Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[N:15]([O-])=[O:16].[Na+].S(=O)(=O)(O)O>N1C=CC=CC=1>[N:15]([C:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]=2[CH:13]=[CH:14][C:2]=1[OH:1])=[O:16]
Reactant: Oc1ccc2oc3ccccc3c2c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: c1ccncc1
Product: O=Nc1c(O)ccc2oc3ccccc3c12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In 100 g of pyridine was dissolved 10 g of 2-hydroxydibenzofuran, and the solution was cooled to 0° C. Then, 60 g of a 20% aqueous solution of sodium nitrite was added to the above solution and 100 g of a 30% aqueous solution of sulfuric acid was added dropwise to the mixture while stirring for 10 minutes. After the dropwise addition, the mixture was stirred at 0° C. for 1 hour and then filtered. The recovered solid was washed with water and dried to obtain 11 g of a red crystal of 1-nitroso-2-hydroxydibenzofuran.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:8][CH2:9][OH:10].[CH2:11]([O:18][C:19]1[C:20]2[CH2:31][C@:30]3([CH3:44])[C@@H:32]([CH3:43])[CH2:33][CH2:34][C@H:35]4[C:36]([CH3:42])([CH3:41])[C@@H:37]([OH:40])[CH2:38][CH2:39][C@@:29]34[O:28][C:21]=2[C:22]2[CH2:23][NH:24][CH2:25][C:26]=2[CH:27]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C=O)C>[CH2:11]([O:18][C:19]1[C:20]2[CH2:31][C@:30]3([CH3:44])[C@@H:32]([CH3:43])[CH2:33][CH2:34][C@H:35]4[C:36]([CH3:42])([CH3:41])[C@@H:37]([OH:40])[CH2:38][CH2:39][C@@:29]34[O:28][C:21]=2[C:22]2[CH2:23][N:24]([CH2:8][CH2:9][OH:10])[CH2:25][C:26]=2[CH:27]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OCCCl
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)CC[C@]23Oc2c4c(cc(OCc5ccccc5)c2C[C@]13C)CNC4
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)CC[C@]23Oc2c4c(cc(OCc5ccccc5)c2C[C@]13C)CN(CCO)C4
Temperature: 50 °C
Reaction time: 3 h
Yield: 56.8 %

Procedure:
Under nitrogen, 35 mg (0.25 mmol) of sodium carbonate and 23 μl (0.33 mmol) of 2-chloroethanol were added to a solution of Compound (33a) (40 mg, 0.087 mmol) in dry DMF (0.5 ml). The mixture was stirred for 3 hours at 50° C. and then for 18 hours at 65° C. After cooling, water was added to the reaction, and extracted with ethyl acetate. The extract was washed with water, saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the resulting residue was purified by a silica gel column chromatography (silica gel 1.5 g; chloroform:methanol=19: 1) to give 25 mg (57%) of Compound (33f).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.C(O)(=O)C.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.[BH4-].[Na+]>C(Cl)Cl>[C:15]1([CH:14]2[C:5]3=[N:4][NH:3][C:2](=[O:1])[C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([C:6]=43)[NH:12][CH:13]2[C:21]2[CH:28]=[CH:27][C:24]([CH2:25][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:23][CH:22]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Reactant: C1CCNC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccc(CN3CCCC3)cc1)C2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.7 %

Procedure:
To a stirred solution of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (367 mg, 1 mmol) in dry DCM (15 mL) was added acetic acid (0.2 mL) followed by pyrrolidine (213 mg, 3 mmol). After the addition, the mixture was stirred at room temperature overnight. Then sodium borohydride (318 mg, 1.5 mmol) was added at 0° C. After the addition, the mixture was stirred at this temperature for 12 hr. DCM was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product, which was purified by prep-HPLC to give the title compound (62 mg, yield 14%) as white solid. LC-MS (ESI) m/z: 423 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.82-1.85 (m, 2H), 1.97 (s, 2H), 3.01-3.05 (m, 2H), 3.26 (d, 2H), 4.27 (d, 2H), 4.36 (d, 1H), 4.84 (d, 1H), 7.13-7.23 (m, 6H), 7.36-7.40 (m, 5H), 7.48 (s, 1H), 7.57-7.61 (t, 1H), 12.18 (s, 1H).
Reaction SMILES: [H-].[Na+].CCCCCC.[CH2:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[OH:20])[CH:10]=[CH2:11].S(C1C=CC(C)=CC=1)(O[CH2:25][C@@H:26]1[O:28][CH2:27]1)(=O)=O>CN(C=O)C>[CH2:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[O:20][CH2:25][C@H:26]1[CH2:27][O:28]1)[CH:10]=[CH2:11]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: C=CCOc1ccc(Cl)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C=CCOc1ccc(Cl)cc1OC[C@H]1CO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.4 %

Procedure:
To 4.0 g (79 mmole) of 60% sodium hydride/mineral oil dispersion in a one liter flask was added 300 ml of hexane. The mixture was swirled briefly, the solid allowed to settle and the supernatant liquid decanted. DMF (500 ml) was added, followed by a solution of 14.6 g (79 mmole) of 2-allyloxy-5-chlorophenol in 100 ml of DMF. The mixture was stirred at room temperature under nitrogen for 30 minutes, then 18.0 g (79 mmole) of (R)-glycidyl tosylate added. The mixture was heated under a nitrogen atmosphere at 80° C. for 24 hours. The solvent was evaporated in vacuum and replaced with 750 ml of methylene chloride. The solution was washed with 500 ml portions of 2N HCl (aq), saturated aqueous sodium bicarbonate, saturated brine, dried over sodium sulfate, filtered and evaporated in vacuum to give 20 g of a crude gum. This was column chromatographed on silica gel using methylene chloride as eluant to give 9.2 g of the title compound as a colorless oil. 1H (CDCl3) singlet, 6.93 δ(1 H); doublet, 6.90 δ(1 H); doublet, 6.80 δ(1 H);.multiplet, 6.05 δ(1 H); doublet, 5.40 δ(1 H); doublet, 5.25 δ(1 H); doublet, 4.55 δ(2 H); doublet of doublets, 4.25 δ(1 H); doublet of doublets, 3.97 δ(1 H); multiplet, 3.35 δ(1 H); triplet, 2.95 δ(2H); triplet, 2.75 δ(1 H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:26]=[CH:25][C:14]([C:15]([NH:17][C@H:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:19][OH:20])=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(S(F)(F)F)CC)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:26]=[CH:25][C:14]([C:15]3[O:20][CH2:19][CH:18]([C:21]([O:23][CH3:24])=[O:22])[N:17]=3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)[C@H](CO)NC(=O)c1ccc(OCCCN2CCCCC2)cc1
Agent: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)C1COC(c2ccc(OCCCN3CCCCC3)cc2)=N1
Reaction time: 1 h

Procedure:
A mixture of methyl N-[4-(3-piperidin-1-ylpropoxy)benzoyl]serinate ax37 (0.922 g, 2.54 mmol, 1 eq) and (diethylamino)sulfur trifluoride (0.34 ml, 2.78 mmol, 1.1 eq) in dichloromethane (25 ml) is stirred under argon at room temperature for 3.5 h before addition of potassium carbonate (0.35 g, 2.53 mmol, 1 eq). The mixture is stirred for a further 1 h and washed with a saturated solution of potassium hydrogencarbonate and the aqueous layer is extracted with dichloromethane. The organic layers are then dried over magnesium sulfate and concentrated under vacuum to give methyl 2-[4-(3-piperidin-1-ylpropoxy)phenyl]-4,5-dihydro-1,3-oxazole-4-carboxylate ax45 as an orange oil (1.036 g) which is used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][C@H:14]([CH2:16][N:17]=[N+:18]=[N-:19])[O:13][C:12]2=[O:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:21]12CC(CC1)=C[CH:22]=2>O1CCOCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:15][C@H:14]([CH2:16][N:17]3[CH:22]=[CH:21][N:19]=[N:18]3)[O:13][C:12]2=[O:20])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C1=C2CCC(=C1)C2
Reactant: CC(C)(C)c1ccc(N2C[C@H](CN=[N+]=[N-])OC2=O)cc1
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C[C@H](Cn3ccnn3)OC2=O)cc1
Yield: 59.4 %

Procedure:
(5R)-3-(4-t-Butylphenyl)-5-azidomethyloxazolidin-2-one (400 mg, 1.46 mM) was dissolved in dioxane (8 ml), treated with norbornadiene (1.3 g, 14.1 mM) and heated under reflux for 6 hours. After removal of the solvent, the residue was dissolved ethyl acetate, and purified by flash chromatography on silica, eluting with the same solvent. Relevant fractions were combined to give the desired product (260 mg, mp 140–142°). MS (EI): 300 (M+) for C16H20N4O2
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Li])CCC.[CH:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)=[O:15]>O1CCCC1>[Br:8][C:4]1[N:3]=[C:2]([CH:14]([OH:15])[N:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:20][CH2:21]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C=O)CC1
Reactant: Brc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(O)c2cccc(Br)n2)CC1
Reaction time: 1 h

Procedure:
2,6-Dibromopyridine (5.45 g, 23.01 mmol) was dissolved in tetrahydrofuran (27.3 mL) and cooled to −78° C. under argon after which n-butyllithium (10.40 mL, 26.0 mmol) was added and the solution was stirred for thirty minutes. A solution of tert-butyl 4-formylpiperazine-1-carboxylate (5.00 g, 23.47 mmol) in tetrahydrofuran (8 mL) was added and the solution was stirred at −78° C. for one hour and then for one hour at ambient temperature. The reaction was quenched with saturated sodium bicarbonate (10 mL) and stirred for ten minutes. The product was extracted with ether, dried over magnesium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)[C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][C:28]=3[O:37][CH3:38])[CH2:19][CH2:18]2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:46].O1CCOCC1.CCOCC>CO>[ClH:46].[ClH:46].[F:45][C:42]1[CH:43]=[CH:44][C:39]([CH:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][C:28]=3[O:37][CH3:38])[CH2:19][CH2:18]2)=[O:16])=[CH:40][CH:41]=1
Reactant: COc1ccc2ccccc2c1CCCCN1CCN(C(=O)C(c2ccc(F)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1ccc2ccccc2c1CCCCN1CCN(C(=O)C(c2ccc(F)cc2)C2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.1 g of 1-t-Butoxycarbonyl-4-(1-(4-fluorophenyl)-2-{4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazin-1-yl}-2-oxoethyl)piperidine was dissolved in 10 ml of methanol, and 10 ml of 4M hydrogen chloride/1,4-dioxane solution was added, followed by stirring at room temperature for 2 hours. After concentration of the reaction solution under reduced pressure, to the residue was added ether, followed by stirring at room temperature. The precipitated crystals were filtered and washed with ether to give 1.7 g of 4-(1-(4-fluorophenyl)-2-{4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazin-1-yl}-2-oxoethyl)piperidine dihydrochloride.
Reaction SMILES: [Br:1][C:2]1[C:3](I)=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.[CH3:20][Zn]C.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH3:20])=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1
Reactant: C[Zn]C
Reactant: C[Si](C)(C)CCOCn1ccc2c(I)c(Br)cnc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Br)cnc2c1ccn2COCC[Si](C)(C)C
Temperature: 23 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
5-Bromo-4-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (1.00 g, 2.21 mmol) and bis(tri-t-butylphosphine)palladium(0) (56 mg, 0.110 mmol) were combined and dissolved in anhydrous tetrahydrofuran (20 mL) in an oven-dried round-bottom flask. Dimethylzinc (552 μL, 1.11 mmol, 2.0 M solution in tetrahydrofuran). The solution was allowed to stir at 23° C. for 1 hour. To the mixture was added water (50 mL) followed by ethyl acetate (50 mL). Layers were mixed well, and the organic layer was stirred over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash silica gel chromatography using a gradient of ethyl acetate in hexanes to afford 5-Bromo-4-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (307 mg, 0.899 mmol, 41%) as a brown oil. 1H-NMR [500 MHz, d6-DMSO]: 8.43 (s, 1H), 7.71 (d, 1H), 6.79 (d, 1H), 5.69 (s, 1H), 3.61 (t, 2H), 2.66 (s, 3H), 0.93 (t, 2H), 0.0 (s, 9H); MS [MH+] m/z: 341.1, 343.0
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][OH:24])[C:16]=2[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:34][C:35]1[CH:36]=[N:37][C:38](Cl)=[N:39][CH:40]=1.CC(N(C)C)=O>O1CCCC1.O>[Br:34][C:35]1[CH:36]=[N:37][C:38]([O:24][CH2:23][CH2:22][O:21][C:17]2[C:16]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)=[C:15]([NH:14][S:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=3)(=[O:12])=[O:13])[N:19]([CH3:20])[N:18]=2)=[N:39][CH:40]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Cc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(OCCOc3ncc(Br)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reaction time: 0.08 h
Yield: 35.5 %

Procedure:
To 4-(tert-butyl)-N-[3-(2-hydroxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]benzenesulfonamide (Example 2) (25 mg) in tetrahydrofuran (2 ml) at room temperature under an atmosphere of nitrogen was added sodium hydride (60% dispersion in oil, 4.5 mg) and the mixture was stirred for 5 minutes. To the mixture was added 5-bromo-2-chloropyrimidine (Liquid Crystals, 1993, 14(3), 741) (12 mg) and the reaction was stirred for 30 minutes after which dimethyl acetamide (0.5 ml) was added to give a homogenous mixture. After further stirring for 3 hrs the reaction was diluted with water (20 ml) and extracted with ethyl acetate (20 ml). The organic fraction was dried over magnesium sulfate, filtered concentrated under reduced pressure. The residue was purified by column chromatography on silica (10 Og) eluted with dichloromethane ether (1:1) to yield the title compound as a white solid (12 mg).
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[CH2:47]([C:52]12[CH2:59][CH2:58][C:55]([CH2:60][OH:61])([CH2:56][CH2:57]1)[CH2:54][CH2:53]2)[CH2:48][CH2:49][CH2:50][CH3:51]>>[Cl:17][C:18]1[C:19]([O:61][CH2:60][C:55]23[CH2:56][CH2:57][C:52]([CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])([CH2:59][CH2:58]2)[CH2:53][CH2:54]3)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: CCCCCC12CCC(CO)(CC1)CC2
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CCCCCC12CCC(COc3cc(F)c(C(=O)NS(=O)(=O)N(C)C)cc3Cl)(CC1)CC2

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with (4-pentylbicyclo[2.2.2]octan-1-yl)methanol, the title compound was obtained as a colorless solid (0.25 g, 51%): 1H NMR (300 MHz, DMSO-d6) δ 11.75 (s, 1H), 7.71 (d, J=7.5 Hz, 1H), 7.19 (d, J=12.4 Hz, 1H), 3.76 (s, 2H), 2.87 (s, 6H), 1.53-1.48 (m, 6H), 1.38-1.06 (m, 14H), 0.85 (t, J=7.0 Hz, 3H); MS (ES−) m/z 487.2, 489.2 (M−1).
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25](=[O:28])[NH:26][N:27]=4)[N:24]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[C:41]([O:47][CH2:48]Cl)(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43]>CN(C)C=O>[C:29]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25](=[O:28])[N:26]([CH2:48][O:47][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[N:27]=4)[N:24]=3)[CH2:13][CH2:14]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=c1[nH]nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCn1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
0.560 g of 6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one was suspended in 3 ml of N,N-dimethylformamide; 0.210 g of potassium carbonate and 0.220 ml of chloromethyl pivalate were added, followed by stirring at room temperature for 15 hours. After ice water was added, the reaction mixture was extracted with ethyl acetate; the extract was washed with saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (185:15:2). The desired fraction was collected and concentrated; the crystal obtained was filtered, washed with diethyl ether, and dried, to yield 0.39 g of the title compound.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH:37]=O)=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[O:29])=[N:26][CH:27]=2)[CH:21]=1.[I:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:37][NH:44][C:43]2[CH:45]=[CH:46][C:40]([I:39])=[CH:41][CH:42]=2)=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[O:29])=[N:26][CH:27]=2)[CH:21]=1
Reactant: COC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C=O)cn1
Reactant: Nc1ccc(I)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(I)cc2)cn1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (1.3 g, 6.0 mmol) was added to a DCM solution (6 mL) of methyl 3-(5-(5-chloro-2-formylphenyl)picolinamido)propanoate (1.0 g, 3.0 mmol) and 4-iodoaniline (723 mg, 3.3 mmol), and the resulting mixture was stirred at room temperature. After 3 h the resulting mixture diluted with DCM and saturated aqueous Na2CO3 and the layers were separated. The aqueous phase was extracted with DCM and the combined organics were dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:32])[C@H:5]([CH2:28][CH2:29][S:30][CH3:31])[NH:6][C:7](=[O:27])[CH2:8][N:9]([CH2:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1)[CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.[NH:33]1[C:37](=[O:38])[CH2:36][CH2:35][C@H:34]1[C:39](O)=[O:40].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl-]>CN(C=O)C>[CH3:2][O:3][C:4](=[O:32])[C@H:5]([CH2:28][CH2:29][S:30][CH3:31])[NH:6][C:7](=[O:27])[CH2:8][N:9]([CH2:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:39](=[O:40])[C@@H:34]1[CH2:35][CH2:36][C:37](=[O:38])[NH:33]1)[CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)CN(Cc1cccc2ccccc12)C[C@@H]1CCCN1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)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: COC(=O)[C@H](CCSC)NC(=O)CN(Cc1cccc2ccccc12)C[C@@H]1CCCN1C(=O)[C@@H]1CCC(=O)N1
Reaction time: 18 h

Procedure:
N-(Pyrrolidin-2(S)-ylmethyl)-N-(1-naphthylmethyl)-glycyl-methionine methyl ester hydrochloride(0.200 g, 0.387 mmol), L-pyroglutamic acid (0.060 g, 0.465 mmol) and diisopropylethylamine (0.300 mL, 2.32 mmol) were dissolved in dry DMF (2 mL). BOP-chloride (0.355 mg, 1.39 mmol) was added and the mixture stirred under Ar for 18 h. The solvent was removed in vacuo and the residue partitioned between saturated NaHCO3 soln and EtOAc. The layers were separated and the organics were washed with H2O, brine, dried over MgSO4, filtered and the solvent removed in vacuo to give an oil which was chromatographed on silica gel (3:97 MeOH:CH2Cl2) to give the title compound. 1H NMR (CD3OD) δ 8.33 (d, 1H, J=8 Hz), 7.91 (d, 1H, J=7 Hz), 7.85 (d, 1H, J=8 Hz), 7.43-7.64 (m, 4H), 4.36-4.54 (m, 3H), 3.98 (d, 1H, J=13 Hz), 3.69 (s, 3H), 3.49-3.58 (m, 1H), 3.21-3.49 (m, 5H), 2.92 (dd, 1H, J=4, 12 Hz), 2.50-2.59 (m, 1H), 2.25-2.50 (m, 3H), 2.08-2.25 (m, 1H), 1.79-2.08 (m, 5H), 1.95 (s, 3H), 1.70-1.79 (m, 1H), 1.46-1.57 (m, 1H). FAB MS 555 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH:11]([F:13])[F:12])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[F:14][C:15]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])=[CH:20][C:19]=1B1OC(C)(C)C(C)(C)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:12][CH:11]([F:13])[O:10][C:4]1[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([C:23]2[CH:22]=[C:21]([NH:24][S:25]([CH2:28][CH3:29])(=[O:26])=[O:27])[CH:20]=[CH:19][C:18]=2[O:17][C:16]2[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:15]=2[F:14])[CH:3]=1
Reactant: Cn1cc(Br)cc(OC(F)F)c1=O
Reactant: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2cc(OC(F)F)c(=O)n(C)c2)c1
Temperature: 70 °C
Yield: 14.8 %

Procedure:
A mixture of 5-bromo-3-(difluoromethoxy)-1-methylpyridin-2-one (50 mg, 0.20 mmol), N-[4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanesulfonamide (88 mg, 0.18 mmol), Pd(dppf)Cl2 (11 mg) and K3PO4 (85 mg, 0.40 mmol) in dioxane (5 mL) and water (5 drops) was purged with nitrogen, capped, and heated to 70° C. for 8 h. After the mixture was filtered, the filtrate was concentrated in vacuo and purified by prep-HPLC to afford the title compound (13 mg, 13%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.53 (m, 2H) 7.25 (m, 1H) 7.05 (m, 1H) 7.12 (m, 1H) 7.02-6.97 (m, 2H) 6.97-6.95 (m, 1H) 6.77 (m, 1H) 6.48 (bs, 1H) 3.67 (s, 3H) 3.15 (q, J=7.4 Hz, 2H) 1.42 (t, J=7.4 Hz, 3H). LCMS (M+H)+=487.