Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@@H:8]1[CH2:32][C:33](=[NH:36])SC)=[O:6])[CH:2]=[CH2:3].[Cl-:37].[NH4+:38]>CO>[ClH:37].[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9][C@H:8]1[CH2:32][C:33](=[NH:36])[NH2:38])=[O:6])[CH:2]=[CH2:3]
Reactant: [NH4+]
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@@H]1CC(=N)SC
Reactant: [Cl-]
Solvent: CO
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CC(=N)N
Product: Cl
Temperature: 50 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
To a solution of (2R,4S)-1-allyloxycarbonyl-2-(2-imino-2-methylthioethyl)-4-(triphenylmethylthio)pyrrolidine (1.95 g) in methanol (39 ml) was added ammonium chloride (222 mg). After stirring at 50° C. for 2 hours, the solution was evaporated under reduced pressure. The residue was triturated with diisopropyl ether to give (2R,4S)-1-allyloxycarbonyl-2-amidinomethyl-4-(triphenylmethylthio)pyrrolidine hydrochloride (1.36 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=4)[CH:17]=[CH:18][C:19]=3[C:11]=2[C:10](C)(C)[CH2:9][NH:8][CH:7]=1)=[O:5])[CH3:2].C(OC(C1C2NC3C=C(C4C=COC=4)C=CC=3C=2C(C)(C)CNC=1)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=4)[CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CNCC(C)(C)c2c1[nH]c1cc(-c3cccc(OC)c3)ccc21
Agent: CCOC(=O)C1=CNCC(C)(C)c2c1[nH]c1cc(-c3ccoc3)ccc21
Product: CCOC(=O)C1=CNCCc2c1[nH]c1cc(-c3cccc(OC)c3)ccc21

Procedure:
In a manner similar to Step C, but replacing 8-(3-methoxyphenyl)-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester with 8-(3-methoxyphenyl)-1,1-dimethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester or 8-furan-3-yl-1,1-dimethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester, the following compounds were prepared:
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[C:22]2[N:21]=[CH:20][CH:19]=[N:18][C:17]=2[C:16]([C:23]([OH:25])=O)=[CH:15][CH:14]=1.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([NH:26][C:23]([C:16]2[C:17]3[N:18]=[CH:19][CH:20]=[N:21][C:22]=3[C:13]([C:3]3[C:2]([F:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=3[F:12])=[CH:14][CH:15]=2)=[O:25])[CH:28]=1
Reactant: Nc1cccnc1
Reactant: COc1cc(OC)c(F)c(-c2ccc(C(=O)O)c3nccnc23)c1F
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3cccnc3)c3nccnc23)c1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (Step 88.1), 3-aminopyridine, and stirring the reaction mixture for 72 h at rt. The crude product was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 96:3:1) followed by trituration in Et2O. Title compound: ESI-MS: 423.1 [M+H]+; tR=3.53 min (System 1); TLC: Rf=0.56 (DCM/MeOH/NH3aq, 96:3:1).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)([CH3:5])[CH3:4])#[N:2].[H][H].N.Cl>[Ni].C(O)C>[NH2:2][CH2:1][C:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[CH:8][CH:7]=1)([CH3:4])[CH3:5]
Reactant: COc1ccc(C(=O)Nc2ccc(C(C)(C)C#N)cc2)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: Cl
Agent: N
Solvent: CCO
Product: COc1ccc(C(=O)Nc2ccc(C(C)(C)CN)cc2)cc1

Procedure:
5 g. N-[4-(1-Cyano-1-methylethyl)-phenyl]-4-methoxybenzamide (Example 27) are hydrogenated at 90° C. and 120 bar hydrogen pressure in 40 ml. ethanol in the presence of 40 ml. liquid ammonia and 2 g. Raney nickel. The reaction mixture is filtered and the filtrate evaporated to dryness in a vacuum. After column chromatographic purification (400 ml. silica gel 60; dichloromethane/methanolic ammonia 30:1 v/v), there are obtained 2.6 g. of colourless crystals which are heated in 100 ml. 1M hydrochloric acid. After cooling, there are obtained 2.3 g. (40% of theory) of the title compound as hydrochloride in the form of colourless leaflets; m.p. 273°-276° C.
Reaction SMILES: C=C.[C:3]([OH:20])(=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\CCCCCC.[C:21](O)(=O)[CH2:22]CCCCCC/C=C\CCCCCCCC.[C:41](OC)(=O)[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH:49]=[CH2:50].C=CCCCCCC>>[C:3]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12].[CH2:41]=[CH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: CCCCCC/C=C\CCCCCCCC(=O)O
Reactant: C=CCCCCCCCC(=O)OC
Agent: C=C
Solvent: C=CCCCCCC
Product: C=CCCCCCCCC
Product: C=CCCCCCCCC(=O)OCC

Procedure:
Ethenolysis comprises a cross-metathesis reaction involving ethene. According to some preferred embodiments of the invention, a mixture of ethyl esters of Palmitoleic acid (C16:1) and Oleic acid (C18:1) are subjected to conditions of ethenolysis to yield a mixture of α-olefins (1-Octene and 1-Decene) and Methyl 9-Decenoate. See FIG. 8. The 1-Octene is a product unique to ethenolysis of Palmitoleic acid (C16:1). In the inventive method, Ethyl 9-Decenoate and 1-Decene will also form from the mixture of Palmitoleic and Oleic acid ethyl esters. Prior art methods using Oleic acid esters (Methyl Oleate) as the starting material only produce Methyl 9-Decenoate and 1-Decene.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[C:6]([C:12]#N)(=O)[C:7]([CH3:10])([CH3:9])[CH3:8].[NH2:14][NH:15][C:16]([NH:18][NH2:19])=[S:17]>O.Cl>[NH2:14][N:15]1[C:12](=[O:2])[C:6]([C:7]([CH3:10])([CH3:9])[CH3:8])=[N:19][N:18]=[C:16]1[SH:17]
Reactant: O=S(=O)(O)O
Reactant: NNC(=S)NN
Reactant: CC(C)(C)C(=O)C#N
Agent: Cl
Solvent: O
Product: CC(C)(C)c1nnc(S)n(N)c1=O
Reaction time: 20 h
Yield: 65 %

Procedure:
200 ml of concentrated sulphuric acid and then 72 g of water were added dropwise to 111 g (1 mol) of pivaloyl cyanide at 20° to 25° C. The reaction mixture was subsequently stirred at 20° to 25° C. for 20 hours and was added to a solution of 106 g (1 mol) of thiocarbohydrazide in 500 ml of water and 150 ml of concentrated hydrochloric acid at the above temperature. The mixture was subsequently stirred at 80° to 90° C. for 2 hours, cooled to 5° to 10° C. and filtered. The solid residue was recrystallized from methanol. 130 g (65% of theory) of 4-amino-6-tert.-butyl-3-mercapto-1,2,4-triazin-5(4H)-one (VII) of melting point 216° C. were obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][OH:24])[C:16]=2[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:34][C:35]1[CH:36]=[N:37][C:38](S(C)(=O)=O)=[N:39][CH:40]=1>O1CCCC1.CC(N(C)C)=O.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][O:24][C:38]3[N:39]=[CH:40][C:35]([Cl:34])=[CH:36][N:37]=3)[C:16]=2[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ncc(Cl)cn1
Reactant: Cc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc(-c2c(OCCOc3ncc(Cl)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reaction time: 0.08 h
Yield: 69.2 %

Procedure:
To 4-(tert-butyl)-N-[3-(2-hydroxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]benzenesulfonamide (Example 2) (196 mg) in tetrahydrofuran (2.5 ml) at room temperature under an atmosphere of nitrogen was added sodium hydride (60% dispersion in oil, 37 mg) and the mixture was stirred for 5 minutes. To the mixture was added a solution of 5-chloro-2-methylsulphonylpyrimidine (94 mg) in tetrahydrofuran (5 ml) and dimethylacetamide (0.5 ml) the mixture was stirred for a further 48 hrs. The reaction was diluted with water (200 ml) and extracted with dichloromethane (3×50 ml). The organic fractions were combined, washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (20 g) eluted with ether:hexane (4:1) to yield the title compound as a white solid (170 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:6]#N.C(O)=[O:16]>O=[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=[O:16]
Reactant: O=CO
Reactant: COc1cc(C#N)cc(C(F)(F)F)c1
Agent: O=[Pt]=O
Product: COc1cc(C=O)cc(C(F)(F)F)c1
Temperature: 60 °C

Procedure:
A mixture of 3-methoxy-5-(trifluoromethyl)benzonitrile (88 mg, 0.43 mmol) and PtO2 (9.8 mg, 0.043 mmol) in 88% formic acid (651 μL) was heated to 60° C. The reaction was stirred at this temperature for thirty minutes. The reaction was then cooled to room temperature, diluted with hexanes (5 mL), loaded on a silica gel column, and purified with 1% to 15% EtOAc/hexanes to afford 3-methoxy-5-(trifluoromethyl)benzaldehyde. Rf=0.56 (25% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 10.01 (s, 1H), 7.71 (s, 1H), 7.56 (s, 1H), 7.39 (s, 1H), 3.92 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[CH:11]=2)[O:6][CH:7]=1.[CH3:18][S:19]([CH2:22][C:23]1[N:24]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)[CH:25]=[CH:26][N:27]=1)(=[O:21])=[O:20].[H-].[Na+]>>[F:17][C:12]1[CH:11]=[C:10](/[CH:9]=[CH:8]/[C:5]2[O:6][CH:7]=[C:3]([CH2:2][O:38][C:35]3[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][N:24]4[CH:25]=[CH:26][N:27]=[C:23]4[CH2:22][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:37][CH:36]=3)[N:4]=2)[CH:15]=[CH:14][C:13]=1[F:16]
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)cc1F
Reactant: CS(=O)(=O)Cc1nccn1CCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Product: CS(=O)(=O)Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(F)c(F)c3)n2)cc1
Yield: 61 %

Procedure:
Using 4-(chloromethyl)-2-[(E)-2-(3,4-difluorophenyl)ethenyl]-1,3-oxazole (228 mg), 4-[4-[2-[(methylsulfonyl)methyl]-1H-imidazol-1-yl]butyl]phenol (250 mg) and 65% sodium hydride (32.9 mg), the same reaction as Example 11-(i) was carried out to yield the titled compound (261 mg) as colorless flaky crystals.
Reaction SMILES: N[C:2]1C=C(NCCOC)C(C#N)=CN=1.[C:15]([C:17]1[C:18]([NH:50][CH2:51][CH2:52][O:53][CH3:54])=[CH:19][C:20]([NH:23][C:24]([N:26]2[C:35]3[C:30](=[CH:31][C:32]([CH2:41][N:42]4[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][C:43]4=[O:49])=[C:33]([CH:36](OC)[O:37]C)[N:34]=3)[CH2:29][CH2:28][CH2:27]2)=[O:25])=[N:21][CH:22]=1)#[N:16]>>[C:15]([C:17]1[C:18]([NH:50][CH2:51][CH2:52][O:53][CH3:54])=[CH:19][C:20]([NH:23][C:24]([N:26]2[C:35]3[C:30](=[CH:31][C:32]([CH2:41][N:42]4[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][C:43]4=[O:49])=[C:33]([CH:36]=[O:37])[N:34]=3)[CH2:29][CH2:28][C@@H:27]2[CH3:2])=[O:25])=[N:21][CH:22]=1)#[N:16]
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(CN4CCN(C)CC4=O)c(C(OC)OC)nc32)ncc1C#N
Reactant: COCCNc1cc(N)ncc1C#N
Product: COCCNc1cc(NC(=O)N2c3nc(C=O)c(CN4CCN(C)CC4=O)cc3CC[C@@H]2C)ncc1C#N

Procedure:
From intermediates 75 and 268, coupled and deprotected in an analogous manner to intermediate 80 and Example 201. The title compound was obtained as a white solid.
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=[CH2:3].[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]2[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[CH:21]=2)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)(Cl)Cl>[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[C:20]3[CH2:21][CH2:3][CH2:2][C:1](=[O:5])[C:25]=3[CH2:24][CH2:23][C:22]2=[O:26])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1C=C(NC2CCN(Cc3ccccc3)CC2)CCC1
Reactant: C=CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=C1CCCC2=C1CCC(=O)N2C1CCN(Cc2ccccc2)CC1
Reaction time: 6 h

Procedure:
Acrylic acid (28.9 ml) is added to 1-(1-benzyl-4-piperidinylamino)-1-cyclohexen-3-on (100 g) and the mixture is refluxed with stirring for 6 hours. After cooling, the reaction mixture is dissolved in chloroform containing 10% methanol and purified by silica gel column chromatography (solvent; dichloromethane:methanol=40:1). The resultant is recrystallized from ethanol/water to give 1-(1-benzyl-4-piperidinyl)-5-oxo-3,4,5,6,7,8-hexahydrocarbostyril (23.98 g) as colorless needles, m.p.: 102°-103° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4](=[N+:14]([O-])[O:15][N:16]=2)[C:5]2[N:6]=[C:7]([OH:13])[C:8]([OH:12])=[N:9][C:10]=2[CH:11]=1.P(OCC)(OCC)OCC>C(O)C.CN(C)C=O>[Cl:1][C:2]1[C:3]2[C:4](=[N:14][O:15][N:16]=2)[C:5]2[N:6]=[C:7]([OH:13])[C:8]([OH:12])=[N:9][C:10]=2[CH:11]=1
Reactant: [O-][n+]1onc2c(Cl)cc3nc(O)c(O)nc3c21
Agent: CCOP(OCC)OCC
Solvent: CN(C)C=O
Solvent: CCO
Product: Oc1nc2cc(Cl)c3nonc3c2nc1O
Yield: 69.9 %

Procedure:
To a solution of 0,6 g (2,4 mmol) 4-chloro-7,8-dihydroxy-1,2,5-oxadiazolo(3,4-f)quinoxaline-1-oxide in a mixture of 14 ml ethanol and 3 ml dimethylformamide was added 0,9 ml (5,3 mmol) triethyl phosphite. The mixture was refluxed for 4 h, and then evaporated in vacuo. The residue was stirred with water and then with ether-ethyl acetate (5:1) to give 0,4 g (71%) 4-chloro-7,8-dihydroxy-1,2,5-oxadiazolo(3,4-f)quinoxaline, m.p.>300° C. NMR (DMSO-d6 +D2O) 7.40 (1H,s).
Reaction SMILES: Cl.[S:2]([N:12]1[C:16]2=[N:17][CH:18]=[C:19]([NH2:21])[N:20]=[C:15]2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[CH2:23][C:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=O.CCN(C(C)C)C(C)C>CCCCO>[CH:26]1([C:24]2[N:21]=[C:19]3[CH:18]=[N:17][C:16]4[N:12]([S:2]([C:5]5[CH:6]=[CH:7][C:8]([CH3:9])=[CH:10][CH:11]=5)(=[O:3])=[O:4])[CH:13]=[CH:14][C:15]=4[N:20]3[CH:23]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(CBr)C1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(N)cnc32)cc1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nc(C4CCCCC4)cn23)cc1
Temperature: 170 °C

Procedure:
To a suspension of 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-amine hydrochloride (0.10 g, 0.35 mmol) and 2-bromo-1-cyclohexylethanone (0.078 g, 0.38 mmol, 3B Pharmachem) in n-BuOH (1.5 mL) was added DIEA (0.067 g, 0.52 mmol) and the resulting solution was heated at about 170° C. in the CEM™ microwave for about 30 min. The solvent was removed under reduced pressure to afford 7-cyclohexyl-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine as a crude solid that was used in Step D without further purification: LC/MS (Table 2, Method a) Rt=2.71 min; MS m/z: 395 (M+H)+.
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:31])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:30])[CH2:17][CH2:18][CH2:19][CH2:20][CH:21]1[CH:28]2[CH:24]([NH:25][C:26](=[O:29])[NH:27]2)[CH2:23][S:22]1.C(N(CC)CC)C.[C:39]([O:43][C:44](=[O:53])[NH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][NH2:52])([CH3:42])([CH3:41])[CH3:40]>CN(C=O)C>[C:39]([O:43][C:44](=[O:53])[NH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][NH:52][C:9](=[O:31])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:30])[CH2:17][CH2:18][CH2:19][CH2:20][CH:21]1[CH:28]2[CH:24]([NH:25][C:26](=[O:29])[NH:27]2)[CH2:23][S:22]1)([CH3:42])([CH3:40])[CH3:41]
Reactant: O=C(CCCCC1SCC2NC(=O)NC21)NCCCCCC(=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)NCCCCCCN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCCCNC(=O)CCCCCNC(=O)CCCCC1SCC2NC(=O)NC21
Temperature: 25 °C

Procedure:
6-[5-(2-Oxo-hexahydro-thieno[3,4-d]imidazol-4-yl)-pentanoylamino]-hexanoic acid 2,5-dioxo-pyrrolidin-1-yl ester (4; 0.39 g, 0.86 mmol) was completely dissolved in DMF (15 mL) with gentle warming. After cooling the solution to room temperature without reprecipitation, it was mixed with triethylamine (Et3N; 0.52 g, 5.15 mmol) followed by the addition of 5 (0.25 g, 1.14 mmol) in DMF (3 mL) dropwise while stirring. After overnight reaction at room temperature, the mixture was filtered, evaporated in vacuo, and loaded to a silica column for further purification. The products were separated by eluting with mobile phases of 5-20% MeOH in DCM to afford 6 (0.45 g; 93.8%) as a yellowish solid. 1H NMR (400 MHz) (CD3OD) δ: 4.53 (t, 1H, CHN), 4.34 (t, 1H, CHN), 3.25 (dd, 1H, CHS), 3.20 (t, 2H, CH2NH), 3.08 (t, 2H, CH2NH), 2.96 (d, 1H, CHHS), 2.73 (d, 1H, CHHS), 2.22 (t, 4H, CH2CO), 1.38-1.80 (m, 29H). 13C NMR (100.67 MHz) (DMSO) δ: 176.02, 175.97, 166.05, 158.50, 79.50, 63.39, 61.63, 57.01, 41.24, 41.04, 40.24, 36.99, 36.82, 30.90, 30.35, 30.13, 29.78, 29.49, 28.80, 27.56, 26.92, 26.74. HRMS (ESI) calculated for C27H49N5O5S, [M+Na]+ 578.3352 (calcd.), 578.3349 (found).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([CH:20]([CH:25]4[CH2:27][CH2:26]4)[CH:21](OC)[OH:22])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:28]([O:37][CH3:38])(=[O:36])[C:29]1[C:30](=[CH:32][CH:33]=[CH:34][CH:35]=1)O.N(C(OC(C)C)=O)=N[C:41](OC(C)C)=[O:42].ClCCl>C1COCC1>[CH3:38][O:37][C:28](=[O:36])[C:29]1[CH:30]=[CH:32][CH:33]=[CH:34][C:35]=1[O:22][CH2:21][C:20]([O:42][CH3:41])([C:16]1[CH:17]=[CH:18][CH:19]=[C:14](/[CH:13]=[CH:12]/[C:8]2[CH:7]=[CH:6][C:5]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=3)[N:9]=2)[CH:15]=1)[CH:25]1[CH2:26][CH2:27]1
Reactant: COC(=O)c1ccccc1O
Reactant: COC(O)C(c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1)C1CC1
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1ccccc1OCC(OC)(c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1)C1CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 9.7 %

Procedure:
To a suspension of ether-alcohol 44 (0.9 g, 0.0024 mol) in THF (5 ml) was added triphenyl phosphene (0.93 g, 0.0035 mol) and methyl salicylate (0.54 ml, 0.0036 mol). The resulting mixture was stirred at ambient temperature for 5 minutes and diisopropyl azodicarboxilate (0.71 g, 0.0035 mol) was added drop wise to the mixture. The reaction mixture was stirred at the same temperature for seven days. Dichloromethane (30 ml) was added to the mixture followed by drying of the resulted solution over sodium sulfate, evaporation of the solvents and FC to give ester 45 (0.12 g, 9.62%).
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:43])[C:11]2[CH:17]=[C:16]([CH2:18][NH:19][CH2:20][C:21]3[CH:42]=[CH:41][C:24]([C:25]([NH:27][C@H:28]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:26])=[CH:23][CH:22]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:44](OC(=O)C)(=[O:46])C>C(O)=O>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:43])[C:11]2[CH:17]=[C:16]([CH2:18][N:19]([CH2:20][C:21]3[CH:42]=[CH:41][C:24]([C:25]([NH:27][C@H:28]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:26])=[CH:23][CH:22]=3)[CH:44]=[O:46])[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:3])([CH3:5])[CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CNCc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cc1)C(=O)OCC
Solvent: O=CO
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CN(C=O)Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.0 g. (1.7 mmol) of diethyl N-[N-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-ylmethyl)-4-aminomethylbenzoyl]-glutamate in 10 mL of 98% formic acid was added 0.35 g. (0.33 mL, 3.5 mmol) of acetic anhydride. The mixture was stirred at 25° C. for 1 h. The solvent was removed under reduced pressure and the solid dissolved in methylene chloride and extracted twice with a saturated solution of sodium bicarbonate. The aqueous layers were back extracted with methylene chloride, and the organic layers combined and dried over anhydrous magnesium sulfate. The solvent was evaporated to dryness to give a quantitative yield of diethyl N-[N-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-ylmethyl)-N-formyl-4-aminomethylbenzoyl]-glutamate which can be employed for further processing without further purification; 1H NMR (Me2SO d6) delta 1.11-1.18 (m, 6H), 1.24 (s, 9H), 1.9-2.15 (m, 2H), 2.39-2.44 (m, 2H), 4.39-4.42 (m, 3H), 4.53-4.55 (m, 2H), 7.21-7.44 and 7.34-7.37 (m, 2H, AA'BB'), 7.76-7.78 and 7.81-7.84 (m, 2H, AA'BB'), 8.12 and 8.13 (s, 1H), 8.61-8.78 (m, 2H).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([NH2:25])=[O:24])=[O:20])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)=O)C1C=CC=CC=1.C[OH:30].O>[Pd].C(O)(=O)C>[O:24]=[C:23]1[NH:25][CH2:27][CH2:28][NH:21][C:22]1=[O:30].[NH2:11][C@H:12]([C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:24])=[O:30])=[O:20])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1
Reactant: NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Reactant: CO
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)O
Product: O=C1NCCNC1=O
Reaction time: 2 h

Procedure:
Benzyloxycarbonyl-L-histidyl-L-prolineamide (500 mg) was dissolved in a solution containing methanol (10 ml), H2O (0.3 ml) and glacial acetic acid (0.3 ml). After adding palladium black catalyst (100 mg), the suspension was hydrogenated under 40 pounds of pressure for 2 hours. The catalyst was then filtered and the resultant solution was heated in boiling water for 30 minutes, then dried in vacuo. After dissolving the product in water, it was purified by passage through a column (2×5 cm) of diethylaminoethylcellulose and subsequently washed with water. The Pauly positive fractions were concentrated to dryness in vacuo to yield crystalline L-histidyl-L-proline diketopiperazine (yield approximately 200 mg). Elemental analysis showed C, H, N, and O at 54.75%, 6.08%, 22.10% and 17.22% respectively. Theoretical calculated values for C, H, N and O are 53.91%, 6.25%, 22.86% and 16.97% respectively. Mass spectrographic analysis showed prominent ions at m/e 234, m/e 154, m/e 81 and m/e 70. Proton NMR showed chemical shifts at 1.95, 2.2, 3.4, 3.5, 4.65, 7.4, 8.25 ppm downfield from trimethylsilane. Amino acid analysis showed the presence of ninhydrin-positive material corresponding to only proline and histidine with a ratio of 1.1 to 1.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([C:11]2[O:15][N:14]=[CH:13][C:12]=2[C:16](=[O:29])[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[C:18]=2[S:25]([CH3:28])(=[O:27])=[O:26])[CH2:10][CH2:9]1>ClCCl>[C:13]([CH:12]([C:11]([CH:8]1[CH2:9][CH2:10]1)=[O:15])[C:16]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[C:18]=1[S:25]([CH3:28])(=[O:26])=[O:27])=[O:29])#[N:14]
Reactant: CS(=O)(=O)c1c(C(=O)c2cnoc2C2CC2)ccc(Cl)c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1c(C(=O)C(C#N)C(=O)C2CC2)ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Triethylamine (0.5 ml) was added to 5-cyclopropyl-4-(3,4-dichloro-2-methylsulphonylbenzoyl)isoxazole (1.0 g) in dichloromethane. The mixture was stirred at room temperature for 2.5 hours and evaporated to dryness. The residue was suspended in hydrochloric acid (2M) and was extracted with dichloromethane. The organic layer was washed with water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give 2-cyano-3-cyclopropyl-1-(3,4-dichloro-2-methylsulphonylphenyl)propan-1,3-dione (COMPOUND 623) as a white solid, m.p. 88°-90° C.45