Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH:25]3[C:30]([OH:32])=[O:31])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[C:40]([N:44]=[C:45]=[O:46])([CH3:43])([CH3:42])[CH3:41]>C1COCC1>[C:40]([NH:44][C:45]([N:27]1[CH2:28][CH2:29][C@@H:24]([NH:23][S:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([CH3:1])[CH:11]=3)=[CH:15][CH:16]=2)(=[O:21])=[O:22])[C@@H:25]([C:30]([OH:32])=[O:31])[CH2:26]1)=[O:46])([CH3:43])([CH3:42])[CH3:41]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)NC3CCNCC3C(=O)O)cc2)c2ccccc2n1
Reactant: CC(C)(C)N=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCN(C(=O)NC(C)(C)C)C[C@@H]3C(=O)O)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 82 %

Procedure:
To a solution of 0.5 g (1.1 mmol) of 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-3-carboxylic acid (Example 29, Step 1) and triethylamine (0.3 mL, 2.197 mmol) in THF (10 mL) at 0° C. was added tert-butylisocyanate (0.130 g, 1.32 mmol). The reaction mixture was allowed to warm to 25° C. and then stirred for 19 h. The THF was removed in vacuo and the resulting oil was diluted with ethyl acetate (100 mL). The organics were washed with saturated aqueous sodium chloride (2×30 mL), dried over MgSO4, filtered and concentrated to obtain a crude solid (0.580 g). The crude product was purified by reverse phase HPLC (Gilson) on a Phenomex C-18 semi-prep column eluting an acetonitrile:water gradient, to afford (3S,4R)-1-tert-butylcarbamoyl-4-[4-(2-methyl-quinolin-4-yl methoxy)-benzenesulfonylamino]-piperidine-3-carboxylic acid as an amorphous white solid (0.5 g, 88.5%). MS: 555 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[O:24][C@@H:25]4[CH2:29][CH2:28][NH:27][CH2:26]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:30].[O:31]1[CH2:34][C:33](=O)[CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[O:24][C@@H:25]4[CH2:29][CH2:28][N:27]([CH:33]5[CH2:34][O:31][CH2:32]5)[CH2:26]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:30]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@@H]1CCNC1)C3
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@@H]1CCN(C2COC2)C1)C3
Yield: 32.3 %

Procedure:
A mixture of Example 80 (150 mg; 0.35 mmol; 1 eq.), 3-oxetanone (38 mg; 0.52 mmol; 1.5 eq.) and sodium triacetoxyborohydride (74 mg; 0.35 mmol; 1 eq.) in DCE (4 mL) was stirred at 50° C. for 16 hours. The reaction mixture was diluted with DCM, washed with 0.1M NaOH, dried over magnesium sulfate and concentrated in vacuo. Purification by mass directed preparative HPLC afforded the title compound (55 mg, 41%) as white foam. 1H NMR (DMSO-d6) δ 7.41-7.31 (m, 1H), 7.01 (dd, J=11.5, 2.2 Hz, 1H), 6.88 (td, J=8.4, 2.3 Hz, 1H), 5.05-4.95 (m, 1H), 4.85-4.78 (m, 2H), 4.69-4.48 (m, 2H), 4.47-4.37 (m, 2H), 4.37-4.21 (m, 2H), 3.60-3.48 (m, 1H), 2.90-2.70 (m, 1H), 2.84 (s, 1.5H), 2.80 (s, 1.5H), 2.62 (s, 1.5H), 2.59-2.53 (m, 2H), 2.56 (s, 1.5H), 2.42-2.15 (m, 2H), 1.84-1.70 (m, 1H). HPLC (max plot) 99.5%, Rt 2.74 min. UPLC/MS: (MS+) 486.5 ([M+H]+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C>CS(C)=O.CS(C)=O.CO>[NH:24]1[C:25]2[C:21](=[C:20]([C:18]3[CH:17]=[C:16]4[C:12]([CH:13]=[N:14][NH:15]4)=[C:11]([NH:10][C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)[N:7]=4)=[O:9])[CH:19]=3)[CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(Cl)n1
Reactant: C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CS(C)=O
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(N2CCCC2)n1
Temperature: 160 °C
Yield: 16 %

Procedure:
To a microwave vial was added 2 ml of a solution of 6-chloro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (350 mg, 0.26 mmol, prepared as described in Example 18) in DMSO (14 ml). Pyrrolidine (0.022 ml, 0.26 mmol) and DIPEA (0.113 ml) were added and the mixture was heated at 160° C. for 3 h under microwave irradiation. The crude reaction mixture was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method B). Product-containing fractions were dried under a stream of nitrogen to afford the title compound (17.6 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[C:24]1([C:34](O)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:34]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][N:25]=2)=[O:35])=[O:8])[N:6]=1
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: O=C(O)c1nccc2ccccc12
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2nccc3ccccc23)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with Isoquinoline-1-carboxylic acid. LC-MS (basic): tR=0.83 min; [M+H]+=488.4.
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Cl:25][C:26]1[CH:27]=[C:28]([CH2:32][CH2:33][NH2:34])[CH:29]=[CH:30][CH:31]=1>>[Cl:25][C:26]1[CH:27]=[C:28]([CH2:32][CH2:33][NH:34][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([C:15]3[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=3)=[CH:18][CH:19]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: NCCc1cccc(Cl)c1
Reactant: CCCCCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Product: CCCCCCCCCCCc1noc(-c2ccc(CNCCc3cccc(Cl)c3)cc2)n1
Yield: 62 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and [2-(3-chlorophenyl)ethyl]amine gave the title compound as a colorless oil (62%). 1H NMR (CDCl3, 300 MHz) δ 7.99 (d, J=8.3 Hz, 2H, 7.37 (d, J=8.3 Hz, 2H), 7.21-6.96 (m, 4H), 3.80 (s, 2H), 2.87-2.78 (m, 2H), 2.77-2.66 (m, 4H), 1.80-1.66 (m, 2H), 1.40-1.10 (m, 16H), 0.80 (t, J=7.2 Hz, 3H). M+(LC/MS(ESI)): 468.4. HPLC (Condition A), Rt: 5.1 min (HPLC purity: 99.1%).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[CH2:18]=O>>[N:12]1([CH2:18][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]=2[OH:11])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Oc1cccc2ccccc12
Reactant: C=O
Reactant: C1CCNCC1
Product: Oc1c(CN2CCCCC2)ccc2ccccc12
Yield: 45 %

Procedure:
Brown (Bull. Natl. Inst. Sci. India, No. 31, 167-178, 1965) discloses the following reaction scheme: Mannich reaction of 1-naphthol with piperidine and formaldehyde afforded 2-(piperidinomethyl)-1-naphthol in a yield of 45%. Reduction of 2-(piperidinomethyl)-1-naphthol in the presence of H2 /Pd/SrCO3 afforded 2-methyl-1-naphthol in a yield of 85%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[CH:7]=[CH:8][CH2:9][Te:10](=[O:11])[C:5]=2[CH:4]=1.[F:14][S:15]([O:18][CH2:19][CH3:20])(=[O:17])=[O:16]>CCOCC>[F:14][S:15]([OH:18])(=[O:17])=[O:16].[CH2:19]([O:18][C:7]1[C:6]2[CH:12]=[CH:13][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[Te:10](=[O:11])[CH2:9][CH:8]=1)[CH3:20]
Reactant: COc1ccc2c(c1)[Te](=O)CC=C2
Reactant: CCOS(=O)(=O)F
Solvent: CCOCC
Product: CCOC1=CC[Te](=O)c2cc(OC)ccc21
Product: O=S(=O)(O)F
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
Five g of 7-methoxybenzotelluropyrone was added to 20 ml of freshly distilled ethyl fluorosulfonate. The resulting mixture was stirred under nitrogen at 60° C. for 10 minutes. Two hundred ml of ether was added precipitating a red solid. The product was collected by filtration and recrystallized from acetonitrile to give 6.0 g (87%) of a red solid.
Reaction SMILES: [CH3:1][NH:2][O:3][CH3:4].C(N(CC)CC)C.[C:12]([C:16]1[O:17][C:18]2[C:24]([S:25](Cl)(=[O:27])=[O:26])=[C:23]([Cl:29])[CH:22]=[CH:21][C:19]=2[N:20]=1)([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[CH3:4][O:3][N:2]([CH3:1])[S:25]([C:24]1[C:18]2[O:17][C:16]([C:12]([CH3:14])([CH3:13])[CH3:15])=[N:20][C:19]=2[CH:21]=[CH:22][C:23]=1[Cl:29])(=[O:26])=[O:27]
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Reactant: CNOC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CON(C)S(=O)(=O)c1c(Cl)ccc2nc(C(C)(C)C)oc12
Temperature: 0 °C

Procedure:
N,O-dimethylhydroxylamine (1.98 g, 2 equiv) was suspended in dry THF (20 ml) and cooled to 0° C. in an ice bath while stirring vigourously. Triethylamine (4.51 ml, 2 equiv) was added maintaining the temperature at 0° C. followed by dropwise addition of 2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl chloride (US 2007/0249672 page 9) (5 g, 16.22 mmol, 1 equiv) in THF (10 ml) over 30 minutes. The reaction mixture was stirred at 0° C. for 1 h and then allowed to warm to room temperature overnight. The resulting mixture was filtered and concentrated in vacuo and the resulting solid was dissolved in EtOAc (75 ml), washed with water (3×20 ml), sat. brine (30 ml) dried (MgSO4) and concentrated in vacuo to afford the title compound as a solid; [M+H]+ 333.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[CH:15]=[C:16]([N+:21]([O-:23])=[O:22])[C:17](=O)[NH:18][CH:19]=2)=[CH:9][CH:8]=1.CN(C=O)C.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Br:3][C:17]1[C:16]([N+:21]([O-:23])=[O:22])=[CH:15][C:14]([CH2:13][C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)=[CH:19][N:18]=1
Reactant: O=c1[nH]cc(Cc2ccc(F)cc2)cc1[N+](=O)[O-]
Reactant: O=P(Br)(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(Cc2ccc(F)cc2)cnc1Br
Temperature: 25 °C

Procedure:
A solution of POBr3 (227 g, 0.79 mol) in toluene (900 mL) was added slowly to a stirred suspension of 5-[(4-fluorophenyl)methyl]-3-nitro-2(1H)-pyridinone (179 g, 0.72 mol) in toluene (900 mL). The mixture was heated to reflux; then cooled to rt and DMF (56 mL, 0.72 mol) was added slowly; the mixture was again heated to reflux and then allowed to cool to rt overnight. After cooling the mixture in an ice-bath, water (500 mL) was added slowly followed by dropwise addition 4 N NaOH (450 mL, 1.76 mol). All insoluble material was removed by filtration and the two liquid phases were separated. The organic layer was concentrated at reduced pressure to afford the product as a beige solid: 1H NMR (d6-DMSO) δ 8.62 (1H, d, J=2 Hz), 8.37 (1H, d, J=2 Hz), 7.33 (2H, m), 7.12 (2H, m), 4.05 (2H, s); ES+ MS: 313 (M+H+, 100), 311 (M+H+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[Cl:37][C:38]1[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:39]=1[CH2:40]Br>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[CH2:40][C:39]2[C:42]([F:46])=[CH:43][CH:44]=[CH:45][C:38]=2[Cl:37])=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1cccc(Cl)c1CBr
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(Cl)n(-c3ccccc3)c3ccccc23)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(Cc3c(F)cccc3Cl)n(-c3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
A solution of 500 mg (1.14 mmol) of the compound of example 16, step 1, in THF (8 ml) was cooled to −78° C. with an acetone/dry ice bath. Within 10 min a solution of n-butyllithium (0.55 ml, 1.36 mmol, 2.5 M in hexane) was added followed by 0.36 ml (2.27 mmol) of 2-chloro-6-fluoro-benzyl bromide. The cooling bath was removed and the reaction mixture was allowed to warm up slowly to room temperature and stirred overnight. The mixture was quenched with water and extracted with EA. The organic layer was separated, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by preparative HPLC. The eluate was lyophilized overnight to give 216 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH:12]2[CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:29]1[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[N:31]=[C:30]1[CH2:38][CH3:39])=[N:6][C:7]=2[N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:14]1[CH2:13][CH:12]([CH2:11][C:10]2[N:2]([CH3:1])[C:3]3[C:8]([N:9]=2)=[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:6]=[C:5]([N:29]2[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[N:31]=[C:30]2[CH2:38][CH3:39])[N:4]=3)[CH2:15]1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 3-((9-methyl-2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purin-8-yl)methyl)azetidine-1-carboxylate (0.64 g, 1.2 mmol) in DCM (10 mL) was added trifluoroacetic acid (1.0 mL, 13 mmol) The reaction mixture was then stirred at room temperature for 1 hour. The reaction mixture was then evaporated to dryness. The residue was then re-dissolved in MeOH and neutralized by adding a 2M NH3 in MeOH. The solution was then concentrated and purified by flash chromatography using a KP—NH2 column (0-10% MeOH in DCM) to give 530. LCMS m/z: 433.2 (MH+)
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C:12]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH:13]=2)(=O)=O)=CC=1.[I-:21].[Na+].O>CC(C)=O>[I:21][CH2:11][CH:12]1[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH2:13]1
Reactant: [I-]
Reactant: Cc1ccc(S(=O)(=O)OCC2=Cc3ccccc32)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: ICC1Cc2ccccc21
Yield: 88 %

Procedure:
6 g of benzocyclobuten-1-ylmethyl para-toluenesulfonate (prepared according to the process described in J.A.C.S., (1975), 154, p. 347) are mixed with 6.2 g of sodium iodide in 85 ml of acetone. The reaction medium is brought to reflux for 8 hours, then introduced into 150 ml of water and extracted several times with ethyl ether. The organic phase is then washed with normal sodium thiosulfate solution, dried over anhydrous magnesium sulfate and concentrated to obtain the expected compound in the form of an oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH:34]([CH3:36])[CH3:35])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][C@H:6]1[C:21]([NH:23][C@H:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)=[O:22])=[O:4].[C:37]([N:44]([CH3:50])[C@H:45]([C:47](O)=[O:48])[CH3:46])([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:40]([O:39][C:37]([N:44]([CH3:50])[C@@H:45]([CH3:46])[C:47]([NH:1][C@@H:2]([CH:34]([CH3:36])[CH3:35])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][C@H:6]1[C:21]([NH:23][C@H:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)=[O:22])=[O:4])=[O:48])=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)[C@H](N)C(=O)N1CCN(C(=O)OCc2ccccc2)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCN(C(=O)OCc2ccccc2)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Yield: 88.5 %

Procedure:
Amine 5 (12.57 g, 25.5 mmol) is then coupled with BOC-N-methyl-L-alanine (5.18 g, 25.5 mmol) using DIEA (22.3 mL, 0.13 mol), HBTU (10.64 g, 28.1 mmol) and HOBt (3.79 g, 28.1 mmol) in DMF (550 mL) under the same conditions as in step 1 above. Purification is carried out by flash chromatography on silica gel (CH2Cl2 as eluent initially, followed by 50% Et2O/CH2Cl2 to elute the desired product). The desired coupled product 6 is isolated as a white foam (15.30 g, 89% yield): 1H NMR δ (CDCl3) 7.28-7.38 (br m, 5H), 7.03-7.19 (br m, 4H), 6.73 (br s, 1H), 6.02-6.35 (br m, 1H), 5.05-5.26 (br m, 4H), 3.84-4.82 (br m, 5H), 2.68-3.56 (br m, 9H), 1.70-2.07 (br m, 5H), 1.47 (s, 9H), 0.60-1.33 (br m, 8H); LCMS (APCl+) 679.0 (MH+), 579.0 (MH+-BOC, 100%); HPLC(C18 column) 99.4%.
Reaction SMILES: FC1C(O[C:9](=[O:27])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[C:11]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=C(F)C(F)=C(F)C=1F.[Cl-].[OH:33][CH:34]1[CH2:38][O:37][NH2+:36][CH2:35]1.CN1CCOCC1.C(OCC)(=O)C>CN(C)C=O>[F:17][C:12]1[C:11]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:10]([C:9]([N:36]2[CH2:35][CH:34]([OH:33])[CH2:38][O:37]2)=[O:27])[CH:15]=[CH:14][C:13]=1[F:16]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: OC1C[NH2+]OC1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)CO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.9 %

Procedure:
To a stirring solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid pentafluorophenyl ester (171 mg, 0.306 mmol) and 4-hydroxytetrahydroisoxazol-2-ium chloride (BIONET, 58 mg, 0.46 mmol) in dimethylformamide (2 mL) was added 4-methylmorpholine (0.1 mL, 0.91 mmol). The resultant reaction mixture was stirred at ambient temperature for 3 h. Ethyl acetate (50 mL) was added the mixture was washed with water (3×10 mL) and saturated brine solution (10 mL). The extracts were dried over magnesium sulfate and concentrated in vacuo. Chromatography (10% methanol-dichloromethane) afforded a tan-colored oil that solidified upon standing. Recrystallization from acetone-ether afforded [3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-phenyl]-(4-hydroxy-isoxazolidin-2-yl)-methanone (61 mg, 43% yield) as a white powder:
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:15][OH:16])[CH2:9][CH2:8][CH2:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[N:32]=[C:33]=[S:34]>O1CCCC1>[OH:16][CH2:15][C:3]1([CH2:2][O:1][C:33](=[S:34])[NH:32][C:26]2[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:25]=2[F:24])[CH2:9][CH2:8][CH2:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14]
Reactant: Fc1ccc(N=C=S)c(F)c1
Reactant: O=C1c2ccccc2CCCC1(CO)CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2CCCC1(CO)COC(=S)Nc1ccc(F)cc1F

Procedure:
To a solution of 6,6-bis(hydroxymethyl)-6,7,8,9-tetrahydrobenzocyclohepten-5-one (500 mg, 2.27 mmol) in 28 ml of tetrahydrofuran were added, at room temperature, triethylamine (0.35 ml, 2.50 mmol) and 2,4-difluorophenyl isothiocyanate (740 μl, 5.68 mmol). The mixture was heated to reflux for 72 hours, concentrated and purified by column chromatography on silica gel (eluent: 1:2 tert-butyl methyl ether/cyclohexane). The product was obtained in a yield of 234 mg (26%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH3:17])=[CH:11][C:10]=2[Br:18])=[CH:5][CH:4]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH3:17])[S:28]([C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)(=[O:30])=[O:29])=[CH:11][C:10]=2[Br:18])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CNCc1ccc(OCc2ccc(OC)cc2)c(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(COc2ccc(CN(C)S(=O)(=O)c3ccc(F)cc3)cc2Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
To a solution of intermediate 33 (2.7 g, 8.0 mmol, 1 eq) in DCM (10 mL) was added 4-fluorobenzene-1-sulfonyl chloride (1.9 g, 9.6 mmol, 1.2 eq) and DIEA (2.8 mL, 16.0 mmol, 2 eq). After stirring at room temperature for 1 h, the reaction was washed with saturated NaHCO3 and brine, dried (Na2SO4), and concentrated in vacuo. The crude product was purified via silica gel chromatography (0-40% EtOAc/hexane) to give 2.48 g (63%) of N-(4-(4-methoxybenzyloxy)-3-bromobenzyl)-4-fluoro-N-methylbenzenesulfonamide (34).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH:21]C(=O)OC(C)(C)C)[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>C(Cl)Cl.CO.O1CCOCC1>[CH3:1][C:2]1[N:7]2[C:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH2:21])[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cccc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n12
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
To a mixture of crude tert-butyl {1-[4-(5-methyl-3-phenylimidazo[1,2-a]pyridin-2-yl)phenyl]cyclobutyl}carbamate (49 mg) in DCM (0.42 mL) and methanol (0.26 mL) was added a solution of 4 M hydrogen chloride in dioxane (0.54 mL) and the mixture was stirred overnight at rt. The mixture was poured onto ice, made alkaline with aqueous sodium hydroxide (2 N) and extracted three times with a mixture of DCM. The combined organic phases were washed with brine, dried and concentrated in vacuo to give 16 mg of the title compound in 42% overall yield.
Reaction SMILES: [CH2:1]([C:3]1[N:8]([CH2:9][CH3:10])[C:7](=[O:11])[C:6]([CH3:12])=[C:5]([OH:13])[N:4]=1)[CH3:2].[F:14][C:15]([F:32])([F:31])[C:16]1[CH:30]=[CH:29][C:19]([O:20][C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([C:3]1[N:8]([CH2:9][CH3:10])[C:7](=[O:11])[C:6]([CH3:12])=[C:5]([O:13][CH2:25][C:24]2[CH:23]=[CH:22][C:21]([O:20][C:19]3[CH:29]=[CH:30][C:16]([C:15]([F:14])([F:31])[F:32])=[CH:17][CH:18]=3)=[CH:28][CH:27]=2)[N:4]=1)[CH3:2]
Reactant: FC(F)(F)c1ccc(Oc2ccc(CBr)cc2)cc1
Reactant: CCc1nc(O)c(C)c(=O)n1CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc(OCc2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)c(C)c(=O)n1CC
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.5 %

Procedure:
In 15 ml of N,N-dimethylformamide were dissolved 0.91 g of 2,3-diethyl-6-hydroxy-5-methyl-4(3H)-pyrimidinone and 1.66 g of 4-(4'-trifluoromethylphenoxy)benzyl bromide, and then 0.69 g of potassium carbonate was added thereto. The mixture was stirred for 18 hours at room temperature. The resulting solution was poured into water and extracted with benzene. The extract was washed with water, dried over anhydrous sodium sulfate and freed of solvent by distillation under reduced pressure. The oil thus obtained was purified by means of column chromatography (on silica gel, eluting with benzene) to give 1.35 g of the intended product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[CH:8][C:7]=1[CH3:20].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:20]
Reactant: [H][H]
Reactant: COC(=O)CCc1ccc(OCc2ccccc2)cc1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc(O)cc1C
Yield: 93.4 %

Procedure:
A mixture of 3-(4-Benzyloxy-2-methyl-phenyl)-propionic acid methyl ester (13.7 g, 48.5 mmol) and Pd/C (5%, 13.7 g) in MeOH (423 mL) is stirred under 60 psi of hydrogen for 24 hrs. Catalyst is filtered off, filtrate is concentrated giving the title compound (8.8 g, 93.5%).