Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[NH:9][C:10]1[S:11][CH:12]=[N:13][N:14]=1>C(O)CC>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:12]2[S:11][C:10]([NH2:9])=[N:14][N:13]=2)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: BrNc1nncs1
Solvent: CCCO
Product: CN1CCN(c2nnc(N)s2)CC1
Temperature: 25 °C

Procedure:
A mixture of 1-methylpiperazine (0.742 ml, 6.6 mmol) and bromo-[1,3,4]thiadiazol-2-ylamine (63a) (0.60 g, 3.3 mmol) in n-propanol (15 ml) is heated at reflux for 6 hours. After cooling to room temperature the solvent is removed and the residue is trituated with ethyl acetate and methanol to afford the required compound as a pink solid.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:5]2[C@@H:4]2[CH2:21][CH2:22][CH2:23][N:3]12.[C-:24]#N.[K+]>CC(O)C>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([O:18][CH:19]([CH3:24])[CH3:20])=[O:17])=[C:5]2[C@@H:4]2[CH2:21][CH2:22][CH2:23][N:3]12
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2
Reactant: [C-]#N
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)OC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2

Procedure:
934 mg (3 mmol) of ethyl (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate are stirred at 60° C. for 48 hours with 198 mg (3 mmol) of potassium cyanide in 30 ml of dry 2-propanol. The mixture is evaporated in vacuo. The residue is treated with 30 ml of 2-propanol and 198 mg (3 mmol) of potassium cyanide and heated to boiling under reflux for 22 hours. After evaporation in vacuo, the residue is treated with water and extracted three times with 30 ml of chloroform each time. The combined chloroform phases are washed three times with 20 ml of water each time, dried over magnesium sulphate and evaporated. After recrystallisation from ethyl acetate/n-hexane, there is obtained isopropyl (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 207°-208° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1>>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH3:26])[N:16]=[CH:15][N:14]=[C:13]2[NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc2ccccc12
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Product: COc1cc2ncnc(Nc3nccc4ccccc34)c2cc1OC
Yield: 13 %

Procedure:
Using an analogous procedure to that described in Example 9, 1-aminoisoquinoline was reacted with 4-chloro-6,7-dimethoxyquinazoline to give 6,7-dimethoxy-4-(1-isoquinolylamino)quinazoline in 13% yield, m.p. 198°-199° C.;
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[C:5](=[O:7])[CH3:6])[CH3:3].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH2:2]([N:4]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=2)[CH2:11][CH2:10]1)[C:5](=[O:7])[CH3:6])[CH3:3]
Reactant: CCN(CC1CCNCC1)C(C)=O
Reactant: FC(F)(F)c1nccc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC1CCN(c2ccnc(C(F)(F)F)n2)CC1)C(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.7 %

Procedure:
A mixture of N-ethyl-N-[(4-piperidinyl)methyl]acetamide hydrochloride (Example 4; 2.14 g, 10 Mole), 4-chloro-2-trifluoromethylpyrimidine (1.83 g, 10 mmole), and sodium carbonate (2.65 g, 25 mmole) in DMF (30 ml) was stirred for 18 hrs at room temperature. The mixture was concentrated in vacuo. The residue was dissolved in methylene chloride (50 ml), filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel using ethyl acetate as the eluent to give formula I product as a yellow oil (2.17 g, 67%).
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][C@@H:8]([C:26]1([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:33][CH:32]=2)[CH:30]=[CH:29][NH:28][CH2:27]1)[C:9]([NH:11]N1[C@@H](CC2C=CC=CC=2)COC1(C)C)=[O:10])(C)(C)C.[Li+].[OH-].[CH3:46][CH2:47][OH:48].Cl>C1COCC1.O>[CH2:26]([C@H:46]([NH:11][C:9](=[O:10])[C@H:8]([C:26]1([C:31]2[CH:32]=[CH:33][C:34]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[CH:35][CH:36]=2)[CH:30]=[CH:29][NH:28][CH2:27]1)[CH2:7][C:6]([OH:5])=[O:43])[CH2:47][OH:48])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)C[C@H](C(=O)NN1[C@@H](Cc2ccccc2)COC1(C)C)C1(c2ccc(-c3ccccc3)cc2)C=CNC1
Reactant: CCO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C[C@H](C(=O)N[C@H](CO)Cc1ccccc1)C1(c2ccc(-c3ccccc3)cc2)C=CNC1
Reaction time: 12 h
Yield: 49 %

Procedure:
To a solution of N-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-3(S)-[3-(biphenyl-4-yl)-1H-pyrrol-3-yl]succinamic acid t-butyl ester (80 mg, 0.14 mmol) in THF (5 mL) was added 2M aqueous LiOH (5 mL). EtOH (few drops) and H2O were added until a homogeneous solution was obtained. The resultant solution was heated at 50° C. After 12 hours, the mixture was acidified with 6N HCl to pH1. After another 5.5 hours at 50° C., the mixture was partitioned between EtOAc and 1M pH 7 phosphate buffer. The aqueousueous phase was separated and extracted with EtOAc two times. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to a residue which, upon trituration with CH2Cl2 /hex, provided 32 mg (49%) of pure N-(1(S)-benzyl-2-hydroxyethyl)-3(S)-[3-(biphenyl-4-yl)-1H-pyrrol-3-yl]succinamic acid as a white solid, mp 151-4° C. 1H NMR: (DMSO-d6): δ 7.83 (d, 1H, J=8.5 Hz), 7.74 (d, 2H, J=8.8 Hz), 7.69 (d, 2H, J=7.4 Hz), 7.59 (d, 2H, J=8.8 Hz), 7.46 (t, 2H, J=7.4 Hz), 7.38-7.31 (m, 2H), 7.28-7.13 (m, 6H), 6.22 (s, 1H), 4.81-4.70 (m, 1H), 3.89-3.78 (m, 2H), 2.85-2.69 (m, 2H). Anal. Calculated for C29H28N2O4.0.4 H2O: C, 73.21; H, 6.10; N, 5.89. Found: C, 73.39; H, 6.09; N, 5.93.
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH:13]2[CH2:15][C:14]2([F:17])[F:16])=[O:12])=[CH:7][CH:6]=1>C(OCC)C>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([CH:13]2[CH2:15][C:14]2([F:16])[F:17])([OH:12])[CH3:1])=[CH:9][CH:10]=1
Reactant: C[Mg]Br
Reactant: O=C(c1ccc(Cl)cc1)C1CC1(F)F
Solvent: CCOCC
Product: CC(O)(c1ccc(Cl)cc1)C1CC1(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.7 ml (17.1 mmol) of a 3N solution of methylmagnesium bromide in diethyl ether were added to 2.47 g (11.4 mmol) of the compound from Example 124A in 40 ml of diethyl ether at RT, and the mixture was stirred at RT overnight. The reaction mixture was added to a saturated, ice-cold aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to result in 2.09 g (78% of theory) of a mixture of the diastereomers of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9](Br)=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=1)=[O:5])[CH3:2].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1>[Cu]>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH3:18])[CH:21]=2)=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(Br)c(C(=O)OCC)c1
Reactant: COc1cccc(O)c1
Agent: [Cu]
Product: CCOC(=O)c1ccc(Oc2cccc(OC)c2)c(C(=O)OCC)c1
Yield: 41.8 %

Procedure:
Following the general procedure of Example 1A, 3.49 g of 4-bromo-1,3-benzenedicarboxylic acid diethyl ester and 1.43 g of 3-methoxyphenol were allowed to react in the presence of powdered copper metal to provide 1.66 g of the desired subtitle intermediate as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[C:34]([O:38][C:39]([NH:41][CH2:42][C:43](O)=[O:44])=[O:40])([CH3:37])([CH3:36])[CH3:35].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@:4]([CH2:3][CH2:2][NH:1][C:43](=[O:44])[CH2:42][NH:41][C:39](=[O:40])[O:38][C:34]([CH3:35])([CH3:36])[CH3:37])([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[O:9][C:8]2=[O:10])[CH3:12])=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCN)(c2ccc(F)cc2)OC1=O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCNC(=O)CNC(=O)OC(C)(C)C)(c2ccc(F)cc2)OC1=O
Yield: 72.8 %

Procedure:
A solution of (R)-6-(2-aminoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (100 mg, 0.22 mmol), 2-(tert-butoxy-carbonyl-amino)acetic acid (58 mg, 0.33 mmol), HOBt (60 mg, 0.44 mmol), EDC (87 mg, 0.44 mmol) and i-Pr2NEt (142 mg, 1.1 mmol) in CH2Cl2 (5 mL) was stirred at rt overnight. After the solvents were evaporated, the crude product was purified by preparative TLC to give tert-butyl 2-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethylamino)-2-oxoethylcarbamate (98 mg, 74%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([CH2:8][CH2:9][N:10]([CH2:15][CH2:16][N:17]([CH2:22][C:23]([O:25]CC)=[O:24])[CH2:18][C:19]([OH:21])=[O:20])[CH2:11][C:12]([OH:14])=[O:13])[CH2:5][C:4](=[O:28])[O:3]1.C(N([CH2:34][CH3:35])CC)C.[NH2:36][CH:37](CCCCCC)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([OH:50])=[O:49].Cl>CN(C)C=O.[OH-].[Na+]>[C:23]([CH2:22][N:17]([CH2:16][CH2:15][N:10]([CH2:11][C:12]([OH:14])=[O:13])[CH2:9][CH2:8][N:6]([CH:5]([C:4](=[O:28])[NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([OH:50])=[O:49])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:34][CH3:35])[CH2:7][C:2]([OH:3])=[O:1])[CH2:18][C:19]([OH:21])=[O:20])([OH:25])=[O:24]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)CN(CCN(CCN1CC(=O)OC(=O)C1)CC(=O)O)CC(=O)O
Reactant: CCCCCCC(N)CCCCCCCCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCCCCC(C(=O)NCCCCCCCCCCCC(=O)O)N(CCN(CCN(CC(=O)O)CC(=O)O)CC(=O)O)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
15.33 g (38 mmol) of N3-(2,6-dioxomorpholinoethyl)-N6-(ethoxycarbonylmethyl)-3,6-diazaoctanedioic acid (Example 13a of EP 0 331 616) is suspended in 100 ml of dimethylformamide and mixed in an ice bath with 21.07 ml (152 mmol) of triethylamine and 11.36 g (38 mmol) of 12-aminooctadecanoic acid. After stirring overnight at room temperature, it is concentrated by evaporation in a vacuum, and the residue is absorptively precipitated with 500 ml of diethyl ether. It is suctioned off and the dried reaction product is dissolved in 50 ml of 2 n sodium hydroxide solution. After three hours of stirring, it is neutralized with dilute hydrochloric acid, evaporated to dryness in a vacuum and recrystallized from water. 15.64 g (61% of theory) of a gray powder is obtained.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]([S:22]([C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[C:27]([CH3:35])=[CH:28][N:29]=[CH:30]2)(=[O:24])=[O:23])[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O)(C)(C)C.[ClH:36].CO>>[ClH:36].[CH3:35][C:27]1[C:26]2[C:31](=[CH:32][CH:33]=[CH:34][C:25]=2[S:22]([N:12]([CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:11][CH2:10][CH2:9][NH2:8])(=[O:23])=[O:24])[CH:30]=[N:29][CH:28]=1
Reactant: Cc1cncc2cccc(S(=O)(=O)N(CCCNC(=O)OC(C)(C)C)CCCc3ccccc3)c12
Agent: Cl
Solvent: CO
Product: Cc1cncc2cccc(S(=O)(=O)N(CCCN)CCCc3ccccc3)c12
Temperature: 25 °C

Procedure:
According to the method of Example 1, Step C, deprotection was performed (5° C., 2 hours) by using Intermediate 8 (87 mg) and 10% hydrogen chloride/methanol solution (5 ml). The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was added with methanol (1 ml) and diethyl ether (3 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (70 mg) as white powdery solid.
Reaction SMILES: C[C@@H:2]1[CH:6]([NH:7][CH3:8])[CH2:5][CH2:4][N:3]1[C:9]1[C:10]2[CH:17]=[CH:16][NH:15][C:11]=2[N:12]=[CH:13][N:14]=1.[Cl:18][C:19]1[N:24]=[C:23](Cl)[CH:22]=[CH:21][N:20]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[N:12]1[C:11]2[NH:15][CH:16]=[CH:17][C:10]=2[C:9]([N:3]2[CH2:4][CH2:5][C@@H:6]([N:7]([CH3:8])[C:21]3[CH:22]=[CH:23][N:24]=[C:19]([Cl:18])[N:20]=3)[CH2:2]2)=[N:14][CH:13]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CNC1CCN(c2ncnc3[nH]ccc23)[C@@H]1C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccnc(Cl)n1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
A mixture of methyl (R)—N-methyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine (0.20 g, 0.92 mmol), 2,4-dichloropyrimidine (0.18 g, 1.21 mmol) and DIPEA (0.25 g, 1.94 mmol) in DMF (6 mL) was stirred at 110° C. for 16 hours. The mixture was poured into water (5 mL) and extracted with ethyl acetate (2×8 mL). The combined extracts was washed with brine (2×30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (v. DCM/MeOH=12/1) to give the title compound. MS (m/z): 330 (M+H)+.
Reaction SMILES: [F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].CO[C:10]1[CH:15]=[CH:14][C:13]([I+:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1.C1(OC)C=CC=CC=1>>[F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[C:13]1([I+:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH:12]=[CH:11][CH:10]=[CH:15][CH:14]=1
Reactant: COc1ccc([I+]c2ccc(OC)cc2)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: COc1ccccc1
Product: COc1ccc([I+]c2ccccc2)cc1

Procedure:
Phenyl-4-methoxyphenyliodonium hexafluorophosphate was synthesized according to the procedure described for the synthesis of bis(p-methoxyphenyl)iodonium hexafluorophosphate from the corresponding aryliodonium diacetate and anisole. (77.9%)
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][CH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([O:26][CH3:27])[CH:20]=1)[OH:18].[CH:28](=O)[CH2:29][CH3:30].C(=O)(O)[O-].[Na+]>ClCCl.O.CO>[NH3:15].[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([CH:17]([OH:18])[CH2:16][NH:15][CH2:28][CH2:29][CH3:30])=[CH:20][C:21]=1[O:26][CH3:27]
Reactant: COc1cc(C(O)CN)ccc1Cl
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCCNCC(O)c1ccc(Cl)c(OC)c1
Product: N
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
Sodium triacetoxyborohydride (1.25 g, 5.89 mmol) was added with care to a solution of 2-amino-1-(4-chloro-3-methoxy-phenyl)-ethanol (J. Med. Chem., 30(10), 1887, (1987)) (600 mg, 2.98 mmol) and propionaldehyde (0.22 mL, 2.96 mmol) in dichloromethane (110 mL), and the reaction mixture was stirred at room temperature for 1 hour. Sodium bicarbonate solution (sat. aq., 10 mL) was added dropwise and then the reaction mixture was diluted further with water (20 mL) and dichloromethane (20 mL). The aqueous layer was separated and re-extracted with dichloromethane (2×20 mL). The combined organic layers were dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica eluting with dichloromethane:methanol:0.880 ammonia (95:5:0.5 to 92:8:0.8) to yield the title compound as a solid (320 mg, 1.31 mmol, 44%). 1H NMR (CDCl3, 400 MHz) δ: 0.90 (t, 3H), 1.50 (q, 2H), 2.50-2.70 (m, 5H), 2.90 (dd. 1H), 3.80 (s, 3H), 4.65 (dd, 1H), 6.85 (d, 1H), 7.00 (1H, d), 7.30 (bd, 1H). LRMS (APCI): m/z 244 (MH+), 226 (MH+ less H2O).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH2:11](I)[CH3:12].C([O-])([O-])=[O:15].[K+].[K+].C(=O)C1C=CC=CC=1.[O-][Mn](=O)(=O)=O.[K+]>O.O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[C:5]([OH:15])=[O:6]
Reactant: CCI
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O=Cc1ccccc1
Solvent: O
Product: CCOc1ccc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A mixture of 3-chloro-4-hydroxybenzaldehyde (0.4 g, 2.55 mmol), EtI (0.31 ml) and K2CO3 (0.421 g; 3.1 mmol) was stirred overnight at room temperature. The mixture was diluted 100 ml with H2O and extracted with EtOAc (50 ml). The organic layer was separated and dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give the crude product (0.41 g, 87%) used as such in next step. 1H-NMR (CDCl3) 1.49 (tr, 3H, J=6.96 Hz); 4.18 (q, 2H, J=6.99, 13.97 Hz); 6.98 (d, 1H, J=8.49 Hz); 7.72 (dd, 1H, J=1.94, 8.46 Hz); 7.87 (d, 1H, J=1.95 Hz); 9.82 (s, 1H). The above benzaldehyde (0.4 g 2.16 mmol) was dissolved in a mixture of dioxane: H2O (30:10) and to it KMnO4 (0.341 g; 2.16 mmol) was added at room temperature and the mixture was stirred for 1 h. The solvent was evaporated and the residue was diluted to 100 ml with EtOAc and the mixture was filtered through a silica gel bead. The filtrate was evaporated to dryness to give the title compound (0.36 g, 83%), as creamy solid. 1H-NMR (DMSO-d6) 2.44 (tr, 3H, J=6.99 Hz); 5.11 (q, 2H, J=13.95 Hz); 6.96 Hz); 7.88 (d, 1H, J=8.55 Hz), 8.9 (d, 1H, J=8.55 Hz); 9.5 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][NH:8][CH2:9][CH:10]1[O:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:23]#[N:24].Cl.[CH3:26][O:27][C:28]1[CH:37]=[C:36]2[C:31]([CH:32]=[CH:33][C:34]([S:38]([NH:41][C@H:42]([C:50](Cl)=[O:51])[CH2:43][CH2:44][CH2:45][NH:46][C:47](=[NH:49])[NH2:48])(=[O:40])=[O:39])=[CH:35]2)=[CH:30][CH:29]=1>C(Cl)(Cl)Cl>[N:23]#[N:24].[C:1]([O:5][C:6](=[O:15])[CH2:7][N:8]([C:50](=[O:51])[C@H:42]([CH2:43][CH2:44][CH2:45][NH:46][C:47](=[NH:48])[NH2:49])[NH:41][S:38]([C:34]1[CH:33]=[CH:32][C:31]2[C:36](=[CH:37][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)[CH:35]=1)(=[O:39])=[O:40])[CH2:9][CH:10]1[O:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CNCC1CCCO1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)cc2c1
Agent: Cl
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N(CC(=O)OC(C)(C)C)CC3CCCO3)cc2c1
Reaction time: 8 h

Procedure:
To a stirred solution of 3.0 g of N-tetrahydrofurfurylglycine tert-butyl ester and 5.6 ml of triethylamine in 80 ml of chloroform which was cooled in an ice bath, there was carefully added N2 -(7-methoxy-2-naphthalene-sulfonyl)-L-arginyl chloride hydrochloride obtained above. The reaction mixture was allowed to stand overnight at room temperature. The reaction mixture was washed twice with 20 ml of saturated sodium chloride solution and evaporated to dryness. The residue was dissolved in water-ethanol and adjusted to pH 12 with 5N NaOH to precipitate a solid. This was collected by filtration to give 4.8 g of N2 -(7-methoxy-2-naphthalenesulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine tert-butyl ester.
Reaction SMILES: [Cl:1][CH:2]([C:8](=O)[CH:9]([CH3:11])[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])(=O)C.[NH4+:17]>CO>[NH2:17][C:8]([CH:9]([CH3:11])[CH3:10])=[C:2]([Cl:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(Cl)C(=O)C(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: CCOC(=O)C(Cl)=C(N)C(C)C
Yield: 88 %

Procedure:
59.5 g (0.31 mol) of ethyl 2-chloro-4-methyl-3-oxo-pentanoate are reacted with 59.8 g (0.78 mol) of ammonium acetate in 120 ml of methanol and worked up in analogy to Example 2. Yield: 88.0% [GC]
Reaction SMILES: [CH3:1][C:2](=[CH:7][CH2:8][C:9]#[CH:10])[CH:3]([OH:6])[C:4]#[CH:5].N1C=CC=CC=1.[CH:17]([CH:20]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:21](Cl)=[O:22])([CH3:19])[CH3:18]>C1C=CC=CC=1>[CH:17]([CH:20]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:21]([O:6][CH:3]([C:2]([CH3:1])=[CH:7][CH2:8][C:9]#[CH:10])[C:4]#[CH:5])=[O:22])([CH3:19])[CH3:18]
Reactant: CC(C)C(C(=O)Cl)c1ccc(Cl)cc1
Reactant: C#CCC=C(C)C(O)C#C
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: C#CCC=C(C)C(C#C)OC(=O)C(c1ccc(Cl)cc1)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
1.40 Grams (11.4 millimoles) of 4-methylocta-4-ene-1,7-diyne-3-ol is dissolved in 20 ml of a dry benzene, followed by cooling in ice water. Thereafter, 1.80 g (22.8 millimoles) of pyridine is rapidly added thereto at a time and immediately a solution of 2.64 g (11.4 millimoles) of α-isopropyl-4-chlorophenylacetyl chloride in 10 ml of dry benzene is dropwise added thereto for about 30 minutes with stirring. After completion of the addition, stirring is continued for 3 hours at room temperature to complete the reaction. The reaction mixture is poured into 20 g of ice water and the layers are separated. The aqueous layer is extracted with two 10-ml portions of ether. The organic layers obtained is combined and washed once with a 10% hydrochloric acid and three times with water, followed by drying over anhydrous sodium sulfate. After the solvent is removed under reduced pressure, the oily substance obtained is mixed with almost the same amount of pyridine. The mixture is adsorbed to 100 g of silica gel column and purified by developing with a mixed solvent (18 : 1 : 1) of carbon tetrachloride : n-hexane : ether. Thus, 3.19 g of the objective ester is obtained as a pale yellow oily substance (85.1% of theoretical yield). nD23.0 1.5233
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[Cl:30][C:31]1[N:36]=[CH:35][N:34]=[C:33]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:32]=1.C(N(CC)CC)C>O1CCCC1.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:12]([N:40]2[CH2:41][CH2:42][N:37]([C:33]3[CH:32]=[C:31]([Cl:30])[N:36]=[CH:35][N:34]=3)[CH2:38][CH2:39]2)=[O:14])[CH2:15][CH2:16]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1cc(N2CCNCC2)ncn1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(c3cc(Cl)ncn3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-tert-butoxycarbonyl isonipecotic acid (12.93 g) in tetrahydrofuran (250 ml) at 0° C. was added a solution of carbonyldiimidazole (8.32 g) in tetrahydrofuran (70 ml). The resulting solution was stirred at ambient temperature for 2 hours. This solution was cooled to 0° C. and a solution of (6-chloro-pyrimidin-4-yl)piperazine hydrochloride (13.25 g) and triethylamine (23.57 ml) in dichloromethane (200 ml) added dropwise over 20 minutes. The suspension obtained was stirred at ambient temperature for 18 hours. The mixture was diluted with dichloromethane and washed with water, 2M aqueous citric acid solution, saturated aqueous sodium bicarbonate solution, dried (Na2SO4) and evaporated to give 1-(tert-butoxycarbonyl)-4-[4-(6-chloro-pyrimidin-4-yl)piperazin-1-ylcarbonyl]piperidine (17.45 G) as a cream solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:14]([OH:16])[CH3:15].Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12](=[NH:13])[O:16][CH2:14][CH3:15])[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: N#CC1(c2ccc(Cl)cc2)CCC1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)C1(c2ccc(Cl)cc2)CCC1
Reaction time: 24 h

Procedure:
Through a cooled solution of 1-(4-chlorophenyl)cyclobutanecarbonitrile (5.0 g, 26.1 mmol, Aldrich) and ethanol (2.3 mL, 39.1 mmol) was bubbled HCl gas at 0° C. for 30 minutes. After standing at 4° C. for 24 hours, the reaction mixture was concentrated and triturated with diethyl ether. The precipitate was collected and dried to obtain the titled compound. MS (ESI+) m/z 238 (M+H)1.