Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[N:5]=[C:4]([N:18]2[CH2:21][CH:20]([NH:22][C:23]([NH2:25])=[O:24])[CH2:19]2)[CH:3]=1.[NH2:26][C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1.O1CCOCC1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:5]=[C:4]([N:18]3[CH2:21][CH:20]([NH:22][C:23]([NH2:25])=[O:24])[CH2:19]3)[CH:3]=[C:2]([NH:26][C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: C[C@H](Nc1nc(Cl)cc(N2CC(NC(N)=O)C2)n1)c1ccc(F)cc1
Reactant: Nc1cnccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CC(NC(N)=O)C2)n1)c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 36.6 %

Procedure:
73 mg of (S)-1-(1-{6-chloro-2-[1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}azetidin-3-yl)urea, 25 mg of 2-aminopyrazine, 38 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 29 mg of sodium t-butoxide and 18 mg of tris(dibenzylideneacetone)dipalladium were added in turn to of a degassed mixed solvent of toluene/1,4-dioxane (1/1), and the mixture was stirred at 90° C. for 1 hour under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with a saturated aqueous solution of ammonium chloride and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 31 mg of the objective compound as brown powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]1([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:22]=[CH:21][C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19][CH:18]=2)[CH3:16])[CH2:10][CH2:9]1.Br[C:38]1[CH:39]=[CH:40][C:41](=[O:45])[N:42]([CH3:44])[CH:43]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]1([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:18]=[CH:19][C:20]([C:38]3[CH:39]=[CH:40][C:41](=[O:45])[N:42]([CH3:44])[CH:43]=3)=[CH:21][CH:22]=2)[CH3:16])[CH2:10][CH2:9]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2F)OC1=O
Reactant: Cn1cc(Br)ccc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2F)OC1=O
Yield: 12.2 %

Procedure:
To a solution of (S)-6-(2-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (120 mg, 0.24 mmol), 5-bromo-1-methylpyridin-2-(1H)-one (54 mg, 0.28 mmo), 2N aq Cs2CO3 (2 mL) in dioxane (8 mL) was added Pd(PPh3)2Cl2 (17 mg, 0.024 mmol) under N2. The reaction mixture was refluxed for 2 h and quenched by addition of water. The mixture was extracted with EtOAc (30 mL), and the organic layer was washed with H2O and brine, dried over Na2SO4, and filtered. The filtrate was concentrated to give the crude product, which was purified by preparative TLC and preparative HPLC to afford (S)-6-(2-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (14 mg, yield: 10%). LC-MS Method 2 tR=1.2 min, m/z=473.9; 1H NMR (CDCl3): δ1.21 (s, 3H), 1.30 (s, 3H), 1.48 (d, J=7.2 Hz, 3H), 2.15-2.26 (m, 3H), 2.33 (dd, J=11.2, 26.4 Hz, 1H), 2.43-2.46 (m, 1H), 2.79-2.85 (m, 1H), 3.63 (s, 3H), 5.62 (q, J=6.8 Hz, 1H), 6.58-6.60 (m, 1H), 6.89-6.94 (m, 1H), 7.00-7.02 (m, 2 H), 7.10-7.24 (m, 3H), 7.34-7.39 (m, 1H), 7.40-7.45 (m, 1H), 7.48-7.70 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl[CH2:15][CH:16]([OH:37])[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>>[C:31]1([CH:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:21]2[CH2:20][CH2:19][N:18]([CH2:17][CH:16]([OH:37])[CH2:15][NH:1][C:2]3[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]4[C:3]=3[CH:4]=[CH:5][CH:6]=[N:7]4)[CH2:23][CH2:22]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COc1ccc(N)c2cccnc12
Reactant: OC(CCl)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Product: COc1ccc(NCC(O)CN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2cccnc12
Yield: 11.6 %

Procedure:
Following the same procedure as in Example 27, reaction and treatment were carried out using 1.81 g of 5-amino-8-methoxyquinoline and 1.23 g of 4-(3-chloro-2-hydroxypropyl)-1-diphenylmethylpiperazine to obtain 200 mg of 5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxy-propylamino]-8-methoxyquinoline.
Reaction SMILES: [CH:1]([N:4](CC)[CH:5](C)C)(C)C.[C:10]([O:14][C:15]([NH:17][C@@H:18]([CH:22]([CH3:24])[CH3:23])[C:19](O)=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].Cl.CN(C)CCCN=C=NCC.CNC>C1COCC1.C(Cl)Cl>[CH3:1][N:4]([CH3:5])[C:19]([C@@H:18]([NH:17][C:15](=[O:16])[O:14][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:22]([CH3:24])[CH3:23])=[O:20]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
N,N-Diisopropylethylamine (1.0 mL, 5.74 mmol) was added to a mixture of (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (0.217 g, 1.0 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.211 g, 1.1 mmol) and dimethylamine in THF (2M, 1.0 mL) in methylene chloride (10 mL). The mixture was stirred overnight at RT. The mixture was washed with water, saturated NaHCO3 solution, brine, dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on silica gel to give the desired product (131 mg, 53.6%).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[O:3].Cl.[CH3:8][Si:9]([O:12][C:13](=[O:20])[C@H:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[NH2:15])([CH3:11])[CH3:10]>>[CH3:11][Si:9]([O:12][C:13](=[O:20])[C@H:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[NH:15][C:1](=[O:5])[C:2]([CH3:4])=[O:3])([CH3:8])[CH3:10]
Reactant: CC(C)C[C@H](N)C(=O)O[Si](C)(C)C
Reactant: CC(=O)C(=O)Cl
Agent: Cl
Product: CC(=O)C(=O)N[C@@H](CC(C)C)C(=O)O[Si](C)(C)C

Procedure:
A method of synthesizing pyruvyl-leucine according to the invention comprises the steps of reacting sodium pyruvate with oxalyl chloride to yield pyruvyl chloride, then reacting the pyruvyl chloride with a suspension of leucine trimethylsilyl ester hydrochloride to yield a pyruvyl-leucine trimethylsilyl ester and then subjecting the pyruvyl leucine trimethylsilyl ester to hydrolysis to yield pyruvyl-leucine. The pyruvyl-leucine synthesized via the route set forth above serves as a pyruvyl-amino acid pyruvate precursor.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]2[C:11](=[O:12])[N:10]([CH3:13])[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[NH:7][C:6]=2[N:18]=1.[H-].[Na+].[O:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29]Cl)[CH2:24][CH2:23]1>CN(C)C=O>[O:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:7]2[C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[N:10]([CH3:13])[C:11](=[O:12])[C:5]3[C:4]([CH3:19])=[CH:3][C:2]([CH3:1])=[N:18][C:6]2=3)[CH2:24][CH2:23]1
Reactant: Cc1cc(C)c2c(n1)Nc1ccccc1N(C)C2=O
Reactant: ClCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c2c(n1)N(CCN1CCOCC1)c1ccccc1N(C)C2=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture consisting of 5.06 gm of 6,11-dihydro-2, 4,6-trimethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, 1.1 gm of 50% sodium hydride in mineral oil and 60 ml of dimethyl formamide was stirred at 80° C. for 1 hour. Then, 4.5 gm of 2-morpholino-ethyl chloride were added, and the mixture was stirred at 120° C. for 3.5 hours more. The precipitate formed thereby was suction-filtered off, the solvent was removed from the filtrate in vacuo, and the oily residue was purified on a silica gel column. The product was recrystallized from petroleum ether (b.p. 100°-140° C.), yielding 64% of theory of the compound named in the heading, which had a melting point of 133°-135° C.
Reaction SMILES: C1C(=O)N(Cl)C(=O)C1.[F:9][C:10]1[CH:11]=[C:12]([CH:23]=[CH:24][C:25]=1[CH:26]=[N:27][OH:28])[CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].[Br:29][C:30]1[CH:31]=[C:32]([C:51]#[CH:52])[C:33]([N:36]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[N:34][CH:35]=1.CCN(CC)CC>CN(C=O)C.C(OCC)(=O)C.O>[Br:29][C:30]1[CH:31]=[C:32]([C:51]2[O:28][N:27]=[C:26]([C:25]3[CH:24]=[CH:23][C:12]([CH2:13][N:14]([C:15]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:21])[CH3:22])=[CH:11][C:10]=3[F:9])[CH:52]=2)[C:33]([N:36]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:37](=[O:43])[O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[N:34][CH:35]=1
Reactant: C#Cc1cc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CN(Cc1ccc(C=NO)c(F)c1)C(=O)OC(C)(C)C
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(Cc1ccc(-c2cc(-c3cc(Br)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)on2)c(F)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
NCS (62.52 mg, 0.4682 mmol) was added to a solution tert-butyl 3-fluoro-4-((hydroxyimino)methyl)benzyl(methyl)carbamate [prepared in an analogous manner to that described in Bioorganic & Medicinal Chemistry, 17(13), 4773-4785; 2009] (132.2 mg, 0.4682 mmol) in DMF (930.0 μL) and the mixture heated at 55° C. for 15 minutes. The reaction mixture was allowed to cool to room temperature, and tert-butyl N-(5-bromo-3-ethynyl-2-pyridyl)-N-tert-butoxycarbonyl-carbamate (186 mg, 0.4682 mmol) and Et3N (56.85 mg, 78.31 μL, 0.5618 mmol) were added. The mixture was stirred at ambient temperature for 45 minutes followed by heating to 65° C. for 1 hour. The mixture was cooled to ambient temperature and diluted with ethyl acetate (5 mL) and water (5 mL) and the layers separated. The aqueous layer was extracted further with ethyl acetate (2×5 mL) and the combined organic extracts washed with water (3×10 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 12 g column, eluting with 0 to 100% EtOAc/Petroleum Ether, loaded in DCM) to give the impure sub-title product as a tacky yellow oil. This was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([OH:15])[C:7]=1[F:16])[CH3:2].[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37](O)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([O:15][C:8]2[CH:9]=[C:10]([O:12][CH2:13][CH3:14])[CH:11]=[C:6]([CH:5]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)[C:4]([O:3][CH2:1][CH3:2])=[O:26])[C:7]=2[F:16])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(O)c1F
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1F

Procedure:
In analogy to example 1.5, (RS)-(4-cyano-phenylamino)-(5-ethoxy-2-fluoro-3-hydroxy-phenyl)-acetic acid ethyl ester described in example 1.4 was reacted with 1-tert-butyloxycarbonyl-4-hydroxy-piperidine to give (RS)-4-{3-[(4-cyano-phenylamino)-ethoxycarbonyl-methyl]-5-ethoxy-2-fluoro-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester. MS: 559.5 ([M+H]+).
Reaction SMILES: Cl[C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([S:24]([C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH2:29][CH2:30][NH:31][CH2:32]3)(=[O:26])=[O:25])[CH2:20][CH2:19]1.C(N(CC)CC)C>CS(C)=O.O>[CH3:14][O:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:15][CH3:16])[N:3]=[C:2]([N:31]1[CH2:30][CH2:29][C:28]3[C:33](=[CH:34][CH:35]=[CH:36][C:27]=3[S:24]([N:21]3[CH2:20][CH2:19][N:18]([CH3:17])[CH2:23][CH2:22]3)(=[O:26])=[O:25])[CH2:32]1)[NH:11][C:10]2=[O:12]
Reactant: COc1cc2nc(Cl)[nH]c(=O)c2cc1OC
Reactant: CN1CCN(S(=O)(=O)c2cccc3c2CCNC3)CC1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1cc2nc(N3CCc4c(cccc4S(=O)(=O)N4CCN(C)CC4)C3)[nH]c(=O)c2cc1OC
Temperature: 80 °C
Reaction time: 18 h
Yield: 37.2 %

Procedure:
A mixture of 2-chloro-6,7-dimethoxy-3H-quinazolin-4-one 1b, (0.77 g, 3.23 mmol), 5-(4-methyl-piperazine-1-sulfonyl)-1,2,3,4-tetrahydro-isoquinoline 11a (1.25 g, 3.41 mmol) and triethylamine (0.75 g, 1.04 mL, 7.46 mmol) in DMSO (15 mL) was heated at 80° C. with stirring for 18 h. After cooling to room temperature the reaction was diluted with water. The precipitated white product was collected by filtration, washed with water, and dried to give 0.6 g of 6,7-dimethoxy-2-[5-(4-methyl-piperazine-1-sulfonyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3H-quinazolin-4-one 401, mp. 230-237° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:18]([CH3:20])[CH3:19])=[N:4][C:5]([O:11][CH2:12][C:13]([O:15]CC)=O)=[N:6][C:7]=1[CH:8]([CH3:10])[CH3:9].[CH2:21]([N:28]1[CH2:33][CH2:32][CH:31]([NH:34][CH3:35])[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[NH2:1][C:2]1[C:7]([CH:8]([CH3:9])[CH3:10])=[N:6][C:5]([O:11][CH2:12][C:13]([N:34]([CH:31]2[CH2:30][CH2:29][N:28]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:33][CH2:32]2)[CH3:35])=[O:15])=[N:4][C:3]=1[CH:18]([CH3:19])[CH3:20]
Reactant: CCOC(=O)COc1nc(C(C)C)c(N)c(C(C)C)n1
Reactant: CNC1CCN(Cc2ccccc2)CC1
Product: CC(C)c1nc(OCC(=O)N(C)C2CCN(Cc3ccccc3)CC2)nc(C(C)C)c1N

Procedure:
As in Example 11, a carboxylic acid derivative was synthesized from Compound 13. Then, the title compound was synthesized from the obtained carboxylic acid derivative and 1-benzyl-N-methylpiperidine-4-amine in the same manner as in Example 49.
Reaction SMILES: C(O)(=O)C.[OH-].[Na+].[NH2:7][C:8]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([NH:12][CH3:13])=[O:11].[Br:19]Br>O>[NH2:7][C:8]1[C:17]([CH3:18])=[CH:16][C:15]([Br:19])=[CH:14][C:9]=1[C:10]([NH:12][CH3:13])=[O:11]
Reactant: BrBr
Reactant: CNC(=O)c1cccc(C)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CNC(=O)c1cc(Br)cc(C)c1N
Temperature: 55 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
A 1000-mL flask equipped with a mechanical stirrer, thermocouple, condenser and Teflon® fluoropolymer tubing ( 1/16″ (0.16) cm I.D.×⅛″ (0.32 cm) O.D.) (positioned such that the end of the tubing was submerged below the surface of the reaction mixture) was charged with acetic acid (226 mL). A solution of aqueous sodium hydroxide (50%, 25 g) in water (85 g) was added over 15 minutes, and then 2-amino-N,3-dimethylbenzamide (50 g, 0.305 mol) (see PCT Patent Publication WO 2006/062978 for a method of preparation) was added and the mixture was heated at 55° C. A two-necked 200-mL flask fitted on one neck with a Teflon® tubing dip tube was charged with liquid bromine (50.1 g), and the other neck was connected to the Teflon® tubing on the 1000-mL flask. Nitrogen gas was then flowed through the dip tube below the surface of the liquid bromine at a rate of about 0.012 m3 (0.4 cu ft) per h for 2.5 h, during which time all of the bromine evaporated and the bromine vapor entrained in the nitrogen gas flowed out of the two-necked 200-mL flask and entered the reaction mixture through the Teflon® tubing. The reaction temperature was held at about 55° C. during the bromine vapor addition and for 30 minutes thereafter, and then cooled to 45° C. and stirred overnight. A solution of aqueous sodium hydroxide (50%, 52 g) in water (88 mL) was added to the reaction mixture at a rate of 0.8 mL/minute. After about 10% of the total volume of the sodium hydroxide solution had been added, the addition was stopped and the reaction mixture was stirred for 1 h at 45° C. After 1 h the remaining sodium hydroxide solution was added at a rate of 0.8 mL/minute. After the addition was complete, the reaction was stirred for 30 minutes at 45° C., and then cooled to 10° C. and stirred for 1 h. The mixture was filtered and the solid collected was washed with methanol (130 mL) and water (260 mL), and then dried to a constant weight in a vacuum-oven at 45° C. to give the title compound as a solid (67 g, 99.4 area % purity by HPLC, 89.7% yield) melting at 133-135° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:32]=[N:31][C:17]3[NH:18][CH2:19][CH2:20][N:21]([CH2:22][C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=4[Cl:30])[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[Cl:30][C:24]1[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:23]=1[CH2:22][N:21]1[CH2:20][CH2:19][NH:18][C:17]2[N:31]=[CH:32][C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)=[CH:15][C:16]1=2
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cnc3c(c2)N(Cc2cc(Cl)ccc2Cl)CCN3)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(Cl)c(CN2CCNc3ncc(C4=CCNCC4)cc32)c1
Yield: 84 %

Procedure:
4-[1-(2,5-Dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (105 mg) was dissolved in CH2Cl2/trifluoroacetic acid (3:1, v/v) and stirred at room temperature for two (2) hours. The reaction mixture was concentrated, diluted with CH2Cl2, washed with NaHCO3 (×2), dried, filtered, and concentrated to give the title compound as a pale orange solid (84% yield). M.p. 133-136° C., LCMS: m/z=375.13 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 2.30-2.38 (m, 2H), 3.00-3.06 (m, 1H), 3.28-3.34 (m, 2H), 3.52-3.58 (m, 2H), 4.49 (s, 2H), 5.80 (s, 1H), 6.47 (s, 1H), 6.59 (s, 1H), 7.29 (d, J=2.5 Hz, 1H), 7.37-7.42 (m, 2H), 7.54 (d, J=8.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.Cl[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2c(Cl)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottomed flask was added 2-chloro-1H-benzo[d]imidazole (1.000 g, 6.55 mmol), 1-(chloromethyl)-4-methoxybenzene (1.540 g, 9.83 mmol), and potassium carbonate (1.359 g, 9.83 mmol) in DMF (21.85 mL) to stir overnight. Reaction was allowed to cool to room temperature. The reaction mixture was diluted with water and extracted with DCM. The organic extract was washed with water, brine, dried with magnesium sulfate, filtered, and concentrated to provide 2-Chloro-1-(4-methoxybenzyl)-1H-benzo[d]imidazole. MS (ESI, pos. ion) m/z: 273.2 (M+1).
Reaction SMILES: Br.[NH2:2][CH2:3][C:4]([N:6]1[C@H:14]([C:15]([OH:17])=[O:16])[CH2:13][C:8]2([S:12][CH2:11][CH2:10][S:9]2)[CH2:7]1)=[O:5].O=[C:19]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[C:20]([CH:19]([NH:2][CH2:3][C:4]([N:6]1[C@H:14]([C:15]([OH:17])=[O:16])[CH2:13][C:8]2([S:12][CH2:11][CH2:10][S:9]2)[CH2:7]1)=[O:5])[CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([O:22][CH2:23][CH3:24])=[O:21]
Reactant: NCC(=O)N1CC2(C[C@H]1C(=O)O)SCCS2
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: Br
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)NCC(=O)N1CC2(C[C@H]1C(=O)O)SCCS2

Procedure:
As described in Example 1F, couple 0.76 g of 7-glycyl-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, hydrobromide (prepared as described in paragraph D next above) with 0.50 g of 2-oxo-4-phenylbutyric acid, ethyl ester to obtain 7-[N-(1-carboethoxy-3-phenylpropyl)glycyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid [α]D26 -39.0° (ethanol).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C)C=O>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C(=O)OCC)cc1
Reaction time: 15 h
Yield: 95.8 %

Procedure:
2 g (12 mmole) of ethyl 4-hydroxybenzoate were added to a N,N-dimethylformamide (10 ml) suspension including 0.32 g of sodium hydride under ice cooling. Furthermore, a N,N-dimethylformamide (5 ml) solution including 2.2 g (13 mmole) of ethyl bromoacetate was added dropwise thereto, and reaction was then carried out for 15 hours. After the reaction mixture had been concentrated, partition was carried out between ethyl acetate and water. The organic layer was then treated in an ordinary manner to obtain 2.9 g (yield: 96%) of ethyl 4-(2-ethoxy-2-oxo-ethoxy)benzoate.
Reaction SMILES: [NH:1]([C:98]([O:100][CH2:101][C:102]1[CH:107]=[CH:106][CH:105]=[CH:104][CH:103]=1)=[O:99])[C@H:2]([C:10]([NH:12][C@H:13]([C:21]([N:23]1[CH2:97][CH2:96][CH2:95][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:46]([NH:48][C@H:49]([C@H:54]([CH2:56][C:57]([NH:59][C@H:60]([C:65]([NH:67][C@H:68]([C:75]([NH:77][C@H:78]([C:91]([O:93][CH3:94])=[O:92])[CH2:79][CH2:80][CH2:81][CH2:82][NH:83]C(OC(C)(C)C)=O)=[O:76])[CH2:69][C:70]1[N:74]=[CH:73][NH:72][CH:71]=1)=[O:66])[C@H:61]([CH2:63][CH3:64])[CH3:62])=[O:58])[OH:55])[CH2:50][CH:51]([CH3:53])[CH3:52])=[O:47])[CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8]>C(O)(C(F)(F)F)=O>[NH:1]([C:98]([O:100][CH2:101][C:102]1[CH:103]=[CH:104][CH:105]=[CH:106][CH:107]=1)=[O:99])[C@H:2]([C:10]([NH:12][C@H:13]([C:21]([N:23]1[CH2:97][CH2:96][CH2:95][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:46]([NH:48][C@H:49]([C@H:54]([CH2:56][C:57]([NH:59][C@H:60]([C:65]([NH:67][C@H:68]([C:75]([NH:77][C@H:78]([C:91]([O:93][CH3:94])=[O:92])[CH2:79][CH2:80][CH2:81][CH2:82][NH2:83])=[O:76])[CH2:69][C:70]1[N:74]=[CH:73][NH:72][CH:71]=1)=[O:66])[C@H:61]([CH2:63][CH3:64])[CH3:62])=[O:58])[OH:55])[CH2:50][CH:51]([CH3:53])[CH3:52])=[O:47])[CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:19])[NH2:20])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: CC[C@H](C)[C@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCN)C(=O)OC
Reaction time: 0.42 h

Procedure:
100 mg of Z-Arg-Arg-Pro-Phe-His-Sta-Ile-His-Lys(Boc)-OMe (Example 4) are dissolved in 500 μl of 95% strength TFA, the whole is left to stand for 25 minutes, and precipitation is effected by the addition of 5 ml of diisopropyl ether. The precipitate is filtered off, dried, dissolved in 2 ml of H2O and, in order to be converted into the acetate, filtered slowly through a column (φ=1 cm, length=8 cm) of weakly basic ion exchanger in acetate form. The eluate is concentrated and lyophilised, yielding Z-Arg-Arg-Pro-Phe-His-Sta-Ile-His-Lys-OMe; Rf (D)=0.35; Rf (M)=0.3; Rf (N)=0.3.