Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([OH:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.[OH-].[Ca+2].[OH-].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].Cl>O1CCOCC1>[CH3:1][C:2]1[NH:3][N:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:5](=[O:7])[C:6]=1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1cc(O)n(-c2ccccc2)n1
Agent: Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1[nH]n(-c2ccccc2)c(=O)c1C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
A suspension of 3-methyl-1-phenyl-1H-pyrazol-5-ol (10.0 g, 57 mmol) and calcium hydroxide (8.5 g, 115 mmol) in dry 1,4-dioxane (100 mL) was heated to 50° C. for 20 min. The suspension was chilled to 10° C. and benzyl chloroformate (8.2 ml, 57 mmol) was in dioxane (10 mL) added. The resultant was heated to 90° C. for 3 h, cooled to 25° C. and then, chilled (0° C.) 1 M HCl (200 mL) was added. The mixture was stirred at 25° C. overnight. A solid collected by filtration was washed with cold EtOH (2×25 mL) and ether (50 mL), dried at 80° C. (sand bath) exposed to air for 4 h to give the title compound (14.0 g, 79% yield) as an off-white solid. MS (ESI pos. ion) m/z: 309 (MH+). Calc'd exact mass for C18H16N2O3 308.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][CH2:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)(=[O:12])=[O:11].[SH:23][C:24]1[C:33]([C:34]([NH:36][CH2:37][C:38]2[S:39][CH:40]=[CH:41][CH:42]=2)=[O:35])=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1.C(Cl)Cl>CC(C)=O>[S:39]1[CH:40]=[CH:41][CH:42]=[C:38]1[CH2:37][NH:36][C:34]([C:33]1[C:24]([S:23][CH2:8][CH2:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)(=[O:12])=[O:11])=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:35]
Reactant: O=C(NCc1cccs1)c1cc2ccccc2nc1S
Reactant: O=S(=O)(CCCl)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=C(NCc1cccs1)c1cc2ccccc2nc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 70 °C
Yield: 30 %

Procedure:
151 mg (1.1 mmol) K2CO3 and 300 mg (1.1 mmol) 1-(2-chloroethylsulfonyl)-3-(trifluoromethyl)benzene were added to a solution of 300 mg (1.0 mmol) 2-mercapto-N-(thiophen-2-ylmethyl)quinoline-3-carboxamide (precursor VVV02) in acetone (10 ml) at RT and the mixture was heated for 3 h at 70° C. Then it was filtered and the filtrate was concentrated to small volume under vacuum. The residue was taken up with EE and washed with water and brine, dried over MgSO4, filtered and concentrated to small volume under vacuum. Column chromatography (DCM/EE 20:1) of the residue yielded 163 mg (0.3 mmol, 30%) N-(2-thienylmethyl)-2-[2-[3-(trifluoromethyl)-phenyl]sulfonylethylthio]-3-quinoline carboxamide. MS: m/z 537.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:13])([CH3:12])[CH2:4][C:3]1=[O:14].[Cl-].[Al+3].[Cl-].[Cl-].[C:19](Cl)(=[O:21])[CH3:20]>C(=S)=S>[C:19]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[N:2]([CH3:1])[C:3](=[O:14])[CH2:4][C:5]2([CH3:12])[CH3:13])(=[O:21])[CH3:20]
Reactant: CN1C(=O)CC(C)(C)c2ccccc21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc2c(c1)C(C)(C)CC(=O)N2C
Temperature: 0 °C
Yield: 74.2 %

Procedure:
21.5 g of 3,4-dihydro-1,4,4-trimethyl-2(1H)-quinolinone were dissolved in 43 g of carbon disulphide and the solution was treated with 85 g of aluminum chloride. 17.8 g of acetyl chloride were slowly added dropwise thereto while cooling with ice and stirring vigorously. The mixture was subsequently heated at reflux for 1.5 hours, cooled and treated cautiously with ice-water. The resulting mixture was extracted three times with ethyl acetate and the ethyl acetate extracts were washed with water, dried and evaporated. The thus-obtained brownish oil was filtered over silica gel [eluting agent: hexane/ethyl acetate (2:1)] and then recrystallized from hexane/ethyl acetate. There were obtained 19.5 g of 6-acetyl-3,4-dihydro-1,4,4-trimethyl-2(1H)-quinolinone in the form of colourless crystals of melting point 75°-77° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[CH3:48][C:49]12[CH2:56][CH:53]([NH:54][CH2:55]1)[CH2:52][C:51]([CH3:58])([CH3:57])[CH2:50]2>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:54]2[CH2:55][C:49]3([CH3:48])[CH2:56][CH:53]2[CH2:52][C:51]([CH3:58])([CH3:57])[CH2:50]3)=[O:15])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: CC1(C)CC2CC(C)(CN2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(OCc3ccccc3)cc2)C1
Reaction time: 0.17 h
Yield: 76.6 %

Procedure:
To a mixture of 4-benzyloxy-benzoic acid (0.5 g, 2.191 mmol) and HOBT (326 mg, 2.41 mmol) in dry THF (50 ml) was added EDAC (462 mg, 2.41 mmol). The resulting mixture was stirred for 10 min. followed by addition of a mixture of DIPEA (420 μl, 2.41 mmol) and 1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane (410 μl, 2.41 mmol). The reaction mixture was stirred for an additional 16 hrs. and evaporated to dryness. To the residue was added water (50 ml) and the resulting mixture was extracted with EtOAc (2×50 ml). The combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo. The resulting residue was purified by column chromatography (silica gel) using a mixture of EtOAc-Heptane (1:3) as eluent. Pure fractions were collected and evaporated to dryness affording 610 mg (77%) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[O:3][C:4]1[CH:45]=[CH:44][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18]3[S:19][C:20]4[C:25](Cl)=[N:24][C:23]([CH:27]5[CH2:29][CH2:28]5)=[N:22][C:21]=4[N:30]=3)[CH2:15][CH2:14][N:13]2[S:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[O:11])=[CH:6][CH:5]=1.C([O-])=O.[NH4+]>C(O)C.C(OCC)(=O)C.[C].[Pd]>[F:47][C:2]([F:1])([F:46])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18]3[S:19][C:20]4[CH:25]=[N:24][C:23]([CH:27]5[CH2:29][CH2:28]5)=[N:22][C:21]=4[N:30]=3)[CH2:15][CH2:14][N:13]2[S:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:41])([F:42])[F:43])=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[O:11])=[CH:44][CH:45]=1
Reactant: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3nc(C4CC4)nc(Cl)c3s2)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3nc(C4CC4)ncc3s2)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a mixture of the compound (0.99 g) obtained in Step 3 and ammonium formate (0.86 g) in ethanol (10 ml) was added 10% palladium carbon (0.50 g) at 80° C. After stirring at 80° C. for 30 min, ammonium formate (0.43 g) and 10% palladium carbon (0.50 g) were added. After stirring at 80° C. for 30 min, ammonium formate (0.43 g) and 10% palladium carbon (0.50 g) were added. After stirring at 80° C. for 30 min, the reaction mixture was allowed to return to room temperature, and the reaction mixture was diluted with ethyl acetate. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=7:3-8:2) to give the title compound (0.71 g).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20]([CH3:24])=[N:19][CH2:18][CH2:17]2.C(N(CC)CC)C>ClCCl>[CH2:5]([O:4][C:2]([N:19]1[CH2:18][CH2:17][C:16]2[C:21](=[CH:22][CH:23]=[C:14]([O:13][CH3:12])[CH:15]=2)[C:20]1=[CH2:24])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc2c(c1)CCN=C2C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C1c2ccc(OC)cc2CCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Benzyl chloroformate (0.30 mL) was added to an ice-cold solution of 6-methoxy-1-methyl-3,4-dihydroisoquinoline (0.36 g) and triethylamine (0.58 mL) in 10 mL dichloromethane. After 0.5 h, the volatile material was evaporated to furnish 0.66 g of 6-methoxy-1-methylene-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester.
Reaction SMILES: [C:1]1([N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([CH:18]=O)[CH:12]=[CH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][C:27]1[S:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1.[OH-].[K+].CS(C)=O>O>[S:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[CH:26]=[CH:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:17]=[CH:16]2
Reactant: Cc1nc2ccccc2s1
Reactant: O=Cc1ccc2cc(N(c3ccccc3)c3ccccc3)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C(=Cc1nc2ccccc2s1)c1ccc2cc(N(c3ccccc3)c3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
A mixture of N,N-diphenyl-6-amino-2-naphthaldehyde (4.8 g, 0.015 mol.), 2-methyl benzothiazole (3.0 g, 0.020 mol.), powdered potassium hydroxide (18.0 g, 0.32 mol.) and DMSO (30 ml) was stirred at room temperature for 1 hour, poured into water, and the solids which separated were collected by filtration. These solids were purified by column chromatography on alumina using 1:3 toluene-heptane as the eluent, to give 3.6 g. of product (53% yield) m.p. 181.1-184.8° C. Recrystallization from 1:1 toluene-ethyl acetate raised the m. p. to 201.8-203.8° C. Mass Spec: m/z 454, (M+). Analysis calculated for C31H22N2S: C, 81.92; H, 4.88; N, 6.16; S, 7.04. Found: C, 81.82; H, 4.93; N; 6.04, and S; 6.91.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([C@@H:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.CCN(CC)CC.[CH3:33][C:34](OC(C)=O)=[O:35]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([C@@H:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:34](=[O:35])[CH3:33])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cnc(CN(CCCCN)[C@H]2CCCc3cccnc32)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCCCN(Cc1ncc(C)cc1C)[C@H]1CCCc2cccnc21
Yield: 41.7 %

Procedure:
To a solution of (S)-N1-(3,5-Dimethyl-pyridin-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine (56 mg, 0.17 mmol) in CH2Cl2 (3 mL) was added Et3N (70 μL, 0.50 mmol) followed by Ac2O (30 μL, 0.32 mmol). The resultant solution was stirred at room temperature for 70 minutes. The mixture was diluted with CH2Cl2 (20 mL), washed with brine (3×5 mL), dried (Na2SO4), and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 40:1:1 CH2Cl2-MeOH—NH4OH) provided 27 mg (43%) of the free base of the title compound as a colorless oil. Using General Procedure D: Conversion of the oil to the HBr salt gave COMPOUND 365 as a white solid. 1H NMR (D2O) δ 1.11-1.39 (m, 4H), 1.82-1.85 (m, 4H), 1.97-2.27 (m, 2H), 2.41-2.49 (m, 8H), 2.65-2.72 (m, 1H), 2.98 (br s, 4H), 4.17 (d, 1H, J=17.7 Hz), 4.36 (d, 1H, J=17.7 Hz), 4.48 (dd, 1H, J=5.4, 10.2 Hz), 7.86 (dd, 1H, J=7.8, 5.7 Hz), 8.22 (s, 1H), 8.34 (d, 1H, J=7.8 Hz), 8.44 (s, 1H), 8.59 (d, 1H, J=5.7 Hz); 13C NMR (D2O) δ 16.95, 17.50, 20.48, 20.60, 22.17, 25.55, 26.51, 27.82, 38.95, 52.01, 52.43, 61.54, 125.80, 136.33, 137.29, 137.53, 139.25, 140.56, 148.02, 149.11, 151.32, 174.09; ES-MS m/z 381 (M+H). Anal. Calcd. For C23H32N4O.3.0HBr.3.0H2O: C, 40.79; H, 6.10; N, 8.27; Br, 35.39. Found: C, 40.73; H, 6.04; N, 8.02; Br, 35.61.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=S)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(N=C=NC(C)C)(C)C.[NH2:22][C:23]1[CH:41]=[CH:40][C:26]([C:27]([N:29]([CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:28])=[CH:25][C:24]=1[NH:42][CH2:43][CH2:44][CH:45]1[O:49][CH2:48][CH2:47][O:46]1>O1CCCC1>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:42]([CH2:43][CH2:44][CH:45]3[O:46][CH2:47][CH2:48][O:49]3)[C:24]3[CH:25]=[C:26]([C:27]([N:29]([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:35][CH2:36][CH:37]([CH3:38])[CH3:39])=[O:28])[CH:40]=[CH:41][C:23]=3[N:22]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc(N)c(NCCC2OCCO2)c1
Reactant: CC(=O)c1ccc(N=C=S)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Nc2nc3ccc(C(=O)N(CCC(C)C)CCC(C)C)cc3n2CCC2OCCO2)cc1
Temperature: 25 °C
Yield: 66 %

Procedure:
4-acetylphenyl isothiocyanate (1.1 g, 1.2 eq) and diisopropylcarbodiimide (1.95 g, 3 eq) are successively added to a solution of 4-amino-3-{[2-(1,3-dioxolan-2-yl)ethyl]amino}-N,N-bis(3-methylbutyl)benzamide (2 g, 1 eq) in tetrahydrofuran (50 ml). The mixture is heated under reflux for 18 hours then cooled down to ambient temperature and concentrated under reduced pressure at 40° C. Water (100 ml) and dichloromethane (200 ml) are added to the residue obtained. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent:heptane/ethyl acetate 4:6) produces the expected compound in the form of a white foam (1.8 g; 66% yield).
Reaction SMILES: [N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:7])[C@H:2]([C:4]([OH:6])=O)[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:49]([O:56][C:57]([C@@H:59]1[CH2:63][C@H:62]([NH:64][C:65]([O:67][CH2:68][CH:69]2[C:81]3[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=3[C:75]3[C:70]2=[CH:71][CH:72]=[CH:73][CH:74]=3)=[O:66])[CH2:61][N:60]1[C:82](=[O:91])[C@@H:83]([NH2:90])[CH:84]1[CH2:89][CH2:88][CH2:87][CH2:86][CH2:85]1)=[O:58])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CN(C=O)C>[CH2:49]([O:56][C:57]([C@@H:59]1[CH2:63][C@H:62]([NH:64][C:65]([O:67][CH2:68][CH:69]2[C:81]3[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=3[C:75]3[C:70]2=[CH:71][CH:72]=[CH:73][CH:74]=3)=[O:66])[CH2:61][N:60]1[C:82](=[O:91])[C@@H:83]([NH:90][C:4](=[O:6])[C@@H:2]([N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:7])[CH3:3])[CH:84]1[CH2:89][CH2:88][CH2:87][CH2:86][CH2:85]1)=[O:58])[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)OCc1ccccc1)C1CCCCC1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)OCc1ccccc1)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a solution of Boc-N-Me-Ala-OH (351 mg, 1.73 mmol) in DMF at 0° C. was added DIPEA (1.27 mL, 8.85 mmol) and HATU (626 mg, 1.65 mmol). After 30 min, (2S,4S)-1-((S)-2-amino-2-cyclohexyl-acetyl)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-2-carboxylic acid benzyl ester hydrochloride (0.97 g, 1.57 mmol) was added, the cooling bath removed and the reaction stirred for 1 h. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution, water, and brine and dried over anhydrous magnesium sulfate. Concentration gave (2S,4S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-2-cyclohexyl-acetyl}-4-(9H-fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-2-carboxylic acid benzyl ester (1.2 g) as an oil that was used without further purification or characterization.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:3]=1.Cl[CH2:30][CH2:31][CH2:32][S:33](Cl)(=[O:35])=[O:34]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:12][CH2:11][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]3[CH2:30][CH2:31][CH2:32][S:33]3(=[O:35])=[O:34])=[CH:3][C:4]=2[N:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:9])[CH2:15][CH2:14]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N)cc3N3CCCC3)CC2)c(C)c1
Reactant: O=S(=O)(Cl)CCCCl
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3N3CCCC3)CC2)c(C)c1

Procedure:
Using [4-amino-2-(pyrrolidin-1-yl)phenyl][4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (268 mg) described in Preparation Example 152 and 3-chloropropane-1-sulfonyl chloride (0.11 mL) and by the reaction and treatment in the same manner as in Example 78, the title compound (31 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]2=[N:8][C:9]3[C:10]([C:24]([OH:26])=O)=[CH:11][N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[C:13](=[O:16])[C:14]=3[CH:15]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:27]1[N:31]=[CH:30][N:29]([C:32](N2C=NC=C2)=O)[CH:28]=1>C(#N)C>[CH3:30][N:29]([CH3:32])[CH2:28][CH2:27][NH:31][C:24]([C:10]1[C:9]2[N:8]=[C:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]3=[CH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:11]=1)=[O:26]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cccc2cc3c(=O)n(Cc4ccccn4)cc(C(=O)O)c3nc12
Solvent: CC#N
Product: Cc1cccc2cc3c(=O)n(Cc4ccccn4)cc(C(=O)NCCN(C)C)c3nc12
Yield: 75 %

Procedure:
From acid 18t, with a reflux time of 48 h and a recharge with an equal amount of CDI after 24 h, and obtained as a bright yellow solid (75%), mp 183-184° C., (from acetonitrile). 1H NMR (CDCl3): δ 2.25 [s, 6H, N(CH3)2], 2.57 (t, J=6.4 Hz, 2H, CH2CH2NMe2), 2.67 (s, 3H, ArCH3), 3.66 (q, J=6.1 Hz, CH2, CH2CH2NMe2), 5.30 (s, 2H, CH2Pyr), 7.10 (dd, J=7.0, 5.2 Hz, 1H, H-5′), 7.26-7.33 (m, 2H, H-3′, H-8), 7.52-7.59 (m, 2H, H-4′, H-7), 7.64 (d, J=8.2 Hz, 1H, H-9), 8.46 (d, J=4.4 Hz, 1H, H-6′), 8.66 (s, 1H, H-3), 9.02 (s, 1H, H-10), 10.79 (br t, J=5.1 Hz, 1H, CONH). 13C NMR (CDCl3): δ 18.3 (ArCH3), 37.3 (CH2CH2NMe2), 45.2 [N(CH3)2], 53.7 (CH2Pyr), 58.6 (CH2CH2NMe2), 109.6 (C-4), 119.1 (C-10a), 122.1 (CH, C-3′), 122.7 (CH, C-5′), 125.5 (C-9a), 126.4 (CH, C-8), 127.0 (CH, C-9), 132.6 (CH, C-7), 135.6 (C-6), 136.7 (CH, C-4′), 139.6 (CH, C-10), 143.4 (CH, C-3), 147.7 (C-5a), 148.5 (C-4a), 149.6 (CH, C-6′), 155.0 (C-2′), 162.2 (C-1), 164.3 (CONH).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.Cl.[CH2:14]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH2:27][CH:26]([O:30][NH2:31])[CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.ON1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:14]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH2:27][CH:26]([O:30][N:31]2[C:37](=[O:38])[C:36]3=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]3[C:34]2=[O:43])[CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: NOC1CCCN(C(=O)OCc2ccccc2)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCCC(ON2C(=O)c3ccccc3C2=O)C1
Reaction time: 4 h
Yield: 90.7 %

Procedure:
10.05 g of diethylazodicarboxylate were added at 25° C. over 30 minutes to a solution of 10.8 g of the product of Step A, 8.24 g of N-hydroxyphthalimide and 13.25 g of triphenylphosphine in 225 ml of tetrahydrofuran and the mixture was stirred for 4 hours. Then, the solvent was evaporated under reduced pressure and the residue was chromatographed on silica (eluant: ethyl acetate-hexane 1-1) to obtain 13 g of the expected product in the form of 2 diastereoisomers.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27]C)=[O:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+].Cl>O1CCCC1>[CH2:1]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccccc1-c1ccc(-c2ccc(C(=O)OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCOc1ccccc1-c1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 80 °C
Yield: 100.5 %

Procedure:
A mixture of 4-(n-pentyloxyphenyl)-4'-methoxycarbonylbiphenyl (220 mg, 0.58 mmol) and 5N sodium hydroxide (1.17 mL, 5.88 mmol) in tetrahydrofuran (20 mL) was heated at 80° C. under reflux for a period of 18 h. The cooled mixture was acidified with 1N hydrochloric acid (35 mL) and partitioned between ethyl acetate and water. The organic suspension was washed with water (3×) and brine. The organic layer was then filtered to give the carboxylic acid, 4-(n-pentyloxyphenyl)-4'-carboxybiphenyl (210 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([OH:29])=[CH:27][C:26]=1[OH:32].Cl>C1(C)C(C)=CC=CC=1>[Cl:24][C:25]1[C:26]([OH:32])=[CH:27][C:28]([OH:29])=[C:30]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:3]=2)[CH:31]=1
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Reactant: Oc1ccc(Cl)c(O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: Oc1cc(O)c(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)cc1Cl
Temperature: 80 °C

Procedure:
To a 350 mL sulfonation flask equipped with a mechanical stirrer, condenser and a nitrogen atmosphere are charged 26.8 g (100 mmol) of 2-chloro-4,6-diphenyl-s-triazine, and 100 mL of xylene (mixture of isomers). To the beige suspension are added 14.9 g (112 mmol) of aluminum chloride in one portion. The mixture is warmed to ca. 80° C. for 2 hours. 17.4 g (120 mmol) of 4-chlororesorcinol are then added in five portions over 40 minutes to the now homogeneous solution. The reaction mixture is heated at 90° C. for 42 hours and refluxed for another 24 hours. After cooling to room temperature, the contents of the flask are poured into 100 mL of 12% aqueous hydrochloric acid. The precipitate formed is removed by filtration, washed to pH 7 with water, rinsed with methanol and dried at 70° C. under vacuum. The title compound is obtained as a crude ocher-red product (29.5 g) and melts at 255°-265° C. It can be used without further purification.