Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[CH2:14][CH2:13][CH2:12][CH:6]([C:7]([O:9]CC)=[O:8])[CH2:5]1)[CH2:2][CH3:3].O.[OH-].[Li+:17]>C(O)C>[CH2:1]([N:4]1[CH2:14][CH2:13][CH2:12][CH:6]([C:7]([O-:9])=[O:8])[CH2:5]1)[CH2:2][CH3:3].[Li+:17]
Reactant: CCCN1CCCC(C(=O)OCC)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCN1CCCC(C(=O)[O-])C1

Procedure:
Ethyl N-propylnipecotate (73.86 g) was dissolved in 500 ml ethanol, treated with lithium hydroxide monohydrate (15.57 g) at reflux for 24 hours. Upon evaporation and drying in vacuo (100° C., eight hours), lithium N-propylnipecotate was obtained (white powder; 60 g). A solution of 17.7 g of this salt in 200 ml THF was treated dropwise with one equivalent of methyl-lithium, at 0° C. After stirring at room temperature overnight, an aqueous work-up yielded 3-acetyl-N-propylpiperidine (mp of HCl salt 108°-111° C.). When 2.5 of this compound were intimately mixed with 2.28 g of thiourea and 3.81 g of iodine and heated on a steam bath for 24 hours, followed by a column chromatography (Silica; acetone) and salt formation by the procedure of Example 2, 1.75 g of 4-(1-propyl-3-piperidyl)-2-thiazolamine hydrochloride (mp 243°-248° C.) were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH2:12]([NH:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:13][CH2:14][CH3:15].O>C(O)C.[OH-].[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:16]([CH2:17][C:18]([OH:20])=[O:19])[CH2:12][CH2:13][CH2:14][CH3:15])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CCCCNCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCN(CC(=O)O)c1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 22.1 %

Procedure:
A mixture of 4-bromo-2-fluoro-nitro benzene (34 g, 0.15 mol), N-n-butyl glycine (20 g, 0.15 mol) in ethanol (600 ml), and water (150 ml) was heated to reflux for 6 hours. After cooling to room temperature, the mixture was diluted with 2N sodium hydroxide, extracted with CH2Cl2 and the pH was adjusted to 5 with 1N HCl. The mixture was extracted with CH2Cl2, the CH2Cl2 solution was dried (MgSO4) and evaporated to obtain the crude product (11 g, 22%) as a brown oil, which was used without further purification. 1H-NMR (DMSO-d6) δ0.84 (t, J=7.30 Hz, 3H), 1.23 (m, 2H), 1.45 (m, 2H), 3.18 (t, J=7.30 Hz, 2H), 3.91 (s, 2H), 7.16 (dd, J=8.68, 1.91 Hz, 1H), 7.40 (d, J=1.94 Hz, 1H), 7.69 (d, J=8.68 Hz, 1H); MS (EI) m/z331 (M+).
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=[O:2].Cl.[CH3:12][NH:13][O:14][CH3:15].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl.C(N(CC)CC)C>[OH:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:1]([N:13]([O:14][CH3:15])[CH3:12])=[O:2]
Reactant: CNOC
Reactant: O=C1OCc2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccccc1CO
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of phthalide (26.8 g) in methylene chloride (600 ml) were successively added N,O-dimethylhydroxylamine hydrochloride (58.5 g) and aluminum chloride (40.0 g) under ice-cooling, and triethylamine (139 ml) was added dropwise over 40 min. The mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into diluted hydrochloric acid, and the organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2-hydroxymethyl-N-methoxy-N-methylbenzamide. The obtained 2-hydroxymethyl-N-methoxy-N-methylbenzamide was dissolved in N,N-dimethylformamide (300 ml), and imidazole (9.53 g) and tert-butyldimethylchlorosilane (21.1 g) were added. The mixture was stirred at room temperature for 3.5 hr and the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentration under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3) to give the title compound (42.0 g).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.C1COCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:17]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)CCC(=O)c1ccc(NC(=O)c2ccc(C)cc2)cc1
Yield: 40.4 %

Procedure:
A mixture of 4-methyl-benzoyl chloride (0.74 mL, 0.0056 mol) and 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.93 g, 0.0045 mol) in toluene (22 mL) was refluxed under nitrogen for 17 hours and allowed to cool. The mixture was diluted with THF (20 mL), and washed with 0.1 M aqueous sodium hydroxide. The solids that remained undisolved were filtered, washed with water, and dried in house vacuum (40° C., air bleed) to give 0.592 g of 4-[4-(4methyl-benzoylamino)-phenyl]-4-oxo-butyric acid, methyl ester as an off-white solid; mp 192-195° C.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:20]([O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[C:21]#[C:22][CH3:23].O>N1C=CC=CC=1>[CH2:18]([O:17][C:15]([CH:11]1[CH2:10][N:9]([C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:8])[CH2:14][CH2:13][N:12]1[S:31]([C:28]1[CH:27]=[CH:26][C:25]([O:24][CH2:20][C:21]#[C:22][CH3:23])=[CH:30][CH:29]=1)(=[O:33])=[O:32])=[O:16])[CH3:19]
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C1CN(C(=O)N2CCOCC2)CCN1
Solvent: O
Solvent: c1ccncc1
Product: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)N3CCOCC3)CC2C(=O)OCC)cc1
Reaction time: 8 h
Yield: 80.7 %

Procedure:
The ethyl 4-(4-morpholinylcarbonyl)-2-piperazinecarboxylate (0.41 g, 1.55 mmol) was dissolved in pyridine (1.44 mL). To this solution was added a solution of 4-but-2-ynyloxy-benzenesulfonyl chloride (0.38 g, 1.55 mmol) in pyridine (1 mL). The reaction was stirred overnight and then poured into water. The mixture was extracted three times with chloroform. The organics were combined, washed with 10% HCl, twice with water, then brine and dried over Na2SO4. The solution was filtered and concentrated in vacuo to provide 0.6 g (81%) of 1-(4but-2-ynyloxy-benzenesulfonyl)-4-(morpholine4-carbonyl)- piperazine-2-carboxylic acid ethyl ester as a gold oil. Electrospray Mass Spec 480.2 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][N:16]1CCCC1=O.CN>O>[CH3:15][NH:16][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: CN1CCCC1=O
Agent: CN
Solvent: O
Product: CNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2.09 g of 4-fluoro-3-nitrobenzo trifluoride and 20 ml of N-methylpyrrolidone was added 2.33 g of a 40% methylamine aqueous solution under ice cool, and the mixture was heated up to room temperature and stirred for 1 hour. Water was poured, and the deposited precipitate was filtrated, then, washed with water, then, dried under reduced pressure to obtain 2.0 g of N-methyl-2-nitro-4-trifluoromethylaniline.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C@H:7]([CH3:16])[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[N:18]#[N:19].[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][CH3:33])[CH:28]=[C:27]([S:34]([NH:37][C@H:38]([C:46](Cl)=[O:47])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:45])[NH2:44])(=[O:36])=[O:35])[CH:26]=[CH:25]2>C(Cl)(Cl)Cl>[N:18]#[N:19].[C:1]([O:5][C:6](=[O:17])[C@H:7]([CH3:16])[N:8]([C:46](=[O:47])[C@H:38]([CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:44])[NH2:45])[NH:37][S:34]([C:27]1[CH:26]=[CH:25][C:24]2[C:29](=[CH:30][C:31]([O:32][CH3:33])=[C:22]([O:21][CH3:20])[CH:23]=2)[CH:28]=1)(=[O:36])=[O:35])[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](NCc1ccccc1)C(=O)OC(C)(C)C
Reactant: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)cc2cc1OC
Agent: N#N
Solvent: ClC(Cl)Cl
Product: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N(Cc3ccccc3)[C@@H](C)C(=O)OC(C)(C)C)cc2cc1OC
Reaction time: 1 h
Yield: 83 %

Procedure:
To a stirred solution of 4.42 g of N-benzylalanine tert-butyl ester in 20 ml of chloroform was carefully added N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl chloride obtained above. The reaction mixture was allowed to stand at room temperature for one hour. At the end of this period, the reaction mixture was washed twice with 20 ml of saturated sodium chloride solution and evaporated to dryness to give 2.50 g (83 percent) of N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-benzylalanine tert-butyl ester in the form of a powder. The flavianate; M.P. 168°-172° C (dec.)
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[C:25]([NH:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][N:29]=4)[C:24](=[O:34])[N:23]([CH3:35])[CH:22]=3)[C:16]=2[CH2:36][O:37][Si](C(C)(C)C)(C)C)=[C:8]([C:10](O)=O)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)[O:64]N1C2N=CC=CC=2N=N1>C(Cl)Cl>[C:1]([C:5]1[S:6][C:7]2[C:13](=[O:64])[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]4[CH:26]=[C:25]([NH:27][C:28]5[CH:33]=[CH:32][N:31]=[CH:30][N:29]=5)[C:24](=[O:34])[N:23]([CH3:35])[CH:22]=4)[C:16]=3[CH2:36][OH:37])[CH2:10][C:8]=2[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1cc(-c2cccc(NCc3sc(C(C)(C)C)nc3C(=O)O)c2CO[Si](C)(C)C(C)(C)C)cc(Nc2ccncn2)c1=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1cc(-c2cccc(N3Cc4nc(C(C)(C)C)sc4C3=O)c2CO)cc(Nc2ccncn2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.2 %

Procedure:
To a solution of 2-tert-butyl-5-((2-((tert-butyldimethylsilyloxy)methyl)-3-(1-methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridin-3-yl)phenylamino)-methyl)thiazole-4-carboxylic acid (125e) (500 mg, 0.78 mmol) in methylene chloride (40 mL) was added N,N-Diisopropylethylamine (503 mg, 3.9 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (900 mg, 2.37 mmol). The mixture was stirred at 25° C. for 2 h. After flash column purification with PE:EA (1:3 to 1:6) as eluent, 125 was obtained as white solid (32 mg, 10%). LCMS: (M+H)+ 503. 1H NMR (500 MHz, MeOD) ppm 8.84 (d, J=2 Hz, 1H), 8.66 (s, 1 H), 8.29 (d, J=5.5 Hz, 1H), 7.49-7.56 (m, 4 H), 7.09 (d, J=5.5 Hz, 2 H), 5.04 (s, 2 H), 4.57 (s, 2 H), 3.73 (s, 3 H), 1.54 (s, 9 H).
Reaction SMILES: [C:1]1([P:7]([CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][C:27]=2[CH2:36][P:37]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=O)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CCCC)CCCC)CCC.C[SiH](Cl)Cl>C1(C)C(C)=CC=CC=1>[C:45]1([P:37]([CH2:36][C:27]2[CH:28]=[CH:29][C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:26]=2[C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:24]=[CH:25][C:16]=2[CH2:15][P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: O=P(Cc1ccc2ccccc2c1-c1c(CP(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12)(c1ccccc1)c1ccccc1
Agent: C[SiH](Cl)Cl
Solvent: Cc1ccccc1C
Solvent: CCCCN(CCCC)CCCC
Product: c1ccc(P(Cc2ccc3ccccc3c2-c2c(CP(c3ccccc3)c3ccccc3)ccc3ccccc23)c2ccccc2)cc1

Procedure:
409.7 g (0.6 mol) of 2,2'-bis(diphenylphosphinylmethyl)-1,1'-binaphthyl are suspended in 1.5 1 of xylene and 715 ml (3.0 mol) of tri-n-butylamine in the absence of air and moisture, and 345.1 g (3.0 mol) of methyldichlorosilane are added dropwise with stirring. The mixture is then refluxed for 12 hours to give a clear solution. Xylene is distilled off at atmospheric pressure, and the mixture is allowed to cool with stirring. This results in the formation of 2,2'-bis(diphenylphosphinomethyl)-1,1'-binaphthyl as a colorless solid, which is filtered off under an inert gas and washed with 200 ml of degassed acetone. 378 g (97%) of colorless crystals of melting point 160° to 161° C. are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[N:21]([S:34]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)(=[O:36])=[O:35])[C:22]([C:24]5[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:26][CH:25]=5)=[CH:23][C:16]=34)=[CH:13][N:12]([CH2:43][CH3:44])[N:11]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[OH-].[Pd+2].[OH-]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[N:21]([S:34]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)(=[O:35])=[O:36])[C:22]([C:24]5[CH:25]=[CH:26][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:28][CH:29]=5)=[CH:23][C:16]=34)=[CH:13][N:12]([CH2:43][CH3:44])[N:11]=2)=[CH:6][CH:5]=1
Reactant: CCn1cc(-c2ccnc3c2cc(-c2ccc(NC(C)=O)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Product: CCn1cc(-c2ccnc3c2cc(-c2ccc(NC(C)=O)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(N)cc2)n1
Yield: 52 %

Procedure:
A stirred solution of 4-[3-(4-nitrophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-(4-acetamidophenyl)-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridine (0.8 mmol) and 20% palladium(II)hydroxide on carbon (0.1 g) was hydrogenated with a balloon of hydrogen for 3 days at room temperature. The reaction was filtered through a pad of Celite, rinsed with ethyl acetate and concentrated under vacuum to give the title product as an off-white solid (52%). ESMS [M+H]+: 577.4
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.CN(C=O)C.Br[CH2:24][C:25]1[CH2:30][CH2:29][C@H:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH:26]=1>O>[OH:34][C:31]([C@H:28]1[CH2:29][CH2:30][C:25]([CH2:24][N:11]2[C:7](=[O:17])[C:8]3[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10]2=[O:12])=[CH:26][CH2:27]1)([CH3:33])[CH3:32]
Reactant: CC(C)(O)[C@@H]1CC=C(CBr)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)[C@@H]1CC=C(CN2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
A mixture of 2.2 g (16 mmol) K2CO3, 1.2 g (8.4 mmol) phthalimide, and 40 ml DMF was stirred at room temperature for 0.5 hours. Thereafter, 1.7 g (7.4 mmol) (S)-2-(4-bromomethyl-cyclohex-3-enyl)-propan-2-ol (Bull, et. al. Aust. J. Chem., 46 1869, 1993) was added and the resulting mixture was stirred at room temperature for 72 h. Water was added and the mixture was then extracted with ethyl acetate. The ethyl acetate extracts were combined; washed with water and brine; dried (MgSO4); and filtered and concentrated in vacuo. Chromatography on silica gel using 20% ethyl acetate/hexanes yielded 0.62 g (28%) of the desired product.
Reaction SMILES: N(CC1CCCC1)=[N+]=[N-].[CH:10]1([CH2:15][N:16]=[C:17]=[S:18])[CH2:14][CH2:13][CH2:12][CH2:11]1.[CH2:19]([CH2:21][NH2:22])[OH:20]>>[CH:10]1([CH2:15][NH:16][C:17]([NH:22][CH2:21][CH2:19][OH:20])=[S:18])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: S=C=NCC1CCCC1
Reactant: NCCO
Agent: [N-]=[N+]=NCC1CCCC1
Product: OCCNC(=S)NCC1CCCC1
Yield: 63 %

Procedure:
The intermediate azidomethylcyclopentane was obtained from commercially available cyclopentanemethanol as described in General Procedure D. Spectroscopic data: 1H NMR (CDCl3, 300 MHz) δ 3.18 (d, J=10.0 Hz, 2H), 2.23-2.05 (m, 1H), 1.87-1.74 (m, 2H), 1.68-1.55 (m, 4H), 1.30-1.15 (m, 2H). The azide was then converted into cyclopentylmethyl isothiocyanate, which was reacted with ethanolamine to afford the title compound (12.68 g, 63%) according to General Procedure A. Spectroscopic data: 1H NMR (D6, DMSO, 300 MHz) δ 7.46 (br s, 1H), 7.31 (br s 1H), 4.72 (br s, 1H), 3.5-3.38 (m, 4H), 3.25 (br s, 2H), 2.03 (quintet, J=6.4 Hz, 1H), 1.70-1.57 (m, 3H), 1.55-1.41 (m, 3H), 1.20-1.10 (m, 2H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O.ClCCl>[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([Cl:3])=[O:23])=[CH:20][CH:19]=1)[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)O)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)Cl)cc1

Procedure:
Thionyl chloride (1.43 ml) and dimethylformamide (2 drops) were added to a solution of (R)-(+)-4-(1-benzyloxycarbonylaminoethyl)-benzoic acid (2 g) in dichloromethane (20 ml), and the mixture was refluxed under heating for 1 hour. Afterthe reaction, the solvent was evaporated under reduced pressure to give (R)-4-(1-benzyloxycarbonylaminoethyl)benzoyl chloride as crystals. Then, the crystals were dissolved in acetonitrile (10 ml) and the solution was dropwise added to a solution of 4-aminopyridine (525 mg) and diisopropylethylamine (1.17 ml) in acetonitrile (20 ml) under ice-cooling, which was followed by stirring at room temperature for 5 hours. After the reaction, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated under reduced pressure. The obtained crystals were recrystallized from methanol-ethyl acetate-hexane to give 1.87 g of (R)-N-(4-pyridyl)-4-(1-benzyloxycarbonylaminoethyl)benzamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1F)=O.O.[NH2:22][NH2:23]>CN(C1C=CN=CC=1)C>[Cl:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]2[C:14]=1[NH:23][N:22]=[C:11]2[C:4]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C(=O)c2cccc(Cl)c2F)c(OC)c1
Reactant: NN
Agent: CN(C)c1ccncc1
Solvent: O
Product: COc1ccc(-c2n[nH]c3c(Cl)cccc23)c(OC)c1
Yield: 52.2 %

Procedure:
Prepared according to Method D Step A from (2,4-dimethoxyphenyl)[2-fluoro-3-chlorophenyl]methanone (1.20 g, 4.1 mmol), hydrazine hydrate (1.61 mL, 51.7 mmol) and DMAP (0.632 g, 5.17 mmol) to give the product (0.618 g) as a yellow solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[O:8][N:7]=1)=[O:5])C.[OH-].[Li+]>C1COCC1.CO>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]1[O:8][N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1
Reactant: CCOC(=O)c1cc(-c2ccco2)on1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(-c2ccco2)on1
Reaction time: 15 h
Yield: 90 %

Procedure:
To a solution of 5-furan-2-yl-isoxazole-3-carboxylic acid ethyl ester (4.14 g) in THF (130 mL) and methanol (25 mL) was slowly added 1N lithium hydroxide aqueous solution (80 mL). The resulting mixture was stirred for 15 hours, and then concentrated under reduced pressure. The remaining solution was acidified with 1N hydrochloric acid to form a solid, and the solid was filtered, washed with distilled water, dried to give 3.22 g of 5-furan-2-yl-isoxazole-3-carboxylic acid (yield: 90%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:14]=[C:6]2[N:7]([CH:11]3[CH2:13][CH2:12]3)[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:15])[N:3]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:30]=[CH:31][C:32]=1[F:33])[O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][C:22]=1[F:29]>>[CH:11]1([N:7]2[CH2:8][CH2:9][CH2:10][N:5]3[C:4](=[O:15])[N:3]=[C:2]([O:28][CH2:27][C:24]4[CH:25]=[CH:26][C:21]([O:20][C:19]5[CH:30]=[CH:31][C:32]([F:33])=[C:17]([F:16])[CH:18]=5)=[C:22]([F:29])[CH:23]=4)[CH:14]=[C:6]23)[CH2:13][CH2:12]1
Reactant: O=c1nc(Cl)cc2n1CCCN2C1CC1
Reactant: OCc1ccc(Oc2ccc(F)c(F)c2)c(F)c1
Product: O=c1nc(OCc2ccc(Oc3ccc(F)c(F)c3)c(F)c2)cc2n1CCCN2C1CC1

Procedure:
The title compound was prepared by a procedure similar to that described for E2 starting from 8-chloro-1-cyclopropyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and (4-(3,4-difluorophenoxy)-3-fluorophenyl)methanol.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:5]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 14 h

Procedure:
In a DMF solution of 0.50 g of Boc-Pro-OH, 0.24 ml of tert-butylamine, 0.36 g of HOBt and 0.53 g of EDC hydrochloride were added under ice cooling and the mixture was stirred for 14 hr. The reaction mixture was treated similarly to that in Example 28 (Process 2) to give 373 mg of the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[C:23]3[O:22][CH2:21][CH2:20][O:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)=[O:13])[CH2:3]1.[CH3:24][C:25]1[S:26][C:27]([C:33]2[CH:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=2)=[C:28]([C:30](O)=[O:31])[N:29]=1>>[CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][N:6]([C:30]([C:28]3[N:29]=[C:25]([CH3:24])[S:26][C:27]=3[C:33]3[CH:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=3)=[O:31])[C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[C:23]3[O:22][CH2:21][CH2:20][O:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)=[O:13])[CH2:3]1
Reactant: CC1C[C@H]2CN[C@H](CNC(=O)c3cccc4c3OCCO4)[C@H]2C1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cccc3c2OCCO3)c1

Procedure:
prepared by reaction of 3,4-dihydro-benzo[1,4]dioxine-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[N:15]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C@@H:25]([C:39](O)=[O:40])[CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[C:30]([NH2:37])=[C:29]([Cl:38])[CH:28]=3)=[O:23])[CH2:18][CH2:17]2)[CH2:14][CH2:13][C:12]2[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=2[NH:10]1.[CH3:46][N:47]1[CH2:52][CH2:51][CH:50]([N:53]2[CH2:58][CH2:57][NH:56][CH2:55][C@H:54]2[C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:49][CH2:48]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[NH2:37][C:30]1[C:31]([C:33]([F:36])([F:35])[F:34])=[CH:32][C:27]([CH2:26][C@@H:25]([O:24][C:22]([N:19]2[CH2:20][CH2:21][CH:16]([N:15]3[CH2:14][CH2:13][C:12]4[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=4[NH:10][C:9]3=[O:8])[CH2:17][CH2:18]2)=[O:23])[C:39]([N:56]2[CH2:57][CH2:58][N:53]([CH:50]3[CH2:49][CH2:48][N:47]([CH3:46])[CH2:52][CH2:51]3)[C@H:54]([C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:55]2)=[O:40])=[CH:28][C:29]=1[Cl:38]
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Reactant: CCOC(=O)[C@@H]1CNCCN1C1CCN(C)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CN(C(=O)[C@@H](Cc2cc(Cl)c(N)c(C(F)(F)F)c2)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)CCN1C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.25 mL (2.88 mmol) triethylamine were added to a mixture of 200 mg (0.36 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1f), 150 mg (0.58 mmol) ethyl(S)-1-(1-methyl-piperidin-4-yl)-piperazine-2-carboxylate (Example A10c) and 140 mg (0.44 mmol) TBTU in 2.0 mL DMF and the reaction mixture was stirred for 5 h at RT. This was purified by HPLC without any further working up; the fractions containing the product were combined and lyophilised.