Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([C:16]([F:19])([F:18])[F:17])=[CH:4][C:3]1=[O:20].CCN(CC)CC.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([C:16]([F:19])([F:18])[F:17])=[CH:4][C:3]1=[O:20]
Reactant: C1CCNCC1
Reactant: Cn1c(=O)cc(C(F)(F)F)c2cc(S(=O)(=O)Cl)ccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(=O)cc(C(F)(F)F)c2cc(S(=O)(=O)N3CCCCC3)ccc21
Reaction time: 8 h
Yield: 53.4 %

Procedure:
A solution of 1-methyl-2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonyl chloride (Preparation 1, 65 mg, 200 μmol) in anhydrous DMF (1.5 mL) was treated with NEt3 (31 μL, 220 μmol) and piperidine (21 μL, 210 μmol), before being stirred overnight under N2. The reaction mixture was diluted with EtOAc (70 mL), before being washed with H2O (30 mL), 1 M HCl (30 mL), H2O (30 mL), saturated aqueous NaHCO3 (30 mL), H2O (30 mL), and brine (30 mL). After drying (MgSO4), the organic phase was filtered and concentrated to give a residue that was recrystallised from EtOAc-PE to furnish the title compound (40 mg, 53%): δH (CDCl3)=1.40–1.50 (m, 2H), 1.60–1.70 (m, 4H), 3.05 (t, 4H), 3.80 (s, 3H), 7.20 (s, 1H), 7.55 (d, 1H), 8.00 (dd, 1H), 8.20 (d, 1H); m/z (ES+)=375.1 [M +H]+.
Reaction SMILES: C(N1CCNCC1)(OC(C)(C)C)=O.C([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:41])[NH:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[N:39]=[C:38]([CH3:40])[O:37][N:36]=3)=[CH:31][CH:30]=2)[CH2:23][CH2:22]1)(OC(C)(C)C)=O>C1(C)C=CC=CC=1>[CH3:40][C:38]1[O:37][N:36]=[C:35]([C:32]2[CH:33]=[CH:34][C:29]([NH:28][C:27]([N:24]3[CH2:25][CH2:26][NH:21][CH2:22][CH2:23]3)=[O:41])=[CH:30][CH:31]=2)[N:39]=1
Reactant: Cc1nc(-c2ccc(NC(=O)N3CCN(C(=O)OC(C)(C)C)CC3)cc2)no1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Solvent: Cc1ccccc1
Product: Cc1nc(-c2ccc(NC(=O)N3CCNCC3)cc2)no1

Procedure:
Heating with BOC-piperazine in toluene gives in a rearrangement reaction, after customary work-up, 1-BOC-4-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylcarbamoyl]-piperazine. Removal of the BOC group with TFA in CH2C2 gives 4-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl-carbamoyl]piperazine (“C”).
Reaction SMILES: OC[P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].N1[C:16]([CH3:17])=[CH:15][CH:14]=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(OCC1C=CC=CC=1)C1C=CC=CC=1.C1(O)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:62]([NH:69][NH2:70])C1C=CC=CC=1.[O-]S(C(F)(F)F)(=O)=O>C1COCC1>[CH2:62]([NH:69][NH2:70])[C:9]1[CH:8]=[CH:14][CH:15]=[CH:16][CH:17]=1.[CH2:5]([O:4][PH:3](=[O:10])[O:7][CH2:8][CH3:9])[CH3:6]
Reactant: Cc1cccc(C)n1
Reactant: CCOP(=O)(CO)OCC
Agent: NNCc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Solvent: c1ccc(COCc2ccccc2)cc1
Product: CCO[PH](=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triflate 12 was prepared from diethyl hydroxymethylphosphonate (2 g, 11.9 mmol), 2,6-lutidine (2.1 mL, 17.9 mmol), and trifluoromethanesulfonic anhydride (2.5 mL; 14.9 mmol) as described for compound 9. To a solution of phenol 8 (60 mg, 0.10 mmol) in THF (2 mL) was added Cs2CO3 (65 mg, 0.20 mmol) and triflate 12 (45 mg, 0.15 mmol) in THF (0.25 mL). The mixture was stirred at room temperature for 2 h and additional triflate (0.15 mmol) in THF (0.25 mL) was added. After 2 h the reaction mixture was partitioned between EtOAc and saturated NaCl. The organic phase was dried (MgSO4), filtered, and evaporated under reduced pressure. The crude product was chromatographed on silica gel (EtOAc) to give a residue that was purified by chromatography on silica gel (5% 2-propanol/CH2Cl2) to afford the diethylphosphonate as a foam: 1H NMR (CDCl3) δ 7.66 (d, 2H), 7.10 (d, 2H), 6.94 (d, 2H), 6.82 (d, 2H), 5.60 (d, 1H), 4.97 (d, 2H), 4.23-4.13 (m, 6H), 3.93-3.62 (m, 10H), 3.12-2.68 (m, 7H), 1.84-1.44 (m, 3H), 1.31 (t, 6H), 0.88-0.82 (2d, 6H); 31P NMR (CDCl3) δ 17.7; MS (ESI) 729 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[NH:12]1[C:20]2[C:15](=[CH:16][C:17]([CH:21]=O)=[CH:18][CH:19]=2)[CH:14]=[N:13]1>>[NH:12]1[C:20]2[C:15](=[CH:16][C:17](/[CH:21]=[C:5]3/[C:6](=[O:11])[NH:7][C:8]4[C:4]/3=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=4)=[CH:18][CH:19]=2)[CH:14]=[N:13]1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: O=Cc1ccc2[nH]ncc2c1
Product: O=C1Nc2ccc(Br)cc2/C1=C\c1ccc2[nH]ncc2c1
Yield: 10.6 %

Procedure:
The title compound was synthesized according to the method described for Example A11B except substituting 5-bromooxindole (40 mg, 0.189 mmol) and 1H-indazole-5-carbaldehyde (30 mg, 0.208 mmol) to obtain the title compound (6.8 mg, 4.0%) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.19 (s, 1H), 8.17 (s, 1H), 7.95 (s, 1H), 7.77 (s, 1H), 7.76-7.68 (m, 2H), 7.38 (d, J=8.59 Hz, 1H), 6.87 (d, J=8.59 Hz, 1H); MS ESI 340.1 [M+H]+, calcd for [C16H10BrN3O+H]+ 340.01.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:39])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]4([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31]4)=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][CH:14]=2)[CH:12]=1.[Cl-].[NH4+]>CO>[CH2:20]([C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:11]2[CH:12]=[C:7]([CH2:6][C:5]([OH:39])=[O:4])[CH:8]=[N:9][CH:10]=2)=[CH:18][CH:17]=1)([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]2([OH:35])[CH2:31][CH2:32][CH2:33][CH2:34]2)=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(CC)(c1ccc(-c2cncc(CC(=O)OC)c2)cc1)c1ccc(C#CC2(O)CCCC2)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)(c1ccc(-c2cncc(CC(=O)O)c2)cc1)c1ccc(C#CC2(O)CCCC2)c(C)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 0.1 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.1 mL, 0.176 mmol) was added to a solution of [5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 148-(1); 14.6 mg, 29.4 mmol) in methanol (0.3 mL), and the mixture was stirred at room temperature for 2.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by thin layer silica gel chromatography (dichloromethane:methanol=9:1) to give the title compound (11.5 mg, 80%).
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CS(C)=O.C(Cl)Cl.O>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:25][CH2:24]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(C)CC3)nc2c1

Procedure:
Methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv) in DMSO (8 mL) and 1-methylpiperazine (90 mg, 0.90 mmol, 2.00 equiv) were stirred for 2 hours at 125° C. in an oil bath in a 20-mL sealed tube. The resulting solution was diluted with 20 ml of DCM/H2O (1:1), extracted with 4×40 mL of DCM, and the organic layers combined. The mixture was dried over Na2SO4, filtered to remove solids, and then concentrated under vacuum, resulting in 200 mg (crude) of methyl 3-(4-methylpiperazin-1-yl)-2-phenylquinoxaline-6-carboxylate as a brown solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17](CCC(O)=O)=[CH:16][CH:15]=3)[C:11]3[CH:25]=[C:26](F)[C:27](F)=[CH:28][C:10]=3[N:9]=2)=[C:4](OCC2CCCC2)[CH:3]=1.[Br:38]C1C=CC=CC=1C1NC2C=CC=CC=2N=1.BrCC1CCCCC1>>[Br:38][C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=1[C:8]1[N:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]2[CH:25]=[CH:26][CH:27]=[CH:28][C:10]=2[N:9]=1
Reactant: Brc1ccccc1-c1nc2ccccc2[nH]1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Agent: BrCC1CCCCC1
Product: Brc1ccccc1-c1nc2ccccc2n1CC1CCCCC1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(2-bromo-phenyl)-1H-benzoimidazole and bromomethyl-cyclohexane (CAS Reg. No. 2550-36-9). Light brown solid (62%). MS (Turbo Spray): m/z=369.4 (M+H).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=O)[CH:9]=2)[N:4]2[C:15]([CH2:18][CH2:19][CH3:20])=[N:16][N:17]=[C:3]12.[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][NH:22]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>O.CN(C)C=O>[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][N:22]1[C:12]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]1[C:15]([CH2:18][CH2:19][CH3:20])=[N:16][N:17]=[C:3]1[C:2](=[O:1])[NH:11]2)=[O:14]
Reactant: c1ccc2c(c1)CCNC2
Reactant: CCCc1nnc2c(=O)[nH]c3cc(C(=O)O)ccc3n12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1nnc2c(=O)[nH]c3cc(C(=O)N4CCc5ccccc5C4)ccc3n12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
To a mixture of 125 mg of 4-oxo-1-propyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylic acid, 73 mg of 1,2,3,4-tetrahydroisoquinoline, 0.26 mL of diisopropylethylamine, and 3 mL of N,N-dimethylformamide was added 262 mg of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, followed by stirring at room temperature overnight. To the reaction liquid was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=99/1 to 95/5). The obtained solid was washed with 2 mL of hot methanol to obtain 159 mg of 7-(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)-1-propyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].[F:36][C:37]1[CH:59]=[CH:58][C:40]([CH2:41][N:42]2[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=3[N:44]=[C:43]2[C:51]2([OH:57])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)=[CH:39][CH:38]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CO>CN(C)C=O.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:54]2[CH2:55][CH2:56][C:51]([C:43]3[N:42]([CH2:41][C:40]4[CH:58]=[CH:59][C:37]([F:36])=[CH:38][CH:39]=4)[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=4[N:44]=3)([OH:57])[CH2:52][CH2:53]2)([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[CH2:9]1)=[O:7]
Reactant: COc1ccc(C2(CCS(C)(=O)=O)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC
Reactant: OC1(c2nc3ccccc3n2Cc2ccc(F)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(C2(CCN3CCC(O)(c4nc5ccccc5n4Cc4ccc(F)cc4)CC3)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC
Temperature: 72.5 °C
Reaction time: 96 h

Procedure:
Combine 1-(3,4,5-trimethoxy-benzoyl)-3-(3,4-dimethoxy-phenyl)-3-(2-methanesulfonyl-ethyl)-pyrrolidine (0.70 g, 1.3 mmol) and 4-[1-(4-fluoro-benzyl)-1 H-benzoimidazol-2-yl]-4-hydroxy-piperidine (0.58 g, 1.8 mmol), and potassium carbonate (0.37 g, 2.7 mmol) in dimethylformamide (22 mL). Heat to 70-75° C. After 4 days, cool and evaporate in vacuo to obtain a residue. Partition the residue between ethyl acetate and water. Extract the organic layer with water and a saturated solution of potassium carbonate. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 2/1 ethyl acetate/methanol to give a foam. Combine the foam with dichloromethane and extract with 5% sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain the title compound: Rf=0.37 (silica gel, 2/1 ethyl acetate/methanol); mp; 110-120° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12](=[O:14])[N:11]([CH3:15])[CH2:10][CH2:9]2.Cl[C:17]1[CH:22]=[C:21]([Cl:23])[N:20]=[CH:19][C:18]=1[C:24]#[N:25]>C1COCC1.CCOC(C)=O>[Cl:23][C:21]1[N:20]=[CH:19][C:18]([C:24]#[N:25])=[C:17]([NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:13]=2[C:12](=[O:14])[N:11]([CH3:15])[CH2:10][CH2:9]3)[CH:22]=1
Reactant: CN1CCc2cccc(N)c2C1=O
Reactant: N#Cc1cnc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCc2cccc(Nc3cc(Cl)ncc3C#N)c2C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 21.2 %

Procedure:
Sodium hydride (2.78 g, 69.46 mmol) was added portionwise to 8-amino-2-methyl-3,4-dihydroisoquinolin-1-one (3.06 g, 17.37 mmol), in THF (8 mL) under an atmosphere of nitrogen. The resulting suspension was stirred at room temperature for 20 minutes and then 4,6-dichloropyridine-3-carbonitrile (3.00 g, 17.37 mmol) was added portionwise and the mixture heated overnight at 60° C. The mixture was allowed to cool to room temperature and then diluted with EtOAc (100 mL). The mixture was washed sequentially with water (100 mL), a saturated solution of NaHCO3 (100 mL), and finally with a saturated solution of NaCl (100 mL). The organic layer was dried over MgSO4 and then evaporated. The residue was loaded onto an SCX column and the product was eluted using a mixture of MeOH in CH2Cl2. Fractions containing product were combined and evaporated. The residue was purified by chromatography on silica, eluting with a gradient of 50-70% EtOAc in isohexane. Fractions containing the required product were combined and evaporated to afford 6-chloro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridine-3-carbonitrile (1.149 g, 21% yield). The mixed fractions were combined and repurified by silica chromatography, eluting with a gradient of 0-20% EtOAc in CH2Cl2. Fractions containing the required product were combined and evaporated to leave 6-chloro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridine-3-carbonitrile (1.287 g, 24% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 2.98 (2H, t), 3.06 (3H, s), 3.58 (2H, t), 7.07 (1H, dd), 7.36 (1H, s), 7.48-7.52 (2H, m), 8.63 (1H, s), 12.00 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=313.34 and 315.33.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.CC1CCCCC1>>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1
Reactant: COc1ccc(O)cc1
Solvent: CC1CCCCC1
Product: COC1CCC(=O)CC1

Procedure:
The procedure of Example I was repeated, but the p-methoxyphenol was used in molten form without addition of methylcyclohexane. After a hydrogenation time of 380 minutes, 62.1% by weight of the p-methoxyphenol had reacted and p-methoxycyclohexanone had been formed in a yield of 46.5% by weight.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][N:9]=2)=[CH:4][CH:3]=1.C1(SSC2C=CC=CC=2)C=CC=CC=1>C1C2C(=CC=CC=2)CCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1CCN=C2c1ccc(Cl)cc1
Agent: c1ccc(SSc2ccccc2)cc1
Solvent: c1ccc2c(c1)CCCC2
Product: Cc1cccc2c(-c3ccc(Cl)cc3)nccc12
Yield: 60.5 %

Procedure:
A mixture of 30 g of 1-(4-chlorophenyl)-5-methyl-3,4-dihydroisoquinoline and 30 g of diphenyl disulfide was dissolved in 800 ml of tetralin, and the solution was heated. After the reaction, the tetralin was distilled off under reduced pressure. The residue was dissolved in benzene, and extracted with a 2 N aqueous solution of hydrochloric acid. The aqueous layer was neutralized with an aqueous solution of sodium hydroxide, extracted with ether, and dried, followed by distilling off the solvent. Recrystallization of the residue from benzenecyclohexane afforded 18 g of 1-(4-chlorophenyl)-5-methylisoquinoline as colorless needles having a melting point of 122° to 123.5° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2.[H-].[Na+].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1.[Cl-].[NH4+]>CN(C)C=O>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[N:7]([CH2:26][C:25]2[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2
Reactant: CS(=O)(=O)c1ccc2[nH]c(C3CCCO3)cc2c1
Reactant: Fc1ccc(CBr)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc2c(c1)cc(C1CCCO1)n2Cc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a solution of the compound obtained in Example 13 (2) (113 mg) in N,N-dimethylformamide (5 ml), 60% sodium hydride (25.6 mg) was added under nitrogen atmosphere at 0° C. and the mixture was stirred for 30 minutes, followed by addition of 4-fluorobenzyl bromide (121 mg), and the mixture was stirred for 1 hour. The reaction solution was then poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (hexane:ethyl acetate=1:1) to obtain 139 mg of the desired product as a white powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:8][CH:7]=1)=[O:5])C.[Li+].[OH-].O.C1COCC1>C(OCC)(=O)C>[N:16]1([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)c1ccc(N2CCCC2)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc(N2CCCC2)c2ccccc12
Yield: 67.8 %

Procedure:
154BG19 (30 mg, 0.11 mmol) was transferred to a Pyrex tube and LiOH×H2O (14 mg, 0.33 mmol) was added, followed by H2O (0.18 mL) and THF (0.37 mL). The tube was capped and the reaction tube was exposed to microwave irradiation (160° C., 5 min). The reaction mixture was transferred to a separation funnel with ethyl acetate and washed with 2 M NaOH. The aqueous phase was acidified with 2 M HCl and extracted with ethyl acetate. The organic phases were collected, dried over Na2SO4, filtered and concentrated to yield 18 mg (68%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:31]([I:32])=[CH:30][C:5]([CH2:6][C@H:7]2[C@H:15]3[C@@H:11]([N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=4)[C:13](=[O:16])[O:14]3)[CH2:10][S:9](=[O:29])(=[O:28])[CH2:8]2)=[CH:4][C:3]=1[F:33].CO[CH:36](OC)[N:37]([CH3:39])[CH3:38]>C1(C)C=CC=CC=1>[C:24]([C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:12]1[C@@H:11]2[C@H:15]([C@H:7]([CH2:6][C:5]3[CH:30]=[C:31]([I:32])[C:2]([N:1]=[CH:36][N:37]([CH3:39])[CH3:38])=[C:3]([F:33])[CH:4]=3)[CH2:8][S:9](=[O:28])(=[O:29])[CH2:10]2)[O:14][C:13]1=[O:16])([CH3:27])([CH3:25])[CH3:26]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4cc(F)c(N)c(I)c4)CS(=O)(=O)C[C@@H]32)c1
Solvent: Cc1ccccc1
Product: CN(C)C=Nc1c(F)cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc1I
Temperature: 150 °C

Procedure:
To a suspension of (3aR,7S,7aS)-7-(4-amino-3-fluoro-5-iodo-benzyl)-3-(3-tert-butyl-benzyl)-5,5-dioxo-hexahydro-1-oxa-5lambda*6*-thia-3-aza-inden-2-one (2.0 g, 3.2 mmol) in toluene (20 mL) was added N,N-dimethylformamid-dimethylacetal (1.18 g, 9.6 mmol) and the reaction mixture was heated in the microwave oven for 0.5 h at 150° C. After evaporation the residue was purified by chromatography (CombiFlash, 40 g silica gel, hexane-EtOAc 10:1 to EtOAc) to yield the title compound as beige crystals: TLC (hexane-EtOAc 1:1) Rf=0.39; HPLC RtA=1.92 min; ESIMS [M+H]+=641; 1H NMR (400 MHz, CDCl3): δ 7.58 (d, 1H), 7.35 (m, 3H), 7.09 (d, 1H), 6.82 (dd, 1H), 4.54 (d, 1H), 4.33 (d, 1H), 3.83 (dt, 1H), 3.76 (t, 1H), 3.1 (m, 2H), 3.08 (s, 3H), 3.02 (s, 3H), 2.83 (t, 1H), 2.74 (dd, 1H), 2.58 (m, 2H), 1.31 (s, 9H).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.CN(C)C=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:25]([CH3:26])=[C:24]([C:27]([OH:29])=[O:28])[CH:23]=[N:22]2)=[CH:17][CH:16]=1>O>[CH3:1][O:28][C:27]([C:24]1[CH:23]=[N:22][N:21]([C:18]2[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=2)[C:25]=1[CH3:26])=[O:29]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cnn(-c2ccc(Cl)cc2)c1C
Reaction time: 5 h
Yield: 99.1 %

Procedure:
Potassium carbonate (8.76 g) and methyl iodide (3.15 ml) were added to a N,N-dimethylformamide solution (42 ml) of 1-(4-chlorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid (10.0 g) in Reference Example 3 at room temperature and stirred for five hours. Potassium carbonate (4.08 g) and methyl iodide (2.1 ml) were subsequently added and the mixture was stirred further for three hours at room temperature. After completion of the reaction, water (200 ml) was added and the precipitated solid was collected by filtration to give 1-(4-chlorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid methyl ester (10.5 g) as a pale yellow solid.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([N:10]1[CH2:24][CH2:23][CH2:22][C@H:11]1[C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl.[CH2:37]([P:44](Cl)([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:45])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C=O)C.O.C(=O)(O)[O-].[Na+]>[CH2:46]([P:44]([NH:1][C@H:2]([C:8]([N:10]1[CH2:24][CH2:23][CH2:22][C@H:11]1[C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[OH:7])([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:45])[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: N[C@@H](CCC(=O)O)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=P(Cl)(Cc1ccccc1)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)CC[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Temperature: -5 °C
Reaction time: 3 h

Procedure:
The thus obtained amorphous L-glutamyl-L-prolyl-L-proline was dissolved in DMF (8 ml) and water (2 ml), and neutralized by addition of triethylamine (0.2 ml) while cooling to -5° C. Dibenzylphosphorylchloride carbon tetrachloride solution (3 m mole) and triethylamine were added dropwise to the mixture while keeping the temperature to not more than 5° C. and usually keeping the pH value to 8-9. The mixture was stirred for 3 hours at room temperature, and the solution was distilled under reduced pressure leaving a residue. The residue was dissolved in 5% sodium bicarbonate and then washed with ethyl acetate. The aqueous phase was acidified with 1N hydrochloric acid, and the desired product was extracted with ethyl acetate. The ethyl acetate phase was washed with sodium chloride solution and dried with anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure. The residue was re-precipitated with ethyl acetate-ethyl ether to obtain dibenzylphosphoryl-L-glutamyl-L-prolyl-L-proline (140 mg).