Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([NH2:17])[C:6](=[O:16])[NH:7]2.Cl.N[OH:20].O>C(O)CCC>[Br:1][C:2]1[CH:11]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[N:17][OH:20])[C:6](=[O:16])[NH:7]2
Reactant: NO
Reactant: Nc1nc2c(Br)cc(C(F)(F)F)cc2[nH]c1=O
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: O=c1[nH]c2cc(C(F)(F)F)cc(Br)c2[nH]c1=NO
Temperature: 25 °C
Yield: 86.1 %

Procedure:
An adaptation of the method of Harsanyi et al., Liebigs Ann. Chem. 190 (1973) was used. A mixture of 5-bromo-7-trifluoromethyl-3-aminoquinoxalin-2(1H)-one (75 mg, 0.24 mmol) and hydroxylamine hydrochloride (38 mg, 0.54 mmol; Aldrich Co.) in 3 mL of 1-butanol was heated to reflux. The resulting suspension was stirred under reflux for 12 h. The resulting suspension was cooled to 25° C., and H2O was added (6 mL). A pale yellow precipitate appeared. The mixture was vacuum filtered and the solid was washed with EtOH (5×2 mL) and dried in vacuum at 60° C. overnight to yield 67 mg (86% ) of 5-bromo-7-trifluoromethyl-3-(hydroxyimino)-1,4-dihydroquinoxalin-2-one (tentatively named as this since the regiochemistry is not sure) as a pale yellow solid of a new compound: mp 221°-223° C. 1H NMR (300 MHz, DMSO-d6) δ 11.205 (br s, 1H, NH), 10.393 (br s, 1H, NH), 7.639 (s, 1H, H-7), 7.435 (s, 1H, H-5). LRMS: 323 (M+, 80%), 293 (100%).
Reaction SMILES: FC1C=C([N+]([O-])=O)C=CC=1C=CC(O)=O.BrBr.Cl.FC1C=C(N)C=CC=1C#CC(O)=O.BrCCCCCCCCCCCCCCCC.[F:49][C:50]1[CH:55]=[C:54]([NH:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[CH:53]=[CH:52][C:51]=1[C:73]#[C:74][C:75]([O:77]CC)=[O:76]>C(O)(=O)C.[OH-].[Na+].[OH-].[NH4+]>[F:49][C:50]1[CH:55]=[C:54]([NH:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[CH:53]=[CH:52][C:51]=1[C:73]#[C:74][C:75]([OH:77])=[O:76]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C#CC(=O)OCC)c(F)c1
Agent: BrBr
Agent: CCCCCCCCCCCCCCCCBr
Agent: Cl
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCNc1ccc(C#CC(=O)O)c(F)c1

Procedure:
Alternatively, the 2-fluoro-4-aminophenylpropiolic acid is prepared from 2-fluoro-4-nitrocinnamic acid by successive treatment with bromine in acetic acid, aqueous sodium hydroxide, ferric sulfate and ammonium hydroxide, and ethanolic hydrogen chloride. The propiolic acid is then converted to the corresponding ethyl ester and alkylated with 1-bromohexadecane in the manner of Example 9. The resulting ethyl 2-fluoro-4-(hexadecylamino)phenylpropiolate is hydrolyzed in the manner of Example 10 to yield 2-fluoro-4-(hexadecylamino)phenylpropiolic acid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C@:14]3([CH2:29][C:30](O)=[O:31])[S:20](=[O:22])(=[O:21])[CH2:19][CH2:18][N:17]([S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])[CH2:16][CH2:15]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[O:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]1[O:39][NH2:40].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(Cl)(Cl)Cl.CO.C(OCC)(=O)C>[O:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]1[O:39][NH:40][C:30](=[O:31])[CH2:29][C@@:14]1([C:12]2[S:13][C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)=[CH:10][CH:11]=2)[S:20](=[O:21])(=[O:22])[CH2:19][CH2:18][N:17]([S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])[CH2:16][CH2:15]1
Reactant: CCCS(=O)(=O)N1CC[C@](CC(=O)O)(c2ccc(-c3ccc(CC)cc3)s2)S(=O)(=O)CC1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)N1CC[C@](CC(=O)NOC2CCCCO2)(c2ccc(-c3ccc(CC)cc3)s2)S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
To a solution of 2-[(S)-7-[5-(4-ethylphenyl)-2-thienyl]-1,1-dioxoperhydro-4-propanesulfonyl-1,4-thiazepin-7-yl]acetic acid (3.95 g) in dimethylformamide (DMF) (40 ml) were added N-(2-tetrahydropyranyloxy)amine (1.30 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC; 1.82 g), and 1-hydroxybenzotriazole (HOBt; 1.28 g) at 0° C. The resulting mixture was stirred for 3 hours at room temperature. Ethyl acetate (500 ml) was added and the solution was washed with water (300 ml×3), saturated sodium bicarbonate, and brine, dried over magnesium sulfate, and evaporated to give a pale yellow solid. Silica gel column chromatography (eluent: 0 to 0.3% methanol in chloroform) afforded N-(2-tetrahydropyranyloxy)-2-[(S)-7-[5-(4-ethylphenyl)-2-thienyl]-1,1-dioxoperhydro-4-propanesulfonyl-1,4-thiazepin-7-yl]acetamide (4.34 g) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@:6]1([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11][C@H:10]([OH:12])[C@@H:9]2[C@H:7]1[C@H:8]2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:5])[CH3:2].N1C=CC=CC=1.[C:32](OC(=O)C)(=[O:34])[CH3:33].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:3][C:4]([C@:6]1([NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:11][C@H:10]([O:12][C:32](=[O:34])[CH3:33])[C@@H:9]2[C@H:7]1[C@H:8]2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)OC(C)(C)C)(C(=O)OCC)C[C@@H]2O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)OC(C)(C)C)(C(=O)OCC)C[C@@H]2OC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
To a solution of (1S,2S,4S,5R,6R)-2-(tert-butoxycarbonyl)amino-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester (1.50 g, 4.20 mmol, U.S. Pat. No. 5,958,960), pyridine (0.365 mL, 4.62 mmol) and DMAP (0.513 g, 4.20 mmol) in dichloromethane (40 mL) under nitrogen add acetic anhydride (0.514 mL, 5.0 mmol). Stir at room temperature for 16 hours, dilute with dichloromethane, and pour into 10% aqueous citric acid solution (50 mL). Wash the organic layer with water (50 mL) and brine (50 mL). Dry over MgSO4, filter and concentrate in vacuo, to produce the title compound as a white solid (1.295 g, 75%).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[C:18]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:17][C:13]=2[N:14]=[CH:15][N:16]=1)C.[OH-].[Na+].Cl>C1COCC1>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([C:19]2[C:12]3[C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:34])=[O:3])=[N:16][CH:15]=[N:14][C:13]=3[O:17][C:18]=2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)CCCCCOc1ncnc2oc(-c3ccccc3)c(-c3ccc(OC)cc3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCCCCCC(=O)O)c23)cc1
Reaction time: 8 h

Procedure:
Dissolve 103 mg (0.224 mmol) 6-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}-hexanoic acid ethyl ester in 2 ml THF and, at RT, add 2.2 ml of 1 N sodium hydroxide solution. Stir the mixture overnight, then neutralize with 1 N hydrochloric acid and concentrate by vacuum evaporation. Purify the residue by preparative RP-HPLC. 23.2 mg (24% of theor.) of the target compound is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH:5]([OH:13])[C:6](=O)[NH:7]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)(=O)C.O>C1COCC1>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH:5]([OH:13])[CH2:6][NH:7]2
Reactant: Nc1cccc2c1CC(O)C(=O)N2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Nc1cccc2c1CC(O)CN2
Temperature: 25 °C

Procedure:
5-Amino-3-hydroxy-3,4-dihydroquinolin-2(1H)-one (300 mg, 1.68 mmol) is dissolved in THF (10 ml) and slowly added to a refluxing mixture of LiAlH4 (319 mg, 8.42 mmol) in 8 ml THF under an argon atmosphere. After 30 min refluxing the mixture is cooled to room temperature, ethyl acetate (10 ml) is added cautiously, thereafter water is added slowly and cautiously until a light grey precipitate formed. The solvent is collected and the precipitate is washed several times with ethyl acetate, the combined organic extracts are washed with water, dried over magnesium sulfate, filtered and evaporated to dryness. The crude material is purified by column chromatography (eluent: ethyl acetate). Yield: 182 mg (65%/).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[C:5](=[C:10]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>C(O)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:30])=[O:2])[C:5]=2[C:6]([OH:8])=[O:7])=[C:16]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:17]=1
Reactant: COC(=O)c1cccc(Nc2ccc(OC)cc2Oc2ccccc2)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(Nc2cccc(C(=O)O)c2C(=O)O)c(Oc2ccccc2)c1
Yield: 93 %

Procedure:
A mixture of 3-(4-methoxy-2-phenoxy-phenylamino)-phthalic acid dimethyl ester (0.80 g, 2.0 mmol) and 3N NaOH (50 mL) in ethanol (100 mL) was heated to reflux for 90 minutes. The mixture was cooled, and the solvent was removed under vacuum. The residue was dissolved in water (100 mL), washed with CH2Cl2 (2×100 mL), and acidified (HCl). The resulting mixture was extracted with ethyl acetate (4×50 mL) and the combined extracts were washed with water (3×100 mL), dried (MgSO4) and evaporated, providing 0.69 g, in 93% yield; 1H NMR (DMSO-d6) δ 3.71 (s, 3H), 6.58 (d, J=2.7, 1H), 6.80 (dd, J=8.8 Hz, J=2.7 Hz, 1H), 6.88-6.94 (m, 3H), 7.03-7.10 (m, 2H), 7.27-7.36 (m, 4H), 8.07 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[CH2:4]1.Br[CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]1=[N:26][S:27]([CH3:30])(=[O:29])=[O:28].C(N(CC)CC)C>CN(C)C=O>[CH3:30][S:27]([N:26]=[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][N:20]1[CH2:19][CH2:18][CH2:17][CH2:16][NH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[CH2:4]1)(=[O:28])=[O:29]
Reactant: CS(=O)(=O)N=c1ccccn1CCCCBr
Reactant: COc1cccc2c1CC(CN)CC2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc2c1CC(CNCCCCn1ccccc1=NS(C)(=O)=O)CC2

Procedure:
The compound is prepared from 1.60 g of 2-aminomethyl-8-methoxytetralin (8.4 mmol), 2.28 g of 1-(4-bromobutyl)-2-methylsulfonylimino-1,2-dihydropyridine (7.4 mmol) and 0.85 ml of triethylamine (8.4 mmol) in 32 ml of dimethylformamide analogously to the working directions of Example 51.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:19][F:20])[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]2[CH:14]=[C:15](I)[CH:16]=[CH:17][C:5]=2[O:4]1.[F:21][C:22]([F:34])([C:30]([F:33])([F:32])[F:31])[C:23]([F:29])([F:28])[C:24](I)([F:26])[F:25].CN(C)P(=O)(N(C)C)N(C)C.Cl>[Cu].C(OCC)(=O)C>[F:21][C:22]([F:34])([C:30]([F:31])([F:32])[F:33])[C:23]([F:28])([F:29])[C:24]([F:25])([F:26])[C:15]1[CH:16]=[CH:17][C:5]2[O:4][C:3]([CH2:19][F:20])([CH2:2][F:1])[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]=2[CH:14]=1
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(I)cc21
Agent: [Cu]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc21
Temperature: 70 °C
Yield: 51.3 %

Procedure:
A mixture of 0.30 g of ethyl 2,2-bis(fluoromethyl)-6-iodo-2H-1-benzopyran-4-carboxylate, 3.50 g of nonafluoro-butyl iodide, 0.30 g of copper powder, 0.32 g of cuprous iodide and 3 ml of hexamethylphosphoric triamide was stirred with heating at 70° C. for 22 hours, added another 1.75 g of nonafluorobutyl iodide, and stirred with heating at 150° C. for 5 hours. A mixture of 2N HCl and ethyl acetate was added to the reaction mixture, and insoluble materials were separated off using a celite. An organic layer was taken up, and an aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution, dried over sodium sulfate, and concentrated in vacuo. The resultant residue was purified with silica gel column chromatography (developing solution, methylene chloride:hexane=5:1) to obtain 0.19 g of ethyl 6-nonafluorobutyl-2,2-bis(fluoromethyl)-2H-1-benzopyran-4-carboxylate as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>C(Cl)Cl>[C:38]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]2)[CH2:3][CH2:2]1)(=[O:40])[CH3:39]
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCNCC2)cn1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCN(C(C)=O)CC2)cn1
Reaction time: 12 h

Procedure:
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (1-piperidin-4-yl-1H-imidazol-4-yl)-amide (200 mg, 4.8 mmol) was dissolved in 5 mL of methylene chloride, charged with 0.08 mL of triethylamine, and 0.03 mL of acetylchloride at 0° C. The reaction was stirred for 12 h, quenched with sodium bicarbonate, extrated with methylene chloride and concentrated. The compound was purified by silica gel chromatography to afford the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 18.9, 21.6, 32.8, 33.7, 36.0, 40.7, 43.0, 45.4, 53.1, 55.5, 102.6, 102.8, 103.1, 105.6, 105.7, 112.3, 112.4, 112.5, 131.5, 137.8, 169.1, 169.3, 169.5; MS 462.25 m/z (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])=[C:4]([N+:16]([O-])=O)[CH:3]=1>O1CCCC1.[Pd]>[NH2:16][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([NH2:8])[C:5]=1[NH:11][CH2:12][CH2:13][CH2:14][OH:15]
Reactant: O=[N+]([O-])c1cc(F)cc([N+](=O)[O-])c1NCCCO
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cc(F)cc(N)c1NCCCO
Yield: 100 %

Procedure:
A solution of 3-[(4-fluoro-2,6-dinitrophenyl)amino]propan-1-ol (3.59 g, 13.8 mmol) in tetrahydrofuran (140 mL) was stirred in the presence of 10% palladium on carbon (50% wet; 720 mg) under hydrogen atmosphere at room temperature for 1.5 h. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to give the title compound as a pale brown oil (2.75 g, 13.8 mmol, 100%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]#[N:29])=[CH:18][CH:17]=2)[C:7]2[N:8]([CH:10]=[C:11]([CH2:13][CH3:14])[N:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:34]=[N+:35]=[N-:36])(C)C>>[CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:36][N:35]=[N:34][N:29]=3)=[CH:20][CH:21]=2)[C:7]2[N:8]([CH:10]=[C:11]([CH2:13][CH3:14])[N:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn2cc(CC)nc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Product: CCCCc1nn2cc(CC)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 24 %

Procedure:
Reaction of 2-butyl-3-[(2'-cyanobiphenyl-4-yl)methyl]-5-ethyl-3H-imidazo[1,2-b][1,2,4]triazole (from Steps B and C) with trimethyltin azide according to the procedure of Example 1, Step G, gave a 24% yield of the title compound as a light tan solid, mp>100° C. (gradual); homogeneous by TLC in 90:10:0.1 CH2Cl2 -MeOH-AcOH.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][N:25]([CH3:32])[CH2:26][CH2:27][CH2:28][C:29](O)=[O:30]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][N:25]([CH3:32])[CH3:24])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CN(C)CCCC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CCCN(C)C

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 4-dimethylamino butyric acid to yield (3aR,4S,7aR)-4-(4-dimethylamino-butyryloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 427; RT 5.026 min; LC-MS Method II
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH2:4]1)=O.[OH:31][C:32]1([CH2:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[OH:31][C:32]1([CH2:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)[CH2:37][CH2:36][N:35]([CH2:1][C@@H:3]2[C@@H:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:6][N:5]([C@H:14]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:15]([OH:17])=[O:16])[CH2:4]2)[CH2:34][CH2:33]1
Reactant: O=C[C@H]1CN([C@@H](C(=O)OCc2ccccc2)C2CCCCC2)C[C@@H]1c1ccccc1
Reactant: OC1(CCCc2ccncc2)CCNCC1
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(O)(CCCc3ccncc3)CC2)[C@@H](c2ccccc2)C1

Procedure:
The title compound was prepared from 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, benzyl ester (from EXAMPLE 1, Step I) and 4-hydroxy-4-(3-(4-pyridyl)propyl)piperidine.HCl (from EXAMPLE 81, Step A) using procedures analogous to those described in EXAMPLE 71, Steps A and B. For the title compound: 1H NMR (500 MHz) δ 1.00-4.00 (35H), 7.04 (d, J=5.7, 2H), 7.24-7.31 (5H), 8.40 (d, J=5.7, 2H); ESI-MS 520 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][CH:8]([N:11]1[C:17](=[O:18])[CH2:16][CH2:15][N:14]([C:19](=[O:29])/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[CH2:13][CH2:12]1)[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].I[CH3:32].[H-].[Na+].OS([O-])(=O)=O.[K+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:30])[CH2:7][CH:8]([N:11]1[C:17](=[O:18])[CH2:16][CH2:15][N:14]([C:19](=[O:29])/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[CH2:13][CH2:12]1)[CH2:9][O:10][CH3:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)CC(CO)N1CCN(C(=O)/C=C/c2cccc(Cl)c2)CCC1=O
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCC(CC(=O)OC(C)(C)C)N1CCN(C(=O)/C=C/c2cccc(Cl)c2)CCC1=O
Yield: 61 %

Procedure:
To a solution of 0.200 g (0.46 mmol) of 3-{4-[(E)-3-(3-chloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-4-hydroxy-butyric acid tert-butyl ester in 0.73 ml of DMF was added dropwise 0.142 ml (2.29 mmol) of iodomethane. The solution was treated at 0° C. with 0.024 g (0.55 mmol) of NaH (55% in oil). The reaction was stirred for 3 h at 0° C., neutralized with cold aqueous 10% KHSO4 and extracted with EtOAc (3×). The organic phases were washed with aqueous saturated NaHCO3 and aqueous 10% NaCl, dried (Na2SO4), evaporated and purified on a SiO2-column (dichloromethane/Isopropanol 99:1-98:2) to give the titled compound in 61% yield as colorless gum. MS: 451.2 (MH+, 1Cl).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH2:7]([CH2:9][NH2:10])[OH:8].O>ClCCl>[OH:8][CH2:7][CH2:9][NH:10][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1]
Reactant: C=C1CC(=O)O1
Reactant: NCCO
Solvent: ClCCl
Solvent: O
Product: CC(=O)CC(=O)NCCO
Reaction time: 2 h

Procedure:
To a solution of diketene (42.1 g, 0.5 mol) in dichloromethane (100 ml), ethanolamine (30.5 g, 0.5 mol) was added dropwise at 10°-20.C with stirring, and the reaction was carried out at room temperature for 2 hrs. After pouring H2O (200 ml) into the reaction solution, an aqueous layer was separated, washed thrice with dichloromethane and was obtained N-(2-hydroxyethyl)-3-oxobutanamide as an aqueous solution.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8][CH2:9][CH2:10][C:11]#[N:12])[N:6]=1.Cl.[C:14](C1C=CNN=1)(=[NH:16])[NH2:15].CN1CCN(C)C1=O>O>[NH:1]([C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8][CH2:9][CH2:10][C:11]#[N:12])[N:6]=1)[C:14]([NH2:16])=[NH:15]
Reactant: N#CCCSCc1csc(N)n1
Reactant: N=C(N)c1cc[nH]n1
Agent: Cl
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: N#CCCSCc1csc(NC(=N)N)n1
Yield: 38.5 %

Procedure:
To 5 g of 3-(2-aminothiazol-4-ylmethylthio)propionitrile were added 11 g of amidinopyrazole hydrochloride and 15 ml of 1,3-dimethyl-2- imidazolidinone and the mixture was heated to 110°-120° C. for 4 hours. After cooling, 120 ml of water was added to the reaction mixture and then the product was extracted twice with 50 ml of ethyl acetate and washed. The aqueous layer thus formed was collected, added with 11 g of anhydrous potassium carbonate and 10 ml of isopropanol, the crystals thus formed were collected by filtration to provide 2.33 g of 3-(2-guanidinothiazol-4-ylmethylthio)propionitrile having a melting point of 127°-128° C.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[S:10]1[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11]1.O>C(Cl)Cl>[Br:1][CH2:2][C:3]([C:14]1[S:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: COC(=O)c1ccsc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1csc(C(=O)CBr)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of bromoacetyl bromide (13.52 g, 0.067 mol) in 20 ml of CH2Cl2 was added dropwise to a solution of aluminum chloride (13.4 g, 0.105 mol) in 50 ml of CH2Cl2 at 0° C. The mixture was stirred for 1 h at 0° C., and then a solution of methyl 3-thiophenecarboxylate (9.49 g, 0.067 mol) in CH2Cl2 (50 ml) was added dropwise. The stirring was continued for 12 h and then the mixture was poured over water and ice and extracted with CH2Cl2. The organic phase was washed twice with water, dried over magnesium sulfate and concentrated in a rotary evaporator under vacuum.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:30]=[CH:29][C:9]([O:10][CH2:11][C:12]2[N:13]=[C:14](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[O:15][CH:16]=2)=[CH:8][CH:7]=1.[NH:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:26][C:25]([F:28])([F:27])[C:22]1[CH:23]=[CH:24][C:19](/[CH:18]=[CH:17]/[C:14]2[O:15][CH:16]=[C:12]([CH2:11][O:10][C:9]3[CH:29]=[CH:30][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:31]4[CH:35]=[CH:34][N:33]=[C:32]4[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:7][CH:8]=3)[N:13]=2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)CCc1ncc[nH]1
Reactant: FC(F)(F)c1ccc(/C=C/c2nc(COc3ccc(CCCCI)cc3)co2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 70 °C
Reaction time: 23 h
Yield: 57.1 %

Procedure:
A suspension of 4-[[4-(4-iodobutyl)phenoxy]methyl]-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole (6.00 g), ethyl 3-(1H-imidazol-2-yl)propionate (3.83 g) and potassium carbonate (1.58 g) in DMF (100 ml) was stirred at 70° C. for 23 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The extract was successively washed with water and saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate) and washed with diethyl ether-hexane to give the titled compound (3.69 g) as a colorless amorphous form.