Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[Br:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][NH2:21])=[O:19])=[CH:16][CH:15]=1>C(O)(=O)C>[Br:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][N:21]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[O:19])=[CH:16][CH:15]=1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)c1ccc(Br)cc1
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(Br)cc1
Temperature: 100 °C
Yield: 82 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-bromobenzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 193 mg of the title compound (82%) as a yellow solid in 99.6% purity by HPLC (Rt: 6.03, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]=2[C:11](O)=[O:12])[CH:7]=1.O[N:21]1[C:25]2N=CC=CC=2N=N1.Cl.CN.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>C(OC(=O)C)C.ClCCl>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]=2[C:11]([NH:21][CH3:25])=[O:12])[CH:7]=1
Reactant: On1nnc2cccnc21
Reactant: O=C(O)c1c(-c2ccccc2)nn2cc(I)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccccc2)nn2cc(I)ccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 62.8 %

Procedure:
To a 250 mL round-bottomed flask equipped with a magnetic stir bar was charged 6-iodo-2-phenylpyrazolo[1,5-a]pyridine-3-carboxylic acid (200 mg, 0.549 mmol), 1-Hydroxy-7-azabenzotriazole (74.8 mg, 0.549 mmol), methylamine hydrochloride (55.6 mg, 0.824 mmol), diisopropylethylamine (671 μL, 3.84 mmol), dichloromethane (5000 μL) and dimethylfomamide (500 μL). To this yellow solution 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (147 mg, 0.769 mmol) was added. The reaction was stirred at room temperature for six hours and diluted with ethylacetate (200 mL). The organic portion was washed 5× with 0.5N hydrochloric acid, 1× saturated sodium bicarbonate and 2× brine. The organic portion was dried over magnesium sulfate. The solvent was removed by rotary evaporation. The residue was place under vacuum overnight to give a white solid (130 mg, 90%). 1H NMR (500 MHz, MeOD) δ ppm 2.87 (m, 3H) 7.51 (m, 3H) 7.63 (dd, J=9.31, 1.37 Hz, 1H) 7.76 (m, 3H) 8.94 (s, 1H). LCMS: 1.8 minutes, M+1=378.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:29]=[C:28]([CH2:30][N:31]4[CH2:36][CH2:35][CH:34]([C:37]([OH:40])([CH3:39])[CH3:38])[CH2:33][CH2:32]4)[CH:27]=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:3][CH2:2]1.[CH2:41]([N:43]1[C:51](I)=[C:50]2[C:45]([CH:46]=[CH:47][CH:48]=[CH:49]2)=[N:44]1)[CH3:42]>O1CCOCC1.S1C=CC=C1C([O-])=O.[Cu+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:41]([N:43]1[C:51]([C:11]2[N:12]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[C:8]3[N:29]=[C:28]([CH2:30][N:31]4[CH2:32][CH2:33][CH:34]([C:37]([OH:40])([CH3:39])[CH3:38])[CH2:35][CH2:36]4)[CH:27]=[CH:26][C:9]=3[N:10]=2)=[C:50]2[C:45]([CH:46]=[CH:47][CH:48]=[CH:49]2)=[N:44]1)[CH3:42]
Reactant: CCn1nc2ccccc2c1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)ccc2n1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: CCn1nc2ccccc2c1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)ccc2n1

Procedure:
To a degassed solution of 2-(1-((4-morpholino-2-(tributylstannyl)pyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol (0.13 g) and 2-ethyl-3-iodo-2H-indazole (1.05 eq) in 1,4-dioxane (1.5 mL) was added copper(I) thiophene-2-carboxylate (1 eq) and tetrakis(triphenylphosphine)palladium(0) (0.05 eq). The reaction was microwaved at 140° C. for 30 minutes and then loaded onto Biotage isolute scx-2 catridge and eluted with 2M ammonia in Methanol. The crude material was purified by reverse phase HPLC to afford 36.6 mg of 136. MS (Q1) 516.3 (M)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:37][CH2:38][CH:39]([OH:44])[CH2:40][CH2:41][CH2:42][CH3:43].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:26](=[O:28])[O:44][CH:39]([CH2:38][CH3:37])[CH2:40][CH2:41][CH2:42][CH3:43])=[C:18]([CH3:24])[CH:17]=1
Reactant: CCCCC(O)CC
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCC(CC)OC(=O)Nc1cc(C)c(Oc2ccnc3cc(OC)c(OC)cc23)cc1C
Yield: 82 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-heptanol (27 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (59 mg, yield 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[CH:6]2.[C:13]1([CH3:22])[CH:18]=[CH:17][C:16]([C:19](Cl)=[O:20])=[CH:15][CH:14]=1.[Cl-].[Cl-].[NH4+]>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[C:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:22])=[CH:14][CH:15]=1)=[O:20]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc2[nH]c(C)cc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn+2]
Solvent: ClCCl
Product: COc1ccc2[nH]c(C)c(C(=O)c3ccc(C)cc3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
To a solution of 5-methoxy-2-methylindole (816 mg, 5.06 mmol) in dichloromethane (15 ml) were added zinc chloride (1.52 g, 11.14 mmol) and ethyl magnesium bromide diethy ether (3.0 mol/l, 2.02 ml, 6.07 mmol) and the mixture was stirred for 1 hour at room temperature. Thereto was added p-toluoyl chloride (1.25 g, 8.10 mmol). After stirring for 1 hour, thereto was added alminium chloride (337 mg, 2.53 mmol) and the mixture was stirred at room temperature for 20 hours. To the reaction mixture was added an aqueous saturated ammonium chloride solution and the mixture was extracted with chloroform. The organic layer was washed with a saturated sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography and by recrystallization to give the subject compound (833 mg, 59%).
Reaction SMILES: [Cl:1][C:2]1[N:3]([C@@H:15]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[C:4]2[C:9]([C:10]=1[CH:11]=O)=[CH:8][C:7]([Cl:13])=[C:6]([Cl:14])[CH:5]=2.[NH:24]([C:26]([O:28][CH3:29])=[O:27])[NH2:25].O>CO>[Cl:1][CH:2]1[C:10](=[C:11]=[N:25][NH:24][C:26]([O:28][CH3:29])=[O:27])[C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]1[C@@H:15]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]1[OH:17]
Reactant: COC(=O)NN
Reactant: O=Cc1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Solvent: CO
Solvent: O
Product: COC(=O)NN=C=C1c2cc(Cl)c(Cl)cc2N([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)C1Cl
Temperature: 25 °C
Yield: 84.9 %

Procedure:
2,5,6-Trichloro-3-formyl-1-(β-D-ribofuranosyl)indole (4.3, 122 mg, 0.32 mmol) was dissolved in MeOH (10 mL) to which was added methyl hydrazinocarboxylate (115 mg, 1.3 mmol). The resulting solution was heated on a 60 C oil bath for 16 h, then cooled to room temperature and poured into 100 mL of water, and the solvent evaporated to approx 50 mL. The resulting suspension was cooled to 4C, then filtered and the solids rinsed with cold water (25 mL). The solids were recrystallized from boiling EtOAc/hexane to yield 123 mg (85%) of 4.31 as a pale pink crystalline solid: mp 217-219 C; Rf 0.2 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 11.17 (b, 1H, D2O exch.), 8.54 (s, 1H), 8.42 (s, 1H), 8.22 (b, 1H), 5.92 (d, 1H), 5.42-5.37 (m, 2H, D2O exch.), 5.25 (d, 1H, D2O exch.), 4.43 (q, 1H), 4.15 (d, 1H), 3.98 (d, 1H), 3.72 (b, 5H). 13C-NMR (125 MHz, DMSO-d6): δ 153.88, 133.17, 129.33, 126.08, 124.96, 124.06, 122.17, 115.34, 108.59, 88.76, 86.03, 71.30, 69.73, 69.62, 61.07, 52.04. HRMS (ES) m/z calcd. for C16H16Cl3N3O6·Na 474.0002, found 473.9999. Anal calcd for C16H16Cl3N3O6·¼H2O: C, 42.03; H, 3.64; N, 9.19. Found: C, 42.11; H, 3.92; N, 9.18.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:35]=[CH:34][C:9]([C:10]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C@H:15]([N:22]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:23](=[O:25])[CH3:24])[CH2:14][C@@H:13]2[CH3:33])=[O:11])=[CH:8][CH:7]=1.C[Si]([N:40]=[C:41]=[O:42])(C)C>C(Cl)Cl>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([N:22]([C@H:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]([C:10](=[O:11])[C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][C:41]([NH2:40])=[O:42])=[CH:35][CH:34]=3)[C@@H:13]([CH3:33])[CH2:14]2)[C:23](=[O:25])[CH3:24])=[CH:27][CH:28]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCN)cc2)c2ccccc21
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCNC(N)=O)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.8 %

Procedure:
To a solution of (2S,4R)-N-{1-[4-(3-Amino-propoxy)-benzoyl]-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl}-N-(4-chloro-phenyl)-acetamide (50 mg, 0.10 mmol) in DCM (1 mL) was added trimethylsilyl isocyanate (23 mg, 0.20 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched by adding 0.2 mL of water and concentrated under reduced pressure. The crude residue was purified by preparatory HPLC to afford the product (9 mg, 17%).
Reaction SMILES: CCN(CC)CC.O[C@@H:9]([CH3:32])[C@@H:10]([NH:14][C:15]([O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH2:20][CH2:19]1)=[O:16])[C:11]([OH:13])=[O:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:24]([N:21]1[CH2:22][CH2:23][CH:18]([O:17][C:15](=[O:16])[NH:14][C@H:10]2[C:11](=[O:12])[O:13][C@H:9]2[CH3:32])[CH2:19][CH2:20]1)(=[O:25])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C[C@H](O)[C@@H](NC(=O)OC1CCN(C(=O)c2ccccc2)CC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1OC(=O)[C@@H]1NC(=O)OC1CCN(C(=O)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 8.8 %

Procedure:
In a four necked round bottom flask, under Argon atmosphere, Et3N (1.2 mL, 8.56 mmol) was added to a solution of (2R,3S)-3-hydroxy-2-[({[1-(phenylcarbonyl)piperidin-4-yl]oxy}carbonyl)amino]-butanoic acid (1.0 g, 2.85 mmol) in dry CH2Cl2 (40 mL). After cooling at 0° C., HBTU (1.62 g, 4.28 mmol) was added and the mixture stirred 3 h at 0° C., then 16 h at rt. The solvent was removed under vacuum, and the resulting crude mixture was purified by column chromatography using a Teledyne ISCO apparatus, eluting with CH2Cl2/AcOEt (50:50). The resulting yellow solid was further purified trough reverse-phase automatic column chromatography, eluting with H2O/CH3CN (70:30) to afford the title compound (0.083 g, 9%) as white solid. Rf=0.47 (SiO2, CH2Cl2/AcOEt 1:1); Rf=0.39 (C18, 7:3 H2O/CH3CN). MS (ESI) m/z: 333 [M−H]+. FTIR (cm−1): 3414, 3222, 3050, 2965, 2929, 2871, 1825, 1720, 1612, 1550, 1449, 1262, 1232, 1119, 1068, 1031, 837, 711. 1H-NMR (CDCl3): δ 1.47 (d, 3H); 1.58-2.04 (m, 4H); 3.30-4.08 (m, 4H); 4.86-4.90 (m, 1H); 4.93-4.97 (m, 1H); 5.45 (t, 1H); 5.56 (br s, 1H); 7.39-7.44 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH2:14][CH3:15])[C:7]=12.[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>>[ClH:1].[CH3:12][C:9]1[N:8]([CH2:13][CH2:14][CH3:15])[C:7]2=[C:2]([NH:22][CH2:21][C:20]3[CH:23]=[CH:24][C:17]([CH3:16])=[CH:18][CH:19]=3)[N:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH3:11]
Reactant: Cc1ccc(CN)cc1
Reactant: CCCn1c(C)c(C)c2ccnc(Cl)c21
Product: CCCn1c(C)c(C)c2ccnc(NCc3ccc(C)cc3)c21
Product: Cl
Yield: 35 %

Procedure:
In accordance with the same procedures as in Step 3 of Example 198, except for using 7-chloro-2,3-dimethyl-1-propyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 and 4-methylbenzylamine, the titled compound was obtained as a white solid. (Yield: 35%)
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH2:32][OH:33])[CH:26]=1)[CH2:10][NH:11][C:12]([CH3:24])([CH3:23])[CH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[Cl:65][C:66]1[CH:67]=[CH:68][C:69]([O:75][CH3:76])=[C:70]([CH2:72][CH2:73][NH2:74])[CH:71]=1>CN(C)C(=O)C>[NH3:11].[Si:1]([O:8][C@H:9]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH2:32][OH:33])[CH:26]=1)[CH2:10][NH:11][C:12]([CH3:23])([CH3:24])[CH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([NH:74][CH2:73][CH2:72][C:70]1[CH:71]=[C:66]([Cl:65])[CH:67]=[CH:68][C:69]=1[O:75][CH3:76])=[O:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(Cc1cccc(C(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Reactant: COc1ccc(Cl)cc1CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1CCNC(=O)c1cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(O)c(CO)c2)c1
Product: N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxy methylphenyl)ethylamino]-2-methylpropyl}benzoic acid (preparation 37) (400 mg, 0.85 mmol), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (320 mg, 0.85 mmol), triethylamine (225 μL, 1.6 mmol) and 2-(5-chloro-2-methoxy-phenyl)-ethylamine (preparation 70), (64 mg, 0.85 mmol) in N,N-dimethylacetamide (8 mL) was stirred for 18 hours at room temperature. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (4 mL) and saturated sodium hydrogen carbonate solution (1 mL). The organic solution was then dried over magnesium sulfate, concentrated in vacuo and the residue was purified using an ISCO Companion® silica cartridge, eluting with dichloromethane:methanol:0.88 ammonia, 90:10:1 to 80:20:2, to afford the title compound in 22% yield.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:18]3)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][CH2:39][OH:40].[ClH:41]>CN(C)C=O.C(OCC)C.O>[ClH:41].[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[N:22]([CH2:38][CH2:39][OH:40])[C@@:16]2([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:17][CH2:18]3)[CH:4]=[C:3]([C:2]([F:29])([F:1])[F:30])[CH:8]=1
Reactant: OCCBr
Reactant: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3CC[C@]2(c2ccccc2)N3)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: OCCN1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(1R*,2R*,5R*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 60; 345 mg, 0.80 mmol) was dissolved in dimethylformamide (3 ml) and potassium carbonate (331 mg, 2.40 mmol) added. This was stirred for 5 minutes at room temperature then 2-bromoethanol (0.086 ml, 1.21 mmol) added and the reaction mixture heated for 5 days at 60° C. Only a small amount of starting material had converted to product so a further 25 equivalents of 2-bromoethanol (1.42 ml, 20 mmol) was added and the temperature increased to 80° C. overnight. The reaction mixture was poured into water and extracted with ethyl acetate (×3), dried (MgSO4) and concentrated in vacuo to give a brown oil. This was purified by flash column chromatography [5%-20% ethyl acetate in iso-hexane] to give a yellow oil and the hydrochloride salt was made by adding 1 equivalent of hydrogen chloride in diethyl ether (1N). The title compound was filtered off and dried at 60° C. in vacuo.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[N:18]=[C:17]([C:19]([OH:21])=O)[CH:16]=[CH:15][CH:14]=2)=[N:4][NH:3]1.C(N(CC)CC)C.C(OC([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=O)(C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[N:36]1([C:19]([C:17]2[N:18]=[C:13]([CH2:12][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2](=[O:1])[NH:3][N:4]=3)[CH:14]=[CH:15][CH:16]=2)=[O:21])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1
Reactant: O=C(O)c1cccc(Cc2n[nH]c(=O)c3ccccc23)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cccc(Cc2n[nH]c(=O)c3ccccc23)n1)N1CCNCC1
Reaction time: 18 h
Yield: 59.8 %

Procedure:
A mixture of 6-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)-pyridine-2-carboxylic acid (ivb)(0.3 g, 1.1 mmol), triethylamine (0.3 ml, 2.1 mmol), tert-butyl-1-piperazine carboxylate (0.23 g, 1.3 mmol) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.5 g, 1.3 mmol) in dimethylformamide (10 ml) was stirred for 18 hours. The reaction mixture was precipitated on the addition of water (50 ml) and air-dried. The white precipitate was dissolved in ethanol (3 ml) and 12 M hydrochloric acid (6 ml) was added to the solution and the reaction was stirred for 30 minutes. The reaction was then concentrated in vacuo, redissolved in water (10 ml) and washed with dichloromethane (2×10 ml). The aqueous layer was basified with ammonium hydroxide and extracted into dichloromethane (2×10 ml). The combined organic layers was dried with MgSO4, filtered and evaporated to yield the expected product (va) as a pink solid (0.23 g, 73%). m/z [M+1]+ 250 (96% purity)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[SH:13])[CH:3]=1.[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23]([NH:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29]Cl)(=[O:25])=[O:24]>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[S:13][CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=2[NH:26][S:23]([C:16]2[C:15]([CH3:14])=[CH:20][C:19]([CH3:21])=[CH:18][C:17]=2[CH3:22])(=[O:24])=[O:25])[CH:3]=1
Reactant: Cc1cc(C)c(S(=O)(=O)Nc2ccccc2CCl)c(C)c1
Reactant: Cc1ccnc(-n2ccnc2S)c1
Product: Cc1ccnc(-n2ccnc2SCc2ccccc2NS(=O)(=O)c2c(C)cc(C)cc2C)c1

Procedure:
1.25 g of 1-(4-methyl-2-pyridyl)-2-mercaptoimidazole and o-(2,4,6-trimethylphenyl)sulfonylaminobenzyl chloride are treated in the same manner as described in Example 1-(1) to give 2.19 g of 1-(4-methyl-2-pyridyl)-2-(2-(2,4,6-trimethylphenyl)sulfonylaminobenzylthio)imidazole.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH:22]=O)=[N:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl-:24].[CH3:25][NH3+:26].[BH4-].[Na+]>CO>[ClH:24].[CH3:25][NH:26][CH2:22][C:13]1[CH:14]=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])[N:12]=1
Reactant: [Cl-]
Reactant: Cc1ccc(S(=O)(=O)n2nc(C=O)cc2-c2ccccc2)cc1
Reactant: C[NH3+]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(C)cc2)n1
Product: Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.5 %

Procedure:
To a solution of 1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrazole-3-carbaldehyde (220 mg) and methylammonium chloride (455 mg) in methanol (5 mL) was added sodium borohydride (127 mg), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→0:1). The obtained colorless oil was dissolved in ethyl acetate (5 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (0.5 mL) was added, and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as a colorless solid (yield 70 mg, 27%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[NH:21][C:22](=[O:25])[CH2:23]Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[CH3:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH3:13])[C:15]=1[NH:21][C:22](=[O:25])[CH2:23][N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(C)c1NC(=O)CN1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.8 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(2,6-dimethylphenyl)-2-chloroacetamide (39 mg, 0.20 mmol, Aldrich) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 43.7 mg (90.9%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ 2.08 (s, 6H), 2.65 (t, J=4 Hz, 4H), 3.18 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.63 (t, J=5 Hz, 1H), 6.83 (d, J=5 Hz, 1H), 7.08 (s, 3H), 7.52 (t, J=5 Hz, 1H), 8.10 (d, J=5 Hz, 1H), 9.23 (s, 1H); MS (ESI/APCI+) m/e 325 (M+H)+.