triethylamine (100:1) gave the title compound as a yellow oil (2.21 g), t.l.c. (Ethyl acetate-triethylamine 100:1) Rf 0.2.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6][C:7](=O)[CH3:8])=[CH:4][CH:3]=1.BrC1C=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[F:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6][C:7]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1ccc(F)cc1
Reactant: Fc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Fc1ccc(Nc2ccc(F)cc2)cc1

Procedure:
A mixture of p-fluoroacetanilide (76.5 g, 0.5 mole), 4-bromofluorobenzene (262.5 g, 1.5 mole), K2CO3 (76 g, 0.55 mole), Cu2Br2 (157.8 g, 0.55 mole) and N-methylpyrrolidone (600 ml) were heated at 175°-180°. After allowing low boiling material to condense off, the mixture was heated at reflux for 7 days. The mixture was cooled to 60° and quenched into a mixture of 2 liters H2O, 600 ml ethylenediamine and 1.2 liters toluene, filtered and the toluene layer separated, back-washed 2×600 ml H2O, treated with activated carbon, dried over MgSO4 and concentrated to oily solids in vacuo. The latter were taken up in 1.5 liters 10% ethanolic KOH, refluxed 18 hours and concentrated in vacuo to an oil. The oil was partitioned between 750 ml H2O and 750 ml. ether. The water layer was washed 2× 200 ml ether. The organic layers were combined, back-washed 2×200 ml H2O, treated with activated carbon, dried over MgSO4, reconcentrated to an oil (60.3 g) and distilled to yield purified title product 41.6 g, b.p. 158°-160°/2 mm.
Reaction SMILES: C(C1C=CC=CC=1)(=O)C.Cl.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18]/[C:19](/[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:23]=2)=[N:20]\[OH:21])[CH2:14][CH2:13]1.CN1CCN(C/C(/C2C=CC=C(CCC3C=CC=CC=3)C=2)=N/O)CC1>>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:23]=2)=[N:20][OH:21])[CH2:14][CH2:13]1
Reactant: CN1CCN(C/C(=N\O)c2cccc(CCc3ccccc3)c2)CC1
Agent: CN1CCN(C/C(=N/O)c2cccc(CCc3ccccc3)c2)CC1
Agent: Cl
Solvent: CC(=O)c1ccccc1
Product: CN1CCN(CC(=NO)c2cccc(CCc3ccccc3)c2)CC1

Procedure:
A Grignard compound synthesized from 1.0 g of magnesium and 10.0 g of 3-(2-phenylethyl)-bromobenzene in 30 ml of tetrahydrofuran was dropped at -60° C. under stirring for 3 min into 7.6 g of anhydrous acetic acid dissolved in 20 ml of tetrahydrofuran in a nitrogen atmosphere and stirred for further one hour. Then, the reaction solution was poured into a mixture of ice and an aqueous saturated solution of ammonium chloride and extracted with toluene. After separating the solution, it was washed with an aqueous 2N-solution of sodium hydroxide and saturated saline solution successively, dried over anhydrous sodium sulfate and then concentrated to solid. The residue was purified by silica gel column chromatography, using benzene/n-hexane (1:1) as an elute, to obtain 7.9 g of 1-(3-(2-phenylethyl)-phenyl)-ethanone as an oily product. Then, by using 5.0 g of the thus obtained acetophenone compound, 3.8 g of (Z)-2-(4-methylpiperazin-1-yl)-1-(3-(2-phenylethyl)-phenyl)-ethanone oxime hydrochloride with the melting point of from 185° to 188° C. (decomposition) and 0.5 g of (E)-2-(4-methylpiperazin-1-yl)-1-(3-(2-phenylethyl)-phenyl)-ethanone oxime with the melting point from 133° to 134° C. were obtained in the same manner as in Example 33.
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[S:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][NH:17][NH2:18].[N-]=C=S>CCCCC>[C:1]([N:5]=[N:6][C:7]1([NH:13][C:14](=[S:15])[N:17]([CH3:16])[NH2:18])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Reactant: CNN
Agent: [N-]=C=S
Solvent: CCCCC
Product: CN(N)C(=S)NC1(N=NC(C)(C)C)CCCCC1

Procedure:
To 10.0 grams (.0434 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane cooled to 5° C. and stirred with a magnetic stirrer in a 50 ml erlenmeyer flask was added 1.99 grams (.0434 moles) of methylhydrazine. The reaction was very exothermic and solids formed immediately. Pentane was added to form a slurry, the reaction mixture stirred for 30 minutes at room temperature and the pentane stripped from the slurry to leave a white solid weighing 10.7 grams (89% crude yield). The product melted at 118°-120° C. with decomposition and its infrared spectrum had a strong band at 1515 cm-1 ##STR22## moderate NH bands at 3225 cm-1 and the isothiocyanate at 2040 cm-1 was absent.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1OCCOCCOCCOCCOCCOC1.[C:29]([O:33][C:34](=[O:52])[CH2:35]P(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O)([CH3:32])([CH3:31])[CH3:30].[S:53]1[C:57]([CH:58]=O)=[CH:56][C:55]2[CH:60]=[CH:61][CH:62]=[CH:63][C:54]1=2>C1COCC1>[C:29]([O:33][C:34](=[O:52])[CH:35]=[CH:58][C:57]1[S:53][C:54]2[CH:63]=[CH:62][CH:61]=[CH:60][C:55]=2[CH:56]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)CP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: O=Cc1cc2ccccc2s1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=Cc1cc2ccccc2s1
Temperature: -78 °C
Reaction time: 3 h
Yield: 74.3 %

Procedure:
Potassium bis(trimethylsilyl)amide (5.4 g, 0.027 mol) was added to a solution of 18-Crown-6 (13.7 g, 0.052 mol) and (diphenoxy-phosphoryl)-acetic acid tert-butyl ester (9.4 g, 0.027 mol) in dry THF (120 mL) at −78° C. After 30 minutes of stirring at this temperature, benzo[b]thiophene-2-carbaldehyde (4.0 g, 0.024 mol) was added and the reaction was stirred for 3 hours at −78° C. after which the reaction was quenched with saturated ammonium chloride (200 mL). The reaction mix was allowed to come to room temperature and was extracted with ethyl acetate (3×200 mL) and the combined organic extracts were washed with 10% HCl (200 mL), brine (200 mL), and dried over MgSO4. The solvent was evaporated in vacuo leaving the crude product that was purified by column chromatography (SiO2) using a 5-40% ethylacetate-hexane gradient to afford the subtitle compound (4.64 g, yield: 74%). MS calculated for C15H16O2S +H: 261, observed: 261.