Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].CCN=C=NCCCN(C)C.[C:17]([CH2:20][N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH:23]([NH:31][C:32]([C:34]2[NH:38][C:37]3[S:39][C:40]([Cl:42])=[CH:41][C:36]=3[CH:35]=2)=[O:33])[C:22]1=[O:43])(O)=[O:18]>CN(C)C1C=CN=CC=1.C(Cl)Cl.CO.C(Cl)Cl>[Cl:42][C:40]1[S:39][C:37]2[NH:38][C:34]([C:32]([NH:31][CH:23]3[CH2:24][C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH2:20][C:17]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:18])[C:22]3=[O:43])=[O:33])=[CH:35][C:36]=2[CH:41]=1
Reactant: O=C(O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Reaction time: 48 h

Procedure:
Methanesulphonamide (90 mg, 0.94 mmol), 4-(dimethylamino)pyridine (287 mg, 2.35 mmol) and EDCI (225 mg, 1.17 mmol) were added to a suspension of N-[1-(carboxymethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 2; 315 mg, 0.78 mmol) in DCM (50 mL) and stirred for 2 days. The reaction was diluted with MeOH:DCM (1:19) (50 mL) and washed with 1M HCl(aq). (50 mL), the organic layer was separated, dried (MgSO4), filtered and evaporated. The residue was purified by applying the material to a 10 g Isolute NH2 column in MeOH:DCM (1:9) (10 mL) and eluted with MeOH:DCM (1:9) (6×10 mL) then MeOH: 2M HCl in Et2O:DCM (5:4:45) (6×10 mL) and the relevant fractions evaporated to give a pink gum which was triturated with refluxing Et2O (25 mL) and after cooling the title product (206 mg, 55%) was collected by filtration as pale pink powder.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]1=[O:7].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2[CH3:33]>>[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]1[C:5](=[O:6])[C:2]([CH3:1])([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)[C:3]=1[OH:7])=[C:27]2[CH3:33]
Reactant: Cc1ccc(C2(C)C(=O)CC2=O)cc1
Reactant: Cc1c[nH]c2ccc(F)cc12
Reactant: O=Cc1ccccc1
Product: Cc1ccc(C2(C)C(=O)C(C(c3ccccc3)c3[nH]c4ccc(F)cc4c3C)=C2O)cc1

Procedure:
Using general procedure C, 2-methyl-2-p-tolyl-cyclobutane-1,3-dione (from Example 4.1) was reacted with benzaldehyde and 5-fluoro-3-methyl-1H-indole to give the title compound as a red solid. MS: 424.5 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=O)[N:8]([C@@H:11]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6](=[O:7])[C:5]2=[CH:24][CH:25]=1.Cl>C(O)C.[Zn]>[NH2:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:24][CH:25]=1)[C:6](=[O:7])[N:8]([C@@H:11]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:9]2
Reactant: CCOC(=O)CC[C@@H](C(=O)OCC)N1C(=O)c2ccc(N)cc2C1=O
Agent: Cl
Agent: [Zn]
Solvent: CCO
Product: CCOC(=O)CC[C@@H](C(=O)OCC)N1Cc2cc(N)ccc2C1=O
Temperature: -10 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
A solution of diethyl (S)-2-(4-aminophthalimido)glutarate (10.5 g, 30.2 mmol) in ethanol (150 ml) was cooled in an acetonitrile/CO2 bath. Concentrated HCl (25 ml) was added followed by 30 mesh granular Zn (10.5 g, 0.161 mole) (Fisher) when the internal temperature had reached -40° C. The reaction mixture was stirred 1.5 hours at this temperature and a further 1 hour at -10° C. The excess of Zn was filtered from the solution, 10% palladium on carbon (1.0 g) was added, and the solution shaken under hydrogen at (30-50 psi) overnight. The catalyst was removed by filtration through celite and the filtrate concentrated in vacuo. The residue was made basic by the addition of saturated NaHCO3 solution (~300 ml), extracted with diethyl ether (3×100 ml), and the ether extracts were dried (K2CO3) and concentrated in vacuo. The residue was absorbed onto silica gel (15 g) and purified by chromatography on silica gel (400 g) eluting with ethyl acetate:methylene chloride (1:4) to give diethyl (S)-2-(5-amino-1-oxo-2-isoindolinyl)glutarate as a viscous oil (4.14 g). 1H NMR (DMSO-d6, 300 MHz) δ: 1.12 (t, J=7 Hz, 3H, 3H, ester CH3), 1.17 (t, J=7 Hz, 3H, ester CH3), 1.98-2.33 (m, 4H, glu CH2CH2), 3.92-4.03 (m, 2H, ester CH2), 4.11 (q, J=7 Hz, 2H, ester CH2), 4.26 (very strongly coupled AB pair, 2H, ArCH2N), 4.77-4.84 (m, 1H, glu CH), 5.83 (br s, 2H, NH2), 6.58-6.65 (m, 2H, Ar), 7.32 (d, J=8 Hz, 1H, Ar). Mass spectrum (CI-CH4): 335 (M+1, 100%). Anal. Calculated for C17H22N2O5 : C, 61.07; H, 6.63; N, 8.38. Found: C, 60.93; H, 6.71; H, 8.30.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:19][CH:20]([CH3:22])[CH3:21])=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]1C(O)=O)=O)[CH3:2].[CH3:27][S:28]([O:31][CH2:32][CH2:33][CH2:34][C:35]#[C:36][C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)(=[O:30])=[O:29]>C(OC(=O)C)(=O)C>[CH:20]([O:19][C:11]1[CH:10]=[C:9]2[C:14]([CH2:15][CH2:16][N:7]3[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:26])=[C:35]([CH2:34][CH2:33][CH2:32][O:31][S:28]([CH3:27])(=[O:29])=[O:30])[C:36]([C:37]4[S:38][CH:39]=[CH:40][CH:41]=4)=[C:8]32)=[CH:13][C:12]=1[O:17][CH3:18])([CH3:21])[CH3:22]
Reactant: CS(=O)(=O)OCCCC#Cc1cccs1
Reactant: CCOC(=O)C(=O)N1CCc2cc(OC)c(OC(C)C)cc2C1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1c(CCCOS(C)(=O)=O)c(-c2cccs2)c2n1CCc1cc(OC)c(OC(C)C)cc1-2
Yield: 58.1 %

Procedure:
A solution of 280 mg of 6b and 165 mg of 2b in 6 ml of acetic anhydride was heated in a microwave oven for 15 min at 140° C. The reaction mixture was cooled and residual solvents were removed by sequential coevaporation with toluene. The residue was purified by chromatography on silica gel, using a gradient of heptane/ethyl acetate as eluent, to provide 215 mg of 6c; MS-ESI: [M+1] 548.15.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)[N:6]=[C:5]2[NH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[N:28]=[CH:27]2.Cl[CH2:41][CH2:42][N:43]([CH3:45])[CH3:44].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:44][N:43]([CH3:45])[CH2:42][CH2:41][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)[N:6]=[C:5]2[NH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[N:28]=[CH:27]2
Reactant: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1O
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCN(C)C
Temperature: 85 °C

Procedure:
A mixture of tert-butyl 5-(6-hydroxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.475 g, 0.898 mmol), 2-chloro-N,N-dimethylethanamine (0.28 g, 1.94 mmol) and K2CO3 (1.18 g, 2.54 mmol) in DMF (8 mL) was heated at 85° C. for 3 h. The volatiles were removed in vacuo and the residue was taken up in CHCl3/MeOH. The solid was removed via filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2, CHCl3/MeOH 93:7 then 90:10) to give tert-butyl 5-(6-(2-(dimethylamino)ethoxy)-7-methoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (0.087 g, 0.145 mmol, 16%). MS 600.4 (M+1).
Reaction SMILES: C([CH:6]1[C:10](=[O:11])[CH2:9][N:8]([CH2:12][CH2:13][CH3:14])[C:7]1=[O:15])(OCC)=O.[CH2:16]([N:19]1[CH2:23][C:22](=O)[CH2:21][C:20]1=[O:25])[CH2:17][CH3:18].[NH2:26][C:27]1[C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][S:29][C:28]=1[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40].O.C1(C)C=CC=CC=1>C(#N)C.C1(C)C=CC=CC=1>[CH2:12]([N:8]1[CH2:9][C:10](=[O:11])[CH2:6][C:7]1=[O:15])[CH2:13][CH3:14].[CH2:16]([N:19]1[CH2:23][C:22]([NH:26][C:27]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][S:29][C:28]=2[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:21][C:20]1=[O:25])[CH2:17][CH3:18]
Reactant: CCCN1CC(=O)C(C(=O)OCC)C1=O
Reactant: CCCCCc1scc(C(=O)OC)c1N
Agent: CCCN1CC(=O)CC1=O
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC#N
Product: CCCCCc1scc(C(=O)OC)c1NC1=CC(=O)N(CCC)C1
Yield: 94 %

Procedure:
Freshly prepared 1-propyl-2,4-dioxopyrrolidine was prepared as described in Example 1e from 3-carboethoxy-1-propyl-2,4-dioxopyrrolidine (3.55 g) in acetonitrile (100 ml). The 1-propyl-2,4-dioxopyrrolidine was mixed with methyl 3-amino-2-pentylthiophene-4-carboxylate (2.70 g) in toluene (65 ml). The mixture was refluxed for 2 hours with removal of the water/toluene azeotrope using a Dean-Stark trap. After distilling off the excess toluene, the residue was taken up in ethyl acetate, washed sequentially with saturated aqueous Na2CO3 and brine, then dried (Na2SO4) and concentrated. Chromatographic purification over silica gel afforded the title product (3.92 g, 94%) as a yellow oil; tlc, Rf =0.12, silica gel, ethyl acetate:hexane (1:1).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5].N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:26]1[CH:27]=[C:28]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:29]=[CH:30][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CN(C=O)C.CCOCC>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][O:5][C:30]1[CH:29]=[C:28]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:27]=[CH:26][CH:31]=1
Reactant: Cc1cccc(C)c1CO
Reactant: CCOC(=O)Cc1cccc(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(OCc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2,6-Dimethylbenzyl alcohol (5.25 g, 38.6 mmol) and diisopropyl azodicarboxylate (DIAD, 8.49 g, 42 mmol) in THF (30 ml) and DMF (13 ml) was added drop wise to a solution of Ethyl 3-hydroxyphenylacetate (Step A, 6.66 g, 37 mmol) and triphenylphosphine (11 g, 42 mmol) in THF (100 ml). The reaction mixture was stirred at room temperature for 4 hours, diluted with ether and washed with water. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex: ethyl acetate 1:1) to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([CH2:7][NH:8][C:9](=[O:25])[CH:10]([O:22][CH2:23][CH3:24])[N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH3:20])[C:12]2=[O:21])=[C:5]([OH:28])[CH:4]=1)#[N:2].I[CH2:30][C:31]([NH2:33])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[C:31]([CH2:30][O:28][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:27]=[CH:26][C:6]=1[CH2:7][NH:8][C:9](=[O:25])[CH:10]([O:22][CH2:23][CH3:24])[N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH3:20])[C:12]1=[O:21])(=[O:32])[NH2:33]
Reactant: NC(=O)CI
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1O)N1Cc2c(C)cccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(C(=O)NCc1ccc(C#N)cc1OCC(N)=O)N1Cc2c(C)cccc2C1=O
Yield: 21.7 %

Procedure:
(RS)-N-(4-Cyano-2-hydroxy-benzyl)-2-ethoxy-2-(4-methyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetamide (300 mg) was dissolved in acetonitrile (10 ml) and treated over night under vigorous stirring at ambient temperature with iodoacetamide (223 mg) and cesium carbonate (411 mg). Pouring onto crushed ice/NH4Cl, twofold extraction with AcOEt, washing with brine, drying over sodium sulfate, and evaporation of the solvents, followed by flash column chromatography (silica gel, AcOEt/MeOH=10/1), afforded 75 mg of (RS)-N-(2-carbamoylmethoxy-4-cyano-benzyl)-2-ethoxy-2-(4-methyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetamide as white solid, MS 437.4 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:5][CH:4]=1.C1COCC1.[OH-].[Na+:39]>CO.O>[Na+:39].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O-:26])=[O:25])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCCCC(=O)O)c23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCCCC(=O)[O-])c23)cc1
Reaction time: 0.08 h

Procedure:
Dissolve 200 mg (0.464 mmol) 6-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}hexanoic acid at RT in 0.75 ml methanol, 0.5 ml THF and a few drops of water, and add 0.464 ml 1 N sodium hydroxide solution. Stir the mixture for 5 min, then concentrate by vacuum evaporation and dry the residue at high vacuum. 221 mg of the target compound is obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O>CCCCCCC.CCOC(C)=O>[C:15]1([CH3:14])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: Cc1ccccc1B(O)O
Reactant: FC(F)(F)CNc1cnccc1I
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccccc1-c1ccncc1NCC(F)(F)F

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-(2,2,2-trifluoro-ethyl)-amine and 2-methylphenylboronic acid (CAS RN 16419-60-6) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Light brown solid (91%). MS (ESI): m/z=267.11 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:4][C:3]=1[C:17]1[S:21][C:20]([N:22]2[CH2:25][C:24]3([CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)[CH2:23]2)=[N:19][N:18]=1.CC1(C)C(C)(C)OB([C:46]2[CH:47]=[N:48][NH:49][CH:50]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[F:1][C:2]1[C:7]([F:8])=[C:6]([C:46]2[CH:47]=[N:48][NH:49][CH:50]=2)[CH:5]=[CH:4][C:3]=1[C:17]1[S:21][C:20]([N:22]2[CH2:25][C:24]3([CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:27][CH2:26]3)[CH2:23]2)=[N:19][N:18]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1nnc(-c3ccc(OS(=O)(=O)C(F)(F)F)c(F)c3F)s1)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1nnc(-c3ccc(-c4cn[nH]c4)c(F)c3F)s1)C2
Temperature: 120 °C
Yield: 18.9 %

Procedure:
A mixture of tert-butyl 2-(5-(2,3-difluoro-4-(((trifluoromethyl)sulfonyl)oxy)phenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (68 mg, 0.119 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (35 mg, 0.179 mmol) in dioxane (1 mL) was stirred under nitrogen atmosphere. To this suspension was added Pd(PPh3)4 (7 mg, 0.006 mmol) followed by a solution of Na2CO3 (38 mg, 0.358 mmol) in water (0.25 mL). The reaction mixture was sealed and heated at 120° C. for 1 hour under microwave irradiation. The reaction mixture was diluted with water (10 mL) and extracted with DCM (20 mL). The organic phase was separated and concentrated in vacuo to afford the crude product as an off-white solid. The crude material was purified by UV directed preparative HPLC under basic conditions (NH4OH modified) to afford he title compound as a white solid (11 mg, 19% yield). MS m/z 489.1 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ 13.30 (s, 1H), 8.18 (s, 2H), 7.85 (ddd, J=8.6, 6.7, 1.8 Hz, 1H), 7.70 (ddd, J=8.7, 7.0, 1.8 Hz, 1H), 3.91 (s, 4H), 3.28-3.31 (m, 4H), 1.74 (t, J=5.6 Hz, 4H), 1.40 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:16])[C:9](=[O:15])[N:10]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:5]2=[CH:4][CH:3]=1.[CH:17](/B(O)O)=[CH:18]\[CH3:19].[CH:23](NC(C)C)(C)C>CN(C=O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:23][C:12]([CH3:13])([CH3:14])[CH2:11][N:10]1[C:5]2[C:6](=[N:7][C:2](/[CH:17]=[CH:18]/[CH3:19])=[CH:3][CH:4]=2)[N:8]([CH3:16])[C:9]1=[O:15]
Reactant: CC(C)NC(C)C
Reactant: C/C=C/B(O)O
Reactant: Cn1c(=O)n(CC2CC2)c2ccc(Cl)nc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: C/C=C/c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Temperature: 100 °C

Procedure:
5-Chloro-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1-4, 1 g, 3.9 mmol, 1.0 equiv), (E)-prop-1-enylboronic acid (0.5 g, 5.9 mmol, 1.5 equiv), diisopropylamine (1.1 ml, 7.8 mmol, 2 equiv), triphenylphosphine-3,3′,3″-trisulfonic acid trisodium salt hydrate (0.27 g, 0.43 mmol, 0.11 equiv), and Pd(OAc)2 (44 mg, 0.197 mmol, 0.05 quiv) were dissolved in DMF (9.85 mL)/water (3.28 mL), placed in a sealed tube and heated to 100° C. for 18 h. Following this duration, LCMS showed complete consumption of 1-4. The contents were filtered through Celite and washed with ethyl acetate (10 mL). The filtrate was diluted with saturated NaHCO3 (50 mL) and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (3×20 mL) and the combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give a brown semi-solid. Purification by normal-phase HPLC (0-40% EtOAc:hexane) afforded 33-1 as a yellow solid. MS m/z (M+H): observed=260.1.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[C:8]([O:15][CH3:16])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH2:18]([O:20][CH2:21][CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[N:32]1[CH2:38][CH2:37][CH2:36][N:35]([CH2:39][CH2:40][C:41]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:45][CH2:44][NH:43][CH2:42]2)[CH2:34][CH2:33]1)[CH3:19]>>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[C:8]([O:15][CH3:16])=[CH:7][C:3]=1[C:4]([N:43]1[CH2:44][CH2:45][C:41]([CH2:40][CH2:39][N:35]2[CH2:36][CH2:37][CH2:38][N:32]([C:24]3[N:23]([CH2:22][CH2:21][O:20][CH2:18][CH3:19])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=3)[CH2:33][CH2:34]2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:42]1)=[O:6]
Reactant: COc1cc(C(=O)O)c(Cl)c(OC)c1OC
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4Cl)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-chloro-3,4,5-trimethoxybenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [CH:1](=O)[CH3:2].Cl.[Cl:5][C:6]1[CH:11]=[C:10]([NH:12][NH2:13])[CH:9]=[CH:8][C:7]=1[CH2:14][N:15]1[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[CH2:17][O:16]1.C([BH3-])#N.[Na+].[C:27](O)(=O)[CH3:28]>C(#N)C.CCOCC>[Cl:5][C:6]1[CH:11]=[C:10]([NH:12][N:13]([CH2:1][CH3:2])[CH2:27][CH3:28])[CH:9]=[CH:8][C:7]=1[CH2:14][N:15]1[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[CH2:17][O:16]1
Reactant: CC(=O)O
Reactant: CC=O
Reactant: CC1(C)CON(Cc2ccc(NN)cc2Cl)C1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Product: CCN(CC)Nc1ccc(CN2OCC(C)(C)C2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetaldehyde (0.3 ml, 0.007 mole) was added by pipet to a stirred solution of 2-[(2-chloro-4-hydrazinophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone hydrochloride (0.8 g, 0.0026 mole) and sodium cyanoborohydride (0.16 g, 0.0026 mole), in acetonitrile 25 ml). Glacial acetic acid (2 ml) was added, and the resulting mixture stirred at ambient temperature overnight. The reaction mixture was diluted with ether (200 ml) and washed with aqueous 0.5N sodium hydroxide (50 ml), then with water (2×50 ml). The ether layer was dried and then concentrated under reduced pressure to yield a yellow oil. The oil was chromatographed on silica gel, eluting with 30:70 ethyl acetate:heptane. Appropriate fractions were combined and concentrated under reduced pressure to yield 0.24 g of 2-[[2-chloro-4-(2,2-diethylhydrazinyl)phenyl]methyl]-4,4-dimethyl-3-isoxazolidinone as a white solid; m.p. 139°-141° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1.Cl[C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34].[C:45]1(=[O:55])[C:49]2([CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)[CH2:48][CH2:47][NH:46]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:28])[F:29])=[CH:24][N:25]=[C:20]2[C@H:19]([NH:31][C:33]([N:52]2[CH2:53][CH2:54][C:49]3([C:45](=[O:55])[NH:46][CH2:47][CH2:48]3)[CH2:50][CH2:51]2)=[O:34])[CH2:18][CH2:17]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C1NCCC12CCNCC2
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21)N1CCC2(CCNC2=O)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.1 %

Procedure:
Triethylamine (32.2 μL, 0.23 mmol) was added to a solution of the hydrochloride salt of (6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-amine (32 mg, 0.077 mmol) and 4-nitrophenyl chloroformate (15 mg, 0.077 mmol) in tetrahydrofuran (1 mL) at 0° C. After 15 min, a solution of the hydrochloride salt of 2,8-diazaspiro[4.5]decan-1-one (15 mg, 0.077 mmol) in dichloromethane (1 mL) and triethylamine (43 μL, 0.31 mmol) were added and the mixture allowed to warm to ambient temperature. After 72 h, saturated aqueous sodium carbonate was added and the mixture was extracted with ethyl acetate (3×). The organic layer was washed with saturated aqueous sodium bicarbonate (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→87% dichloromethane/methanol) gave the title compound (13 mg). MS 526.2204 (M+1).