Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]2[C:12]([O:15][CH3:16])=[N:13][NH:14][C:10]=2[CH:9]=[C:8]([NH:17][C:18]([NH:20][C@@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:22])=[O:19])[N:7]=1)(=[O:3])[CH3:2].[B-](F)(F)(F)[F:30].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(O)(C(F)(F)F)=O>CO>[C:1]([O:4][CH2:5][C:6]1[C:11]2[C:12]([O:15][CH3:16])=[N:13][NH:14][C:10]=2[C:9]([F:30])=[C:8]([NH:17][C:18]([NH:20][C@@H:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH3:22])=[O:19])[N:7]=1)(=[O:3])[CH3:2]
Reactant: COc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)nc(COC(C)=O)c12
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1n[nH]c2c(F)c(NC(=O)N[C@H](C)c3ccccc3)nc(COC(C)=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
(R)-(3-methoxy-6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-4-yl)methyl acetate (108 mg, 0.282 mmol, Example 257, derived from Intermediate 41B according to Scheme 3/Method A) was dissolved in MeOH (1 mL) and charged with selectfluor (150 mg, 0.423 mmol). The reaction was allowed to stir overnight at rt. The solvents were removed in vacuo and the residue was purified on RP-HPLC 30×150 mm column (25-60% CH3CN/H2O w/0.1% TFA) to provide (R)-(7-fluoro-3-methoxy-6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-4-yl)methyl acetate (60 mg, 0.149 mmol, 53.1% yield) as TFA salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:7][CH:6]=[CH:5][C:4]=1CC#N.Cl.[C:21]([OH:24])(=[O:23])[CH3:22]>>[CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:22][C:21]([OH:24])=[O:23]
Reactant: COc1c(CC#N)cccc1Oc1ccccc1C
Reactant: CC(=O)O
Agent: Cl
Product: COc1c(CC(=O)O)cccc1Oc1ccccc1C

Procedure:
2-[2-Methoxy-3-(o-tolyloxy)phenyl]acetonitrile (43.0 g) was added to a mixture of acetic acid (200 ml) and conc. hydrochloric acid (50 ml), and the mixture ws refluxed under heating for 5 hrs. The reaction mixture was evaporated, and water was added to the residue and extracted with diethyl ether. The extract was washed with water and extracted with aqueous sodium bicarbonate. The aqueous extract was washed with diethyl ether, acidified with conc. hydrochloric acid and then extracted with diethyl ether. The ether extract was dried over magnesium sulfate and evaporated. The crystalline residue (37.50 g) was recrystallized from a mixture of diisopropyl ether and n-hexane to give 2-[2-methoxy-3-(o-tolyloxy)phenyl]acetic acid (34.5 g). mp 90°-92° C.
Reaction SMILES: C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[NH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([NH:23][C:24]2[CH:25]=[C:26]([N:43]([CH:53]3[CH2:55][CH2:54]3)CC3C=CC(OC)=CC=3)[C:27]3[N:28]([C:30]([C:33]([NH:35][C:36]4[CH:41]=[CH:40][N:39]=[CH:38][C:37]=4[F:42])=[O:34])=[CH:31][N:32]=3)[N:29]=2)[CH2:19][CH2:18]1.[N:56]1([C:62](OC(C)(C)C)=[O:63])[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1.C(O)(C(F)(F)F)=O>ClCCl.CN(C1C=CN=CC=1)C>[CH:53]1([NH:43][C:26]2[C:27]3[N:28]([C:30]([C:33]([NH:35][C:36]4[CH:41]=[CH:40][N:39]=[CH:38][C:37]=4[F:42])=[O:34])=[CH:31][N:32]=3)[N:29]=[C:24]([NH:23][C@H:20]3[CH2:21][CH2:22][C@H:17]([NH:16][C:62]([N:56]4[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]4)=[O:63])[CH2:18][CH2:19]3)[CH:25]=2)[CH2:54][CH2:55]1
Reactant: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)C2CC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccncc1F)c1cnc2c(NC3CC3)cc(N[C@H]3CC[C@H](NC(=O)N4CCNCC4)CC3)nn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To di-tert-butyl dicarbonate (10.66 μL, 0.046 mmol) in dichloromethane (1 mL) was added DMAP (2.80 mg, 0.023 mmol) followed by 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (25 mg, 0.046 mmol, 83A). The clear yellow solution was stirred at room temperature for 10 minutes then tert-butyl piperazine-1-carboxylate (8.55 mg, 0.046 mmol) was added, and stirred at room temperature for 1 hr. TFA (0.5 mL) was added, and after 10 minutes, the reaction mixture was concentrated to dryness, taken up in DMSO and methanol and purified using reverse phase HPLC to isolate 8-(cyclopropylamino)-N-(3-fluoropyridin-4-yl)-6-((trans)-4-(piperazine-1-carboxamido)cyclohexylamino)imidazo[1,2-b]pyridazine-3-carboxamide (22 mg, 0.027 mmol, 59.5% yield) as a white solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=1.39 minutes [M+H]=537.37. 1H NMR (500 MHz, METHANOL-d3) δ ppm 8.90 (1H, t, J=6.64 Hz), 8.76 (1H, d, J=3.67 Hz), 8.50 (1H, d, J=5.96 Hz), 8.05-8.22 (1H, m), 6.11 (1H, s), 3.84-4.03 (1H, m), 3.61-3.72 (4H, m), 3.58 (1H, t, J=10.77 Hz), 3.14-3.27 (4H, m), 2.51-2.62 (1H, m, J=6.76, 6.76, 3.67, 3.44 Hz), 2.19 (2H, d, J=12.37 Hz), 1.98 (2H, d, J=13.29 Hz), 1.21-1.69 (4H, m), 0.84-1.05 (2H, m), 0.51-0.71 (2H, m)
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)=[C:17]([Cl:30])[CH:16]=2)[NH:7][N:6]=1.[OH:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:30][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:35]4[CH2:36][CH2:37][CH:32]([OH:31])[CH2:33][CH2:34]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1
Reactant: OC1CCNCC1
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)c1
Product: OC1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)CC1
Yield: 39 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine and 4-hydroxypiperidine to give the title compound in 39% yield; NMR Spectrum: 1.32-1.39 (m, 2H), 1.66-1.69 (m, 2H), 2.15 (t, 2H), 2.75-2.80 (m, 4H), 3.40-3.44 (m, 1H), 4.40 (t, 2H), 4.53 (br s, 1H), 5.25 (s, 2H), 7.18 (t, 1H), 7.23 (d, 1H), 7.29-7.33 (m, 2H), 7.44-7.47 (m, 1H), 7.56 (d, 1H), 7.90 (s, 1H), 8.29 (s, 1H), 8.50 (br s, 1H); Mass Spectrum: 513 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=2)=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:25](I)[CH3:26]>CN(C=O)C>[CH2:25]([O:14][C:12]1[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=[C:8]([C:5]2[N:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[N:13]=1)[CH3:26]
Reactant: Nc1ccc(-c2nc(O)cc(C(F)(F)F)n2)nc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(C(F)(F)F)nc(-c2ccc(N)cn2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of compound of example 15 (0.100 g, 0.390 mmol) in DMF (3 mL), was added K2CO3 (0.080 g, 0.58 mmol) and stirred at 25° C. for 10 minutes. To the reaction mixture, ethyl iodide (0.0913 g, 0.58 mmol) was added slowly and stirred at 25° C. for 1 hour. DMF was removed under vacuum, and the reaction mass was quenched by water, extracted with ethyl acetate (3×10 mL), dried over sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 8% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH:10]([O:13][CH3:14])[O:11][CH3:12])[CH:3]=1.[CH3:15][N:16]1[CH:21]2[CH2:22][CH2:23][CH:17]1[CH2:18][C:19](=O)[CH2:20]2.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:19]2[CH2:20][CH:21]3[N:16]([CH3:15])[CH:17]([CH2:23][CH2:22]3)[CH2:18]2)=[C:4]([CH2:9][CH:10]([O:13][CH3:14])[O:11][CH3:12])[CH:3]=1
Reactant: CN1C2CCC1CC(=O)C2
Reactant: COC(Cc1cc(Br)ccc1N)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(Cc1cc(Br)ccc1NC1CC2CCC(C1)N2C)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.1 %

Procedure:
Crude compound 67 (225.4 mg, 0.866 mmol) and 8-methyl-8-azabicyclo[3.2.1]octan-3-one (241.1 mg, 1.732 mmol) were stirred in acetic acid (10 mL) under argon in the presence of anhydrous sodium sulfate (1.230 g, 8.660 mmol) at room temperature for 30 minutes. Sodium triacetoxyborohydride (550.6 mg, 2.598 mmol) was then added and the mixture stirred for 24 hours at room temperature. After dilution with a mixture of 8:1 ethyl acetate:Hexanes, the reaction is quenched with saturated sodium bicarbonate. The mixture was transferred to a separatory funnel and the organic layer separated. The organic layer was dried over sodium sulfate and concentrated under reduced pressure and the residue purified via chromatography on silica gel (2M NH3 in methanol:CH2Cl2, 5:95%) to yield a pale yellow residue, 83 (120 mg, 36.1%) as an 5:1 or 1:5 mixture of endo/exo stereoisomers. 1H NMR (major isomer-DMSO-d6) δ 1.56-1.70 (m, 2H), 1.87-1.99 (m, 4H), 2.04-2.09 (m, 2H), 2.21 (s, 3H), 2.79 (d, 2H, J=5.3 Hz), 3.03-3.17 (m, 2H), 3.28 (s, 6H), 3.40-3.49 (m, 1H), 4.54 (t, 1H, J=5.3 Hz), 4.98 (s, 1H), 6.36 (d, 1H, J=9.3 Hz), 7.11-7.21 (m, 2H); ESI-MS (m/z, %): 383/385 (MH+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[CH2:12][C:13]([OH:15])=O.[N:16]1([CH:22]2[CH2:25][N:24]([C:26](=[O:29])[CH:27]=[CH2:28])[CH2:23]2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[CH2:12][C:13]([N:19]1[CH2:20][CH2:21][N:16]([CH:22]2[CH2:25][N:24]([C:26](=[O:29])[CH:27]=[CH2:28])[CH2:23]2)[CH2:17][CH2:18]1)=[O:15]
Reactant: O=C(O)Cc1c[nH]c2cc(Cl)c(Cl)cc12
Reactant: C=CC(=O)N1CC(N2CCNCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CC(N2CCN(C(=O)Cc3c[nH]c4cc(Cl)c(Cl)cc34)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.7 %

Procedure:
A mixture of 2-(5,6-dichloro-1H-indol-3-yl)acetic acid (90 mg, 0.372 mmol), 1-(3-(piperazin-1-yl)azetidin-1-yl)prop-2-en-1-one (87 mg, 0.446 mmol), EDCI.HCl (107 mg, 0.558 mmol), HOBt (75 mg, 0.558 mmol) in DMF (3 mL) at 0° C., Et3N (112 mg, 1.11 mmol) was added. The resulting mixture was stirred at RT for 16 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=30:1) to afford the desired product (12 mg, 7.66% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ:11.19 (bs, 1H), 7.79 (s, 1H), 7.59 (s, 1H), 7.35 (d, 1H), 6.28 (dd, J=9.6, 16.8 Hz, 1H), 6.09 (dd, J=2.4, 17.2 Hz, 1H), 5.66 (dd, J=2.4, 10.4 Hz, 1H), 4.21-4.18 (m, 1H), 4.02-3.98 (m, 1H), 3.93-3.88 (m, 1H), 3.78 (s, 2H), 3.74-3.70 (m, 1H), 3.53-3.47 (m, 4H), 3.10-3.07 (m, 1H), 2.25-2.19 (m, 4H). ESI-MS m/z: 423.3[M+1].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].Cl[C:13]1[N:14]=[C:15]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[C:16]2[S:21][C:20]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([N:29]([CH3:31])[CH3:30])[CH2:25][CH2:24]3)=[CH:19][C:17]=2[N:18]=1>CN(C=O)C.O>[N:1]1([C:13]2[N:14]=[C:15]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[C:16]3[S:21][C:20]([CH2:22][N:23]4[CH2:24][CH2:25][CH:26]([N:29]([CH3:31])[CH3:30])[CH2:27][CH2:28]4)=[CH:19][C:17]=3[N:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: c1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C1CCN(Cc2cc3nc(-n4ncc5ccccc54)nc(N4CCOCC4)c3s2)CC1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 48.9 %

Procedure:
A solution of indazole (0.118 g) in DMF (8 mL) was cooled to 0° C. then sodium hydride (0.06 g) added. After 15 min, [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.395 g) was added and the reaction vessel sealed and heated at 150° C. After 1 h the reaction mixture was cooled to room temperature then diluted with water. The resulting precipitate was collected by filtration then purified by chromatography (silica, 0 to 20% of a 49:1 MeOH:NH4OH mixture in dichloromethane) to furnish 116 (0.233 g, 49%) as a white solid after trituration with ethyl acetate. MS m/e 478 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.41 (dd, J=11.68, 3.39 Hz, 2 H) 1.73 (d, J=10.93 Hz, 2 H) 2.07 (t, J=10.74 Hz, 3 H) 2.17 (s, 6 H) 2.94 (d, J=11.68 Hz, 2 H) 3.75-3.90 (m, 6 H) 3.93-4.13 (m, 4 H) 7.31 (t, J=7.54 Hz, 1 H) 7.39 (s, 1 H) 7.56 (dd, J=7.91, 6.40 Hz, 1 H) 7.88 (d, J=7.91 Hz, 1 H) 8.39 (s, 1 H) 8.68 (d, J=8.67 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:25]=1.ClC1C=C(C=CC=1)C(OO)=[O:31]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:17][CH2:18][N:19]([C:22](=[O:24])[CH3:23])[CH2:20][CH2:21]3)[C:10]3=[N+:11]([O-:31])[CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:25]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Solvent: ClCCl
Product: CC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3ccc[n+]([O-])c32)CC1
Yield: 29.7 %

Procedure:
To a mixture of 711 mg (2.01 mmole) of 8-chloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6] cyclohepta[1,2-b]pyridine in 30 ml of dry CH2Cl2 at -10° C. and under a nitrogen atmosphere was added 246 mg (1.60 mmole) of m-chloroperoxybenzoic acid. After 95 min. the mixture was taken up in CH2Cl2 and washed once with 10% aqueous sodium bisulfite and once with 10% aqueous sodium hydroxide. It was dried over magnesium sulfate, filtered, and concentrated in vacuo. The product was purified via flash chromatography (MeOH in CH2Cl2) and recrystallized from ethyl acetate/hexanes to give 175 mg of the title compound as a hemi-ethyl acetate solid. (m.p. 90.5°-93° C.)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:14])[CH2:12][CH3:13])[CH:7]=[CH:6][C:5]=1[O:15][CH3:16])([O-])=O.CO.N.[H][H]>[Pd].O>[CH3:16][O:15][C:5]1[CH:6]=[CH:7][C:8]([NH:10][C:11](=[O:14])[CH2:12][CH3:13])=[CH:9][C:4]=1[NH2:1]
Reactant: [H][H]
Reactant: CCC(=O)Nc1ccc(OC)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: N
Solvent: O
Solvent: CO
Product: CCC(=O)Nc1ccc(OC)c(N)c1
Reaction time: 1 h

Procedure:
114 parts of 2-nitro-4-propionamidoanisole, 160 parts of methanol, 2.5 parts of a 30% aqueous solution of ammonia and 1 part of a 50% suspension of palladium on activated charcoal, moist with water, in 2 parts of water are charged to an autoclave equipped with an aerating stirrer. The autoclave is pressurised with hydrogen and, at a pressure of 18 bar and a temperature of 80° C., hydrogenation is carried out for 1 hour. 2-Methoxy-5-propionamidoaniline is obtained in quantitative yield in a purity of >97% (analysis by liquid chromatography).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:6]2[C:7](OC(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[CH3:14][NH2:15].C1COCC1>C1COCC1>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=1[C:7]([NH:15][CH3:14])=[O:8]
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromoisatoic anhydride (4.84 g, 20.0 mmol) in THF (20 mL) was added 2M MeNH2/THF (15 mL, 30 mmol). The resulting mixture was stirred at rt overnight. The solvent was evaporated under reduced pressure and the crude material was used in next step without further purification. MS (ESI): m/z=229.03/231.06 [M+H]+. HPLC: tR=3.14 min (ZQ3: polar—5 min).
Reaction SMILES: C1(C)C=C[C:4]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:9])=[O:8])=CC=1.[C:18]([N:21]1[CH2:29][CH2:28][CH:24]([C:25](Cl)=[O:26])[CH2:23][CH2:22]1)(=[O:20])[CH3:19].C(N1CCCC(C(Cl)=O)C1)(=O)C1C=CC=CC=1>>[C:18]([N:21]1[CH2:22][CH2:23][CH:24]([C:25](=[O:26])[C:14]2[CH:13]=[CH:12][C:11]([NH:10][S:7]([CH3:4])(=[O:8])=[O:9])=[CH:16][CH:15]=2)[CH2:28][CH2:29]1)(=[O:20])[CH3:19]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Agent: O=C(Cl)C1CCCN(C(=O)c2ccccc2)C1
Product: CC(=O)N1CCC(C(=O)c2ccc(NS(C)(=O)=O)cc2)CC1

Procedure:
The same procedure as above was repeated except that methanesulfonamilide was replaced with p-toluenesulfonanilide or 1-acetylisonipecotoyl chloride was replaced with (±)-N-benzoylnipecotoyl chloride or (±)-N-benzoyl-β-prolyl chloride prepared in Referential Example 2 to obtain the following compounds:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[N:3]=1.N1C(C)=CC=CC=1C.[Cl:19][C:20]1[CH:21]=[C:22]([C@@H:30]([CH2:34][C@H:35]2[CH2:39][CH2:38][C:37](=[O:40])[CH2:36]2)[C:31](Cl)=[O:32])[CH:23]=[CH:24][C:25]=1[S:26]([CH3:29])(=[O:28])=[O:27]>C(Cl)Cl>[Cl:19][C:20]1[CH:21]=[C:22]([C@@H:30]([CH2:34][C@H:35]2[CH2:39][CH2:38][C:37](=[O:40])[CH2:36]2)[C:31]([NH:1][C:2]2[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[N:3]=2)=[O:32])[CH:23]=[CH:24][C:25]=1[S:26]([CH3:29])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)c1ccc([C@@H](C[C@H]2CCC(=O)C2)C(=O)Cl)cc1Cl
Reactant: Nc1ccn(CCCO)n1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](C[C@H]2CCC(=O)C2)C(=O)Nc2ccn(CCCO)n2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
In a round bottom flask was placed 3-(3-amino-pyrazol-1-yl)-propan-1-ol (prepared in Example 23, 32 mg, 0.22 mmol), 2,6-lutidine (35 μL, 0.30 mmol) and methylene chloride (5 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionyl chloride in methylene chloride (prepared as in Example 96, ˜0.10 M solution, 2 mL, 0.20 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was diluted with methylene chloride (5 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 70% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-3-((R)-3-oxo-cyclopentyl)-propionamide (83 mg, 88%) as a white foam: [α]30589=−88.0° (c=0.10, methylene chloride); ES-HRMS m/e calcd for C21H26N3O5SCl (M+H)+ 468.1355, observed 468.1354; 1H NMR (300 MHz, DMSO-d6) δ 1.51 (m, 1H, CH), 1.78-2.32 (m, 10H, 5×CH2), 3.34 (brs, 5H, OCH2 and SO2CH3), 3.95 (m, 1H, ArCHCO), 4.02 (t, J=6.5 Hz, 2H, NCH2), 4.56 (t, J=4.7 Hz, 1H, OH), 6.41 (s, 1H, Ar), 7.56 (s, 1H, Ar), 7.61 (d, Jo=8.3 Hz, 1H, Ar), 7.73 (s, 1H, Ar), 8.02 (d, Jo=8.3 Hz, 1H, Ar), 10.84 (s, 1 H, NH).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH2:12][N:13]1[C:18](=[O:19])[CH:17]=[CH:16][C:15]([CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:14]1)[CH2:7]2.Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:38]([O:37][C:35]([CH2:34][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH2:12][N:13]1[C:18](=[O:19])[CH:17]=[CH:16][C:15]([CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[N:14]1)[CH2:7]2)=[O:36])[CH3:39]
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)nn1CC1CCc2c(O)cccc2C1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1cccc2c1CCC(Cn1nc(C(c3ccccc3)c3ccccc3)ccc1=O)C2
Yield: 84.1 %

Procedure:
A suspension of 2-[(1,2,3,4-tetrahydro-5-hydroxy-2-naphthyl)methyl]-6-diphenylmethyl-3(2H)-pyridazinone (425 mg), ethyl bromoacetate (184 mg) and potassium carbonate (152.9 mg) in acetonitrile (15 ml) was refluxed for 6 hours. After cooling, the precipitated solid was filtered off and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give 2-[(1,2,3,4-tetrahydro-5-ethoxycarbonylmethoxy-2-naphthyl)methyl]-6-diphenylmethyl-3(2H)-pyridazinone (0.43 g) as pale yellow oil.
Reaction SMILES: O(CC)[C:2]([S-])=[S:3].[K+].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([NH2:16])[CH:10]=1>C(O)C>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][C:2]([SH:3])=[N:16][C:11]=2[CH:10]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1cc(Cl)ccc1O
Agent: [K+]
Solvent: CCO
Product: Sc1nc2cc(Cl)ccc2o1
Yield: 99.1 %

Procedure:
A mixture of potassium ethyl xanthate (13.4 g, 84.0 mmol) and 4-chloro-2-aminophenol (10 g, 69.6 mmol) was dissolved in absolute ethanol (200 mL). The mixture was stirred under reflux overnight. After cooling, the solvent was evaporated under reduced pressure, the residue was dissolved in water (200 mL) and treated with HOAc to adjust pH to 5. A solid formed, which was filtered and dried to afford 5-chloro-2-mercaptobenzoxazole (12.8 g, yield 99.1%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[CH2:15][NH:14][CH:13]([CH3:21])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Cl>CCO>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][N:14]1[CH:13]([CH3:21])[CH2:12][C:11]2[C:16](=[CH:17][C:18]([O:19][CH3:20])=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[CH2:15]1
Reactant: COc1cc2c(cc1OCc1ccccc1)CC(C)NC2
Reactant: COc1cccc(CCl)c1
Solvent: CCO
Product: COc1cccc(CN2Cc3cc(OC)c(OCc4ccccc4)cc3CC2C)c1
Yield: 80.4 %

Procedure:
A solution of 213 (300 mg, 1.1 mmol), TEA (0.3 ml, 2.1 mmol) and 3-methoxybenzyl chloride (0.18 ml, 1.3 mmol) in EtOH (3 ml) was heated in the microwave at 130° C. for 1.5 h. The reaction mixture was concentrated in vacuo and the crude residue was dissolved in EtOAc (30 ml) and washed with brine (30 ml). The organic layer was dried (MgSO4) and concentrated in vacuo. Purification (flashmaster: 20 g, 100% hex to 100% EtOAc over 25 min) afforded the title compound (357 mg, 84%) as a colourless oil. 1H NMR (270 MHz; CDCl3) 1.12 (3H, d, J=6.4 Hz, CH3CH), 2.47 (1H, dd, J=16.1, 5.7 Hz, CHH), 2.86 (1H, dd, J=16.1, 4.9 Hz, CHH), 3.0-3.11 (1H, m, CH3CH), 3.55 (2H, t, J=13.4 Hz, CH2), 3.76-3.81 (2H, m, CH2), 3.80 (6H, s, 2×OCH3), 5.10 (2H, s, CH2Ph), 6.47 (1H, s, CH), 6.60 (1H, s, CH), 6.79 (1H, ddd, J=8.2, 2.5, 1.0 Hz, CH), 6.94-6.97 (2H, m, 2×CH), 7.15-7.45 (6H, m, 5×CH, phenyl and CH). 13C (67.5 MHz; CDCl3) 15.31 (CH3), 35.03 (CH2), 51.51 (CH2), 52.27 (CH), 55.32 (CH3), 56.11 (CH3), 57.24 (CH2), 71.21 (CH2), 109.95 (CH), 112.48 (CH), 114.36 (CH), 114.56 (CH), 121.32 (CH),125.83 (C), 126.95 (C), 127.37 (CH), 127.82 (CH), 128.59 (CH), 129.30 (CH), 137.47 (C), 141.35 (C), 146.73 (C), 147.91 (C), 159.77 (C). LC/MS (ES+) tr=1.52 min, m/z 404.25 (M++H).