Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[OH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([O:12][CH3:13])[CH:7]=1.[OH-].[Na+]>C(O)C>[Br:1][C:11]1[C:6]([CH2:5][CH2:4][OH:3])=[CH:7][C:8]([O:12][CH3:13])=[N:9][CH:10]=1
Reactant: COc1cc(CCO)ccn1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(CCO)c(Br)cn1
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
Bromine (2.95 g, 18.4 mmol) was slowly added to a stirred solution of 4-(2-hydroxyethyl)-2-methoxypyridine (1.4 g, 9.2 mmol) in 15 mL of absolute ethanol at 0° C., and the reaction mixture was stirred at this temperature for 30 min. The mixture was neutralized by the addition of 2 N aq. NaOH and extracted with EtOAc (50 mL×3). The organic layers were combined and washed with 5% aq. NaHSO3 and brine, dried (Na2SO4), and concentrated. The residue was purified by chromatography with hexane/EtOAc (4:1) to afford 5-bromo-4-(2-hydroxyethyl)-2-methoxypyridine (1.93 g, 91%). 1H NMR (CDCl3) δ 8.14 (s, 1H), 6.68 (s, 1H), 3.86 (s, 3H), 3.85 (t, 2H, J=6.6 Hz), 3.13 (br s, 1H), 2.90 (t, 2H, J=6.6 Hz); 13C NMR (CDCl3) δ 163.27, 149.24, 148.00, 114.41, 112.60, 60.56, 53.63, 38.34.
Reaction SMILES: [B:1]([OH:4])([OH:3])[OH:2].[OH:5][CH2:6][CH:7]([CH2:9]O)[OH:8].[CH2:11]([N:15]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:16][CH2:17][OH:18])[CH2:12][CH2:13][CH3:14]>C1(C)C=CC=CC=1>[CH2:11]([N:15]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:16][CH2:17][OH:18])[CH2:12][CH2:13][CH3:14].[B:1]([O:4][CH2:9][CH:7]([CH2:6][OH:5])[OH:8])([OH:3])[OH:2]
Reactant: OCC(O)CO
Reactant: OB(O)O
Agent: CCCCN(CCO)CCCC
Solvent: Cc1ccccc1
Product: OCC(O)COB(O)O
Reaction time: 8 h

Procedure:
N,N-dibutylethanolamine glycerol borate was prepared as follows. Boric acid (10.3 grams), glycerol (15.3 grams), and N,N-dibutylethanolamine (28.9 grams) were added to a 250 milliliter flask. One hundred fifty milliliters of toluene was then added. The reaction was allowed to proceed overnight at 110° C., and the byproduct water (˜9 grams) was continuously removed from the reaction by azeotropic distillation. The final solution was evaporated to remove toluene under vacuum, and a brownish viscous liquid product (˜45 grams) of N,N-dibutylethanolamine/glycerol borate was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[C:12]1([CH3:21])[CH:17]=[CH:16][CH:15]=[C:14](B(O)O)[CH:13]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>ClCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C:14]2[CH:13]=[C:12]([CH3:21])[CH:17]=[CH:16][CH:15]=2)=[C:4]([Cl:11])[N:3]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: ClCCl
Product: Cc1cccc(-n2cnc3c(Cl)nc(Cl)nc32)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
2,6-Dichloropurine (1.3 mmol), m-Tolyl boronic acid (4.0 mmol), anhydrous cupric acetate (1.32 mmol), 4 Å molecular sieves (1 g) [1,10]-Phenanthroline (2.64 mmol) in 25 ml of anhydrous dichloromethane were stirred at room temperature in a round bottomed flask. The reaction mixture was stirred at room temperature and monitored by TLC, LC-MS. Reaction was complete after 24 h. The molecular sieves and inorganic material were removed by filtration through a celite bed. The bed was thoroughly washed with methanol. The combined organics were purified by flash chromatography to yield 50% of the desired compound as a solid. m/z: 279.02 [MH]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[C:15]([O:22][CH2:23][CH3:24])[CH:14]=3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[C:25]([O:28][C@@H:29]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[O:32][C@H:30]1O)(=[O:27])[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:25]([O:28][C@@H:29]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[O:32][C@H:30]1[O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[C:15]([O:22][CH2:23][CH3:24])[CH:14]=3)[S:11][CH:12]=2)=[CH:4][CH:3]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC[C@H]1O[C@@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCOc1ccc(-c2nc(-c3ccc(O)cc3)cs2)cc1OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOc1ccc(-c2nc(-c3ccc(O[C@@H]4O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)cc3)cs2)cc1OCC
Temperature: 25 °C
Reaction time: 14 h
Yield: 56.3 %

Procedure:
In 45 ml of tetrahydrofuran were dissolved 1.5 g of 4-(4-hydroxyphenyl)-2-(3,4-diethoxyphenyl)thiazole, 1.4 g of 2,3,4,6-tetra-O-acetyl-β-D-glucopyranose and 1.3 g of triphenylphosphine. Thereto was added, in small portions at 0° C., a solution of 0.9 g of diethyl azodicarboxylate dissolved in 5 ml of tetrahydrofuran. The mixture was stirred at room temperature for 14 hours. The solvent was removed by distillation. The residue was purified by silica gel column chromatography (elutant: dichloromethane) and recrystallized from ethyl acetate-n-hexane to obtain 1.52 g of 4-[4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)phenyl]-2-(3,4-diethoxyphenyl)thiazole.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:21][C:22]2[CH:26]=[C:25]([O:27][CH:28]([CH3:30])[CH3:29])[NH:24][N:23]=2)=[N:4][C:5]([NH:10][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:12][OH:13])=[C:6]([CH:9]=1)[C:7]#[N:8].[OH-:31].[K+].OO>CO>[F:1][C:2]1[C:3]([NH:21][C:22]2[CH:26]=[C:25]([O:27][CH:28]([CH3:30])[CH3:29])[NH:24][N:23]=2)=[N:4][C:5]([NH:10][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:12][OH:13])=[C:6]([CH:9]=1)[C:7]([NH2:8])=[O:31]
Reactant: [OH-]
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](CO)c3ccc(F)cc3)c(C#N)cc2F)n[nH]1
Agent: OO
Agent: [K+]
Solvent: CO
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](CO)c3ccc(F)cc3)c(C(N)=O)cc2F)n[nH]1
Temperature: 65 °C
Yield: 85.6 %

Procedure:
(R)-5-Fluoro-2-(1-(4-fluorophenyl)-2-hydroxyethylamino)-6-(5-isopropoxy-1H-pyrazol-3-ylamino)nicotinonitrile (Example 11; 0.06 g, 0.1 mmol) was placed in MeOH (5 ml) at 25° C. A 25% aqueous solution (0.2 ml) of KOH (0.05 g, 0.7 mmol) was then added, followed by the addition of 0.05 ml of 30% H2O2. The resulting dark red solution was heated to 65° C. for 1 h, cooled to 25° C., and concentrated. The resulting residue was dissolved in EtOAc (50 ml), washed with water (30 ml), dried, filtered, and concentrated. The resulting solid was purified by column chromatography (DCM-MeOH=30:1) to give the title compound (0.037 g, 60%). 1H NMR (400 MHz, CD3OD) δ 7.75 (d, J=11.9 Hz, 1H), 7.43-7.39 (m, 2H), 7.06-7.02 (m, 2H), 5.37 (br s, 1H), 5.10-5.02 (m, 1H), 4.60-4.54 (m, 1H), 3.90-3.86 (m, 1H), 3.79-3.74 (m, 1H), 1.32 (d, J=6.0 Hz, 6H). MS: Calcd.: 432. Found: [M+H]+433.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH3:16])[C:13]([C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19])=[C:12](Cl)[N:11]3[CH:24]=2)[CH:5]=[CH:6][CH:7]=1.C(C1(C)CCN([C:35]2[N:40]3C=C(C(OCC)=O)N=[C:39]3[CH:38]=[C:37]([CH3:49])[C:36]=2C(=O)C(OC)=O)CC1)CC=C>>[CH2:18]([O:19][C:37]1([CH3:49])[CH2:36][CH2:35][N:40]([C:12]2[N:11]3[CH:24]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=4)[N:9]=[C:10]3[CH:15]=[C:14]([CH3:16])[C:13]=2[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19])[CH2:39][CH2:38]1)[CH:17]=[CH2:13]
Reactant: C=CCCC1(C)CCN(c2c(C(=O)C(=O)OC)c(C)cc3nc(C(=O)OCC)cn23)CC1
Reactant: COC(=O)C(=O)c1c(C)cc2nc(-c3cccc(Br)c3)cn2c1Cl
Product: C=CCOC1(C)CCN(c2c(C(=O)C(=O)OC)c(C)cc3nc(-c4cccc(Br)c4)cn23)CC1
Yield: 77 %

Procedure:
Prepared from methyl 2-(2-(3-bromophenyl)-5-chloro-7-methylimidazo[1,2-a]pyridin-6-yl)-2-oxoacetate in 77% yield following the same procedure as ethyl 5-(4-(but-3-en-1-yl)-4-methylpiperidin-1-yl)-6-(2-methoxy-2-oxoacetyl)-7-methylimidazo[1,2-a]pyridine-2-carboxylate. 1H NMR (500 MHz, CDCl3) δ 8.10 (s, 1H), 8.00 (s, 1H), 7.93 (d, J=7.6 Hz, 1H), 7.53-7.49 (m, 1H), 7.41 (br. s., 1H), 7.34 (t, J=7.8 Hz, 1H), 6.24-6.09 (m, 1H), 5.53 (d, J=16.9 Hz, 1H), 5.41 (d, J=10.2 Hz, 1H), 4.03-4.00 (m, 2H), 3.97 (s, 3H), 3.86 (t, J=11.3 Hz, 2H), 2.81 (d, J=7.6 Hz, 2H), 2.42 (s, 3H), 1.96 (d, J=12.6 Hz, 2H), 1.64 (br. s., 2H), 1.32 (s, 3H); LCMS (ESI, M+1): 526.2.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:17]=[C:16](B3OC(C)(C)C(C)(C)O3)[C:10]3[N:11]([CH3:15])[C:12](=[O:14])[NH:13][C:9]=3[CH:8]=2)=[C:5]([CH3:27])[O:4][N:3]=1.Br[C:29]1[C:38]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:37][CH:36]=[C:35]2[C:30]=1[CH:31]=[CH:32][CH:33]=[N:34]2.C([O-])([O-])=O.[Cs+].[Cs+]>ICCC.COCCOC.O>[CH3:1][C:2]1[C:6]([C:7]2[CH:17]=[C:16]([C:29]3[C:38]([O:39][C:40]([F:41])([F:42])[F:43])=[CH:37][CH:36]=[C:35]4[C:30]=3[CH:31]=[CH:32][CH:33]=[N:34]4)[C:10]3[N:11]([CH3:15])[C:12](=[O:14])[NH:13][C:9]=3[CH:8]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1cc(B2OC(C)(C)C(C)(C)O2)c2c(c1)[nH]c(=O)n2C
Reactant: FC(F)(F)Oc1ccc2ncccc2c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCI
Solvent: O
Solvent: COCCOC
Product: Cc1noc(C)c1-c1cc(-c2c(OC(F)(F)F)ccc3ncccc23)c2c(c1)[nH]c(=O)n2C
Temperature: 120 °C

Procedure:
To a microwave vial containing 5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one (52 mg, 0.14 mmol, 1 equiv.) was added 5-bromo-6-(trifluoromethoxy)quinoline (124 mg, 0.42 mmol, 3 equiv.), Cs2CO3 (230 mg, 0.70 mmol, 5 equiv.) and PEPPSI™-IPr catalyst (9.5 mg, 0.014 mmol, 0.1 equiv.) and dissolved in DME-H2O (4 mL, 0.2 M, 2/1, v/v). The mixture was heated to 120° C. for 30 min in microwave. The reaction was concentrated in vacuo and purification was then carried out by reverse phase HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[NH2:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1.F[P-](F)(F)(F)(F)F.[PH4+].C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1)=[O:8]
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Reactant: Nc1cccc(O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: [PH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a solution of the (2,4-dichloro-phenoxyacetic acid (600 mg, 2.71 mmol) and 3-amino-phenol (592 mg, 5.43 mmol) in DMF (20.0 mL) were added benzotriazol-1-yl-N-oxy-trispyrrolidino)-phosphonium hexafluorophosphate (PyBOP) (2.8 g, 5.43 mmol), and N,N-diisopropylethylamine (DIPEA) (0.95 ml, 5.43 mmol). The reaction mixture was stirred at room temperature overnight, and then partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4anh), and concentrated. Purification by silica gel column chromatography (n-Hexane:EtOAc:MeOH=10:3:1) gave 2-(2,4-Dichloro-phenoxy)-N-(3-hydroxy-phenyl)-acetamide as a white solid (837 mg, 99% yield)
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:9][CH:10]=[O:11])=[CH:4][N:3]=1.[BH4-].[Na+]>CO.C1COCC1>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH:8]=[CH:9][CH2:10][OH:11])=[CH:6][N:7]=1
Reactant: Cc1ncc(C=CC=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ncc(C=CCO)cn1
Reaction time: 0.08 h

Procedure:
To a suspension of 4-2 (0.5 g, 3.7 mmol) in MeOH (5 mL) and THF (15 mL) at −78° C. was added sodium borohydride (0.042 g, 1.11 mmol) in one portion. After 5 minutes, the cooling bath was removed, and the mixture allowed to warm and stir for 10 minutes. Concentrated HCl (0.3 mL) was added dropwise, and the volume of the mixture reduced to 2 mL by evaporation. Following the addition of sat. NaHCO3 (10 mL), the mixture was extracted with chloroform, the organics dried over MgSO4, and the solvents evaporated to give alcohol 4-3 as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:19]>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH2:11][Br:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cc(Br)ccc1OCc1ccccc1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: BrCc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
A solution of 2-benzyloxy-5-bromobenzyl alcohol (14.75 g, 50.2 mmol) in anhydrous ethyl ether (150 ml) was cooled to 4 ° C. A solution of PBr3 (13.68 g, 50 mmol) in anhydrous ether (40 ml) was added dropwise keeping the temperature below 10 ° C. The reaction was allowed to warm to ambient temperature and stirred for 1 hour. The reaction was filtered through silica gel (200 g). The silica gel was washed with ethyl ether to remove all the product. The filtrate was washed with water (1×150 ml), aqueous saturated sodium hydrogen carbonate (1×150 ml) and brine (1×150 ml). The organic layer was dried (Na2SO4) and evaporated to give 2-benzyloxy-5-bromobenzylbromide as a pale yellow oil (15.2 g, 85%) which crystallized on standing.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21]C)=[O:20])[CH:17]=4)[N:12](S(C4C=CC(C)=CC=4)(=O)=O)[CH:11]=3)[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[OH-].[K+]>CO.O>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=4)[NH:12][CH:11]=3)[CH:7]=[N:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc2c(c1)c(-c1cncc(C3CC3)n1)cn2S(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2[nH]cc(-c3cncc(C4CC4)n3)c2c1
Temperature: 60 °C
Yield: 94.8 %

Procedure:
An orange-brown suspension of methyl 3-(6-cyclopropylpyrazin-2-yl)-1-tosyl-1H-indole-5-carboxylate (353.7 mg, 0.790 mmol) and KOH (310 mg, 5.53 mmol) in a mixture of MeOH (6.0 mL) and water (1.20 mL) was heated at 60° C. for 6 h. The mixture was subsequently cooled to RT and MeOH was removed in vacuo. 1.0 N aq HCl (4.0 mL) was added to the resulting slurry, and the precipitated solid was collected by vacuum filtration, washed with water (10 mL), and dried in vacuo to provide 3-(6-cyclopropylpyrazin-2-yl)-1H-indole-5-carboxylic acid (209.2 mg, 0.749 mmol, 95%) as a yellow solid: MS (ESI, pos. ion) m/z: 280.1 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 11.96 (1H, br. s.), 9.12 (1H, s), 8.91 (1H, s), 8.33-8.40 (2H, m), 7.80 (1H, dd, J=8.3, 1.2 Hz), 7.51 (1H, d, J=8.5 Hz), 2.23 (1H, br. s.), 1.17 (2H, br. s.), 1.11 (2H, m, J=7.9 Hz).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].C(O)(=O)C.[C:10]([NH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[C:16]([F:22])[CH:15]=1)(=[O:12])[CH3:11]>O.C(O)C>[C:10]([NH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[N:1][NH:2][C:3]([NH2:5])=[S:4])=[C:16]([F:22])[CH:15]=1)(=[O:12])[CH3:11]
Reactant: NNC(N)=S
Reactant: CC(=O)Nc1ccc(C=O)c(F)c1
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1ccc(C=NNC(N)=S)c(F)c1
Reaction time: 0.5 h
Yield: 23.6 %

Procedure:
A solution of 0.182 g (0.002 mole) of thiosemicarbazide (Aldrich T3,340-5) in 6 mL of water containing 0.4 mL of acetic acid was added to a solution of 0.36 g (0.002 mole) 4-acetamido-3-fluorobenzaldehyde (20) in 5 mL of ethanol at 70°. The mixture was stirred at this temperature for 30 minutes. A white precipitate developed in the reaction mixture, which was filtered after cooling down to give 0.22 g (44% crude) of white powder which was recrystallized from methanol and dried, yielding 0.12 g (24%) of 17 as white crystals, mp 232-235° (dec.). Infrared (IR) and NMR analysis gave the following results: IR (potassium bromide): 3441, 3317, 3167,1673 (C=O), 1600, 1534,1415 cm1. 1H nmr (90 MHz, DMSO-d6):δ 11.53 (1H, s, thiosemicarbazone NH), 10.35 (1H, s, amide NH), 8.25 (1H, s, imine H), 8.08 (1H; t, 3JH5-H6=9Hz, 4JF-H6=9 Hz; H-6), 8.04 (2H; br s; thiosemicarbazone NH2), 7.7 (1H; dd, 3JF-H3=12.6 Hz, 4JH5-H3=1.8 Hz; H-3), 7.27 (1H; dd, 3JH6-H5=9 Hz, 4JH3-H5=1.8 Hz; H-5), 2.11 (3H, s, CH3). Anal. Calcd. for C10H11FN40S (254.28): C, 47.23; H, 4.36; F, 7.47; N, 22.03; S, 12.61. Found: C, 46.88; H, 4.35; F, 7.30; N, 21.62; S, 12.11.
Reaction SMILES: [N:1]1([C:7]2[N:21]=[C:10]3[N:11]=[CH:12][CH:13]=[C:14]([C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)[N:9]3[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH:23]([CH3:32])[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25].CC(O)C>C(N(CC)CC)C>[C:26]1([C:24](=[O:25])[CH:23]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[N:21]=[C:10]4[N:11]=[CH:12][CH:13]=[C:14]([C:15]5[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=5)[N:9]4[N:8]=3)[CH2:6][CH2:5]2)[CH3:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1cc(-c2ccnc3nc(N4CCNCC4)nn23)ccn1
Reactant: CC(Br)C(=O)c1ccccc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C(=O)c1ccccc1)N1CCN(c2nc3nccc(-c4ccncc4)n3n2)CC1
Yield: 27.8 %

Procedure:
A mixture of 5.6 g (0.02 moles) of 2-(1-piperazinyl)-7-(4-pyridyl)[1,2,4]triazolo[1,5-a]pyrimidine (prepared as described in Example 47) and 4.2 g (0.02 moles) of α-bromopropiophenone in 100 ml of 2-propanol containing 3.6 ml (0.026 moles) of triethylamine was heated at the reflux temperature for 24 hours. The reaction mixture was evaporated to dryness in vacuo. Then 100 ml of water was added to the residue and the mixture was extracted three times with a total of 100 ml of chloroform. The combined extracts were dried over magnesium sulfate and filtered. The filtrate was passed through a pad of magnesium silicate, washing with chloroform. The filtrate was evaporated to a syrup. The syrup was dissolved in 20 ml of ethanol and 200 ml of diethyl ether was added, then hexane was added until cloudy. The mixture was evaporated by boiling to about 100 ml, then was cooled and filtered to collect the precipitate, which was washed with ether and gave 2.3 g of the desired product as yellow crystals, mp 142°-144° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]([N:17]3[C:21](=[O:22])[C@@H:20]([CH2:23]CC(O)=O)[NH:19][C:18]3=[O:28])[CH:14](C)[CH3:15])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.C(OC(=O)N[C@H](C1NC([C:50]2[CH:55]=C[CH:53]=[CH:52][C:51]=2[F:56])=CN=1)[C@H](C1C=CC=CC=1)C)(C)(C)C.IC1C=CC(C(=O)C)=CC=1.C(OC(N[C@H](C1[CH:85]=[CH:84][C:83]([O:86][CH2:87][C:88](=[O:92])N(C)C)=[CH:82][CH:81]=1)C(O)=O)=O)(C)(C)C.ClN1C(=O)CCC1=O>>[F:56][C:51]1[CH:50]=[CH:55][C:15]([CH2:14][C@H:13]([N:17]2[C:21](=[O:22])[C@@H:20]([C:23]3[CH:85]=[CH:84][C:83]([O:86][CH2:87][CH2:88][OH:92])=[CH:82][CH:81]=3)[NH:19][C:18]2=[O:28])[C:11]2[NH:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=3)=[CH:9][N:10]=2)=[CH:53][CH:52]=1
Reactant: CC(C)[C@@H](c1ncc(-c2ccc(I)cc2)[nH]1)N1C(=O)N[C@H](CCC(=O)O)C1=O
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)c1ncc(-c2ccccc2F)[nH]1
Reactant: CN(C)C(=O)COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: CC(=O)c1ccc(I)cc1
Agent: O=C1CCC(=O)N1Cl
Product: O=C1N[C@H](c2ccc(OCCO)cc2)C(=O)N1[C@@H](Cc1ccc(F)cc1)c1ncc(-c2ccc(I)cc2)[nH]1

Procedure:
Prepared by the same method as described in example 1 except that (i) steps A, B, and C were omitted; (ii) commercially available 1-(4-iodo-phenyl)-ethanone was used in place of 1-(2-fluoro-4-iodo-phenyl)-ethanone in step 41-D; (iii) (S)-2-tert-butoxycarbonylamino-3-(4-fluoro-phenyl)-propionic acid was used in place of (2S,3S)-2-tert-butoxycarbonylamino-3-phenyl-butyric acid in step 41-E and (iv) chlorination of the 5-position of the imidazole ring with N-chlorosuccinimide in step 41-F was omitted. HR-MS: calcd for C28H24FlN4O4 [M+H+] 627.0899. Found 627.0904.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([S:20]([OH:23])(=O)=[O:21])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>CN(C=O)C>[C:1]([NH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([S:20]([Cl:26])(=[O:23])=[O:21])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1ccc(S(=O)(=O)O)c2ccccc12)c1ccccc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(S(=O)(=O)Cl)c2ccccc12)c1ccccc1
Yield: 88.2 %

Procedure:
To a solution of the pyridinium salt of 4-benzoylamino-napthalene-1-sulfonic acid (2.4 g, 5.9 mmol) in DMF (10 mL), was added thionyl chloride (0.6 mL, 8.8 mmol). The resultant solution was stirred at 25° C. for 3 hours. The reaction mixture was quenched by pouring into ice water and filtered to give the title compound (1.8 g) a pale white solid. This material was used without further purification.1H NMR (300 MHz, DMSO) δ 8.88 (d, 1H), 8.09 (d, 2H), 7.97 (d, 2H), 7.55 (m, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:18](=[O:32])[NH:19][C:20]2([C:29]([OH:31])=[O:30])[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)[CH2:9]1)=O)(C)(C)C.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].[CH2:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([C:18]([NH:19][C:20]3([C:29]([OH:31])=[O:30])[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:32])[C:15]=2[CH2:16][CH2:17][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(cccc2C(=O)NC2(C(=O)O)Cc3ccccc3C2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1cccc2c1CCNC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
5-(2-Carboxy-indan-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (72) (650 mg, 1.49 mmol) is dissolved in 30% solution of TFA in DCM (10 mL) and the resulting solution is stirred at RT for 2 h. The solution is concentrated to give a TFA salt of 2-[(1,2,3,4-tetrahydro-isoquinoline-5-carbonyl)-amino]-indan-2-carboxylic acid (670 mg, 100%). This TFA salt (250 mg, 0.56 mmol) is dissolved in 6N aqueous solution of HCl (20 mL). The resulting suspension is stirred overnight and turned into a clear solution. The solution is concentrated to give a pure product (73) as white solid (130 mg, 62%).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].C(=O)([O-])[O-].[Ca+2].ClCCl.[CH:13]([C:17]1[CH:23]=[C:22]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[C:20]([CH:31]([CH2:33][CH3:34])[CH3:32])[C:18]=1[NH2:19])([CH2:15][CH3:16])[CH3:14]>ClC(Cl)C.O>[CH:31]([C:20]1[CH:21]=[C:22]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[C:17]([CH:13]([CH2:15][CH3:16])[CH3:14])[C:18]=1[N:19]=[C:1]=[S:2])([CH2:33][CH3:34])[CH3:32]
Reactant: S=C(Cl)Cl
Reactant: CCC(C)c1cc(Cc2ccccc2)cc(C(C)CC)c1N
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CCC(C)c1cc(Cc2ccccc2)cc(C(C)CC)c1N=C=S
Reaction time: 2 h

Procedure:
14.3 g of thiophosgene, 23.0 g of calcium carbonate and 460 ml of dichloromethane are stirred with 230 ml of water. A solution of 30.8 g of 2,6-di-sec-butyl-4-benzylaniline in 200 ml of dichloroethane is stirred dropwise into this mixture at room temperature. The reaction mixture is stirred for two hours under reflux and, after cooling, is filtered over diatomaceous earth. The organic phase is separated from the filtrate, dried over sodium sulfate and freed of the solvent to give the title compound of formula ##STR15## in the form of a yellow oil which is used without further purification for the next reaction.