Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([F:20])=[CH:13][C:3]=1[CH2:4]P(=O)(OCC)OCC.O=[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1.[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([F:20])=[CH:13][C:3]=1[CH:4]=[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1
Reactant: CCOP(=O)(Cc1cc(F)c([N+](=O)[O-])cc1Cl)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cc(F)c([N+](=O)[O-])cc2Cl)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 28.5 %

Procedure:
Diethyl 2-chloro-5-fluoro-4-nitrobenzylphosphonate (4.06 g, 12.47 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (2.48 g, 12.47 mmol) were stirred in tetrahydrofuran (47.9 ml) and cooled in an ice bath. Sodium hydride (0.65 g, 16.21 mmol) was added and the reaction taken off the ice bath and stirred for 3.5 hours at room temperature. The reaction was quenched with water and extracted with dichloromethane, dried (magnesium sulphate), filtered and evaporated under reduced pressure. The crude material was purified by silica chromatography using a dichloromethane solvent system. The oil obtained was triturated with heptane and filtered to give the title compound as a yellow solid (1.32 g). 1H NMR (CDCl3, 400 MHz): δ 8.12 (d, 1H), 7.13 (d, 1H), 6.33 (s, 1H), 3.55 (t, 2H), 3.44 (t, 2H), 2.41 (t, 2H), 2.34 (t, 2H), 1.48 (s, 9H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16]>C(Cl)Cl>[Si:18]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19]
Reactant: Oc1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
3-Bromophenol (6 mmol, 1.04 g), imidazole (10 mmol, 0.68 g) and TBDMSCl (6.6 mmol, 0.99 g) were dissolved in DCM (20 ml). The solution was allowed to stir at room temperature overnight. The solid generated during the reaction was filtered off and the solvent removed under reduced pressure. The resulting residue was subjected to flash chromatography (EtOAc/Hexanes=3%˜15%) giving compound 2 (1.56 g, 5.44 mmol, yield 91%). 1H NMR (CDCl3): δ 7.11-7.08 (m, 2H), 7.03-7.02 (m, 1H), 6.80-6.77 (m, 1H), 0.99 (s, 9H), 0.31 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:24])[CH2:15][C@H:16]3[O:20]C(C)(C)[O:18][C:17]3=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:25][OH:26]>CC(O)C.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:24])[CH2:15][C@@H:16]([OH:20])[C:17]([NH:25][OH:26])=[O:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)OC(=O)[C@@H](CC(=O)N2CCN(c3ccc(F)cc3)CC2)O1
Reactant: NO
Solvent: CC(C)O
Solvent: C1CCOC1
Product: O=C(NO)[C@H](O)CC(=O)N1CCN(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
To a solution of (5R)-5-{2-[4-(4-fluorophenyl)-1-piperazinyl]-2-oxoethyl}-2,2-dimethyl-1,3-dioxolan-4-one (336 mg; 1.0 mmol; 1.0 eq.) in i-PrOH/THF (25/75) (5 mL) wad added an aqueous solution of hydroxylamine (50%, 0.295 mL; 5.0 mmol; 5.0 eq.). After stirring 3 h at RT, the solvents were evaporated to give a solid. This solid was crystallized from AcOEt (by addition of Et2O and c-Hex) to give the title compound as a white powder (250 mg, 80%). M+(ESI): 312.1; M−(ESI): 310.1. 1H NMR (DMSO-d6, 300 MHz) δ 10.50 (s, 1H), 8.72 (s, 1H), 7.12-6.91 (m, 4H), 5.46 (d, J=3.0 Hz, 1H), 4.28 (q, J=6.3 Hz, 1H), 3.60 (s, 4H), 3.14-2.95 (m, 4H), 2.65 (d, J=6.3 Hz, 2H). HPLC (Condition A): Rt: 1.6 min (HPLC purity: 85.6%).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[S:8])[O:6][CH:7]=1)[CH3:2].C(N1C(=O)C2=CC=CC=[C:13]2[C:12]1=[S:21])C>>[CH2:1]([C:3]1[N:4]=[C:5]([S:8][S:21][CH2:12][CH3:13])[O:6][CH:7]=1)[CH3:2]
Reactant: CCc1coc(=S)[nH]1
Reactant: CCN1C(=O)c2ccccc2C1=S
Product: CCSSc1nc(CC)co1

Procedure:
Starting from 4-ethyl-2-thiono-4-oxazoline and N-ethylthiophthalimide there is obtained (4-ethyl-2-oxazolyl)ethyl-disulphide. nD20 = 1.5549. IR (liq.): bands inter alia at 3000, 2970, 1590, 1485, 1250, 1135, 1080, 950, 760 cm-1.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1>>[F:36][C:32]1[CH:31]=[C:30]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:12]=[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][C:24]([F:26])([F:27])[F:25])[CH:14]=[CH:15][CH:16]=3)[CH:10]=2)=[O:5])[CH:35]=[CH:34][CH:33]=1
Reactant: Fc1cccc(Br)c1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1
Product: O=C(c1cccc(F)c1)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12f and 1-bromo-3-fluorobenzene
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[C:16]([O:20][C:21](=[O:33])[CH2:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21](=[O:33])[CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([NH:15][C:13]2[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([C:3]4[CH:4]=[CH:5][O:1][CH:2]=4)[N:11]3[N:12]=2)=[O:29])=[CH:31][CH:32]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)COc1ccc(C(=O)O)cc1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Product: CC(C)(C)OC(=O)COc1ccc(C(=O)Nc2nc3cccc(-c4ccoc4)n3n2)cc1

Procedure:
The title compound was prepared following procedure and work up described for example 2, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 75 mg; 0.37 mmol; 1.0 eq.) and 4-(2-t-butoxy-2-oxoethoxy)benzoic acid (113 mg; 0.45 mmol; 1.2 eq.) as a white foam (21.6 mg, 13%). HPLC, Rt: 3.98 min. (purity 98.3%). LC/MS, M+(ESI): 435.1, M−(ESI): 433.1.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16]OS(C)(=O)=O)[CH2:10][C@H:9]1[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:7].[C:41]1([CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(#N)C>[F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:37])([F:36])[F:38])[CH:34]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:50]2[CH2:51][CH2:52][CH:47]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:48][CH2:49]2)[CH2:10][C@H:9]1[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:7]
Reactant: CS(=O)(=O)OCCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: CC#N
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCCN2CCC(c3ccccc3)CC2)C[C@H]1Cc1c[nH]c2ccccc12
Yield: 81.1 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine (100 mg) and 4-phenylpiperidine (60 mg) in acetonitrile (3 ml) was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel using ethyl acetate-methanol (5:1) as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[3-(4-phenylpiperidino)propyl]piperazine (90 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:6][CH:7]=1.Cl.[NH:14]1[CH2:18][CH2:17][C:16]2([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][O:19]2)[CH2:15]1>C(N(CC)CC)C>[N:8]1([C:5]2[N:4]=[N:3][C:2]([N:14]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15]3)=[CH:7][CH:6]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: Clc1ccc(-n2ccnc2)nn1
Reactant: c1ccc2c(c1)COC21CCNC1
Agent: Cl
Solvent: CCN(CC)CC
Product: c1ccc2c(c1)COC21CCN(c2ccc(-n3ccnc3)nn2)C1

Procedure:
The object product (195 mg, 61%) was obtained in the same manner as in Example 165 and using 3-chloro-6-(1H-imidazol-1-yl)pyridazine (180 mg), 3H-spiro[2-benzofuran-1,3′-pyrrolidine] hydrochloride (200 mg) obtained in Example 43(5) and triethylamine (0.42 mL).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:15](=[O:16])[N:14]([CH3:17])[C:12](=[O:13])[C:11]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH3:27])[CH:19]=2)=[CH:2]1>CN(C=O)C.[C].[Pd]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[C:15](=[O:16])[N:14]([CH3:17])[C:12](=[O:13])[CH:11]2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH3:27])[CH:19]=2)=[CH:2]1
Reactant: CN1C(=O)C(c2c[nH]c3ccccc23)=C(c2cn(C)c3ccccc23)C1=O
Agent: [Pd]
Solvent: CN(C)C=O
Product: CN1C(=O)C(c2c[nH]c3ccccc23)C(c2cn(C)c3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.8 %

Procedure:
To a solution of 3-(1H-indol-3-yl)-2-(1-methyl-1H-indol-3-yl)-N-methylmaleimide (60 mg, 0.17 mmol) in DMF (1 mL) was added a small amount of 10% palladium-carbon, and the whole was stirred at room temperature for 1 day under hydrogen atmosphere. The palladium-carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (ethyl acetate:n-hexane =2:1) to obtain 4-(1H-indol-3-yl)-3-(1-methyl-1H-indol-3-yl)-1-methyl-2,5-dioxopyrrolidine (60 mg, 99.6%) as pale red solids. 1H-NMR(CDCl3): δ 3.27(s, 3H), 3.34(s, 3H), 4.76(s, 2H) 6.58-7.32(m, 10H), 7.72(br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[C@:15]1([CH2:34][F:35])[CH2:20][C@@H:19]([C:21]([F:24])([F:23])[F:22])[O:18][C:17]([NH:25]C(=O)C2C=CC=CC=2)=[N:16]1.N12CCCN=C1CCCCC2>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[C@:15]1([CH2:34][F:35])[CH2:20][C@@H:19]([C:21]([F:23])([F:24])[F:22])[O:18][C:17]([NH2:25])=[N:16]1
Reactant: O=C(NC1=N[C@](CF)(c2cc(Oc3cnccn3)ccc2F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: NC1=N[C@](CF)(c2cc(Oc3cnccn3)ccc2F)C[C@@H](C(F)(F)F)O1
Temperature: 60 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
To a solution of N-((4S,6S)-4-(2-fluoro-5-(pyrazin-2-yloxy)phenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (85 mg, 0.173 mmol) in MeOH (690 μL) was added 1,8-diazabicyclo-[5.4.0]undec-7-ene (77 μL, 0.518 mmol) dropwise. The reaction mixture was stirred at 60° C. for 1 h, then at 80° C. for another hour. After cooling to room temperature, the crude material was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 70% over 30 min. The fractions were combined and concentrated. It was partitioned between DCM and saturated NaHCO3. The aqueous layer was back extracted with DCM and the combined organic was dried (Na2SO4) and concentrated to provide (4S,6S)-4-(2-fluoro-5-(pyrazin-2-yloxy)phenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (38 mg, 0.098 mmol, 56.7% yield) as white solid. MS m/z=389 [M]+. Calculated for C16H13F5N4O2: 388.29.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([N:21]([CH3:25])[CH2:22][CH2:23][OH:24])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:26]1[C:31](O)=[CH:30][CH:29]=[C:28]([CH3:33])[CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([N:21]([CH3:25])[CH2:22][CH2:23][O:24][C:31]3[CH:30]=[CH:29][C:28]([CH3:33])=[CH:27][CH:26]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CCO)[C@H]1CC[C@H](c2ccc(OCc3ccccc3)cc2)CC1
Reactant: Cc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(OCCN(C)[C@H]2CC[C@H](c3ccc(OCc4ccccc4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of trans-2-{[4-(4-benzyloxy-phenyl)-cyclohexyl]-methyl-amino}-ethanol (0.3 g, 0.88 mmol), p-cresol (96 mg, 0.88 mmol), triphenylphosphine (232 mg, 0.88 mmol), diethyl-azodicarboxylate (154 mg, 0.88 mmol) and THF was stirred at rt for 3h. The solvent was evaporated and the rsidue was treated with MeOH/H2O (3:1, 50 ml) and hexane (50 ml). The aq. layer was extracted with hexane (30 ml). The combined hexane extracts were dried and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2—MeOH 95:5) to give trans-[4-(4-benzyloxy-phenyl)-cyclohexyl]-methyl-(2-p-tolyloxy-ethyl)-amine (135 mg, 69%, white solid, MS: m/e=430.5 (M+H+)).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[Li]C(C)(C)C.C(O[B:24]1[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]1)(C)C>C1COCC1>[CH3:14][O:13][C:5]1[CH:4]=[CH:3][C:2]([B:24]2[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]2)=[CH:7][C:6]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(Br)cc1N1CCCC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1N1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a −78° C. solution of 1-(5-bromo-2-methoxy-phenyl)-pyrrolidine (270 mg, 1.1 mmol) in THF (17 mL) was added dropwise a solution of t-BuLi (1.3 mL, 1.7 M solution in pentane, 2.2 mmol). The resultant yellow solution was stirred for 30 min, treated with additional t-BuLi (1.3 mL, 1.7 M solution in pentane, 2.2 mmol), stirred for 45 min, and treated dropwise with 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.8 mL, 4.4 mmol). The reaction was allowed to slowly warm to room temperature, stirred at room temperature overnight, and partitioned between saturated NH4Cl and EtOAc. The combined organic phases were dried with Na2SO4 and concentrated to give a tan oil. The crude product was purified by flash chromatography using 25 g of silica gel and 0-50% EtOAc in hexanes as eluant to afford 120 mg (35%) of 1-[2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-pyrrolidine as a white solid. M+H 304.
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:37]1(=[O:43])[NH:41][C:40](=[O:42])[CH2:39][CH2:38]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O>[F:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:41]4[C:40](=[O:42])[CH2:39][CH2:38][C:37]4=[O:43])=[CH:20][CH:19]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(CO)cc1
Reactant: O=C1CCC(=O)N1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(CN2C(=O)CCC2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
In an atmosphere of argon, N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-4-hydroxymethyl-N-(2-methoxyphenyl)benzamide (54 mg, 0.11 mmol), succinimide (13 mg, 0.132 mmol) and triphenylphosphine (34.6 mg, 0.132 mmol) were dissolved in THF (1 ml) to which was subsequently added dropwise diethyl azodicarboxylate (21 μl, 0.132 mmol) while cooling in an ice bath. After 30 minutes of stirring at room temperature, the reaction solution was diluted with water (10 ml) and extracted with ethyl acetate. The resulting organic layer was washed with water and saturated brine, and dried on anhydrous sodium carbonate. Thereafter, the solvent was removed by evaporation, and the resulting residue was purified by a PTLC (chloroform:methanol=20:1) to obtain 42 mg (66.8%) of the title compound in a light yellow amorphous form.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[OH:16])=[O:5])[CH3:2].CCN(C(C)C)C(C)C.[F:26][C:27]([F:42])([C:38]([F:41])([F:40])[F:39])[C:28]([F:37])([F:36])[C:29]([F:35])([F:34])[S:30](F)(=[O:32])=[O:31]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[O:16][S:30]([C:29]([F:34])([F:35])[C:28]([F:36])([F:37])[C:27]([F:26])([F:42])[C:38]([F:41])([F:40])[F:39])(=[O:32])=[O:31])=[O:5])[CH3:2]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCOC(=O)c1c(O)c2cnccc2n1C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c2cnccc2n1C
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a stirred solution of 3-hydroxy-1-methyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (695 mg, 3.16 mmol) and DMAP (19 mg, 0.16 mmol) in DCM (10 ml) at 0° C. was added DIPEA (1.35 ml, 7.58 mmol) and nonafluorobutylsulfonyl fluoride (0.74 ml, 4.10 mmol). After 10 minutes the reaction was warmed to room temperature and stirred for an additional 4.5 hours. The reaction mixture was diluted with DCM (50 ml) and washed with water (30 ml). The organic phase was isolated, dried over sodium sulphate then filtered and evaporated to give a yellow oil. The oil was purified by flash chromatography (Si-PPC, pentane:ethyl acetate, gradient 100:0 to 60:40) to afford the title compound as a colourless oil which crystallised on standing (1.43 g, 90%). LCMS (method B): RT=3.28 min, M+H+=505.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]([OH:9])[C:6]2[S:10][C:11]([CH3:13])=[CH:12][C:5]=2[CH2:4]1)[CH3:2].[C:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](F)=[CH:18][CH:17]=1)#[N:15]>>[C:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([O:9][CH:7]2[CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][C:5]3[CH:12]=[C:11]([CH3:13])[S:10][C:6]2=3)=[CH:18][CH:17]=1)#[N:15]
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: CCN1Cc2cc(C)sc2C(O)C1
Product: CCN1Cc2cc(C)sc2C(Oc2ccc(C#N)c3ccccc23)C1

Procedure:
The same method as in Example 1 was conducted using 5-ethyl-2-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 32) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-cyano-1-fluoronaphthalene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14]([CH:17]=[N:18][N:19]=[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=3)[NH:22][C:21]2=[O:30])[NH:13][C:12]=1[CH3:31])=[O:10].CO.[Li+].[OH-].Cl>O>[F:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:30])[C:20]2=[N:19][N:18]=[CH:17][C:14]1[NH:13][C:12]([CH3:31])=[C:11]([C:9]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:32])=[O:2])=[O:10])[C:15]=1[CH3:16]
Reactant: COC(=O)CCCCNC(=O)c1c(C)[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 39.1 %

Procedure:
5-(5-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)-pentanoic acid methyl ester (441 mg, 1 mmol) and 300 ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 24 hours at room temperature. The mixture is neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (167 mg, 39% yield) as a red solid. LC-MS (m/z) 428 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])/[N:7]=[C:8](/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])\[C:9]([F:12])([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([Mg]Cl)[CH:22]=[CH2:23].C1COCC1>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])([C:9]([F:10])([F:11])[F:12])[CH2:23][CH:22]=[CH2:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)/N=C(/c1ccccc1F)C(F)(F)F
Reactant: C=CC[Mg]Cl
Solvent: C1CCOC1
Product: C=CCC(NC(=O)OC(C)(C)C)(c1ccccc1F)C(F)(F)F
Reaction time: 0.5 h

Procedure:
To a solution of [2,2,2-Trifluoro-1-(2-fluoro-phenyl)-eth-(Z)-ylidene]-carbamic acid tert-butyl ester (16.63 g, 57.1 mmol) in 170 mL THE at −75° was added dropwise allylmagnesium chloride solution 2 mol/L in THF (31.4 ml, 62.8 mmol). The reaction temperature was not allowed to exceed −60° C. After 30 minutes, the reaction was quenched with 10% aqueous NH4Cl and extracted with TBME. The organic phase was washed with brine, dried with MgSO4.H2O and evaporated. The crude product was chromatographed on silica gel with hexane/TBME 95/5 to give 18.52 g of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[N:11]([CH2:22][C:23](O)=[O:24])[C:10](=[O:26])[CH:9]1[CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=O)(C)(C)C.[NH2:33][C:34]1[CH:35]=[C:36]2[C:49](=[CH:50][CH:51]=1)[CH2:48][C@:38]1([C:46]3[C:41](=[N:42][CH:43]=[CH:44][CH:45]=3)[NH:40][C:39]1=[O:47])[CH2:37]2.Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:20][C:18]1[CH:19]=[C:14]([CH:12]2[N:11]([CH2:22][C:23]([NH:33][C:34]3[CH:35]=[C:36]4[C:49](=[CH:50][CH:51]=3)[CH2:48][C@:38]3([C:46]5[C:41](=[N:42][CH:43]=[CH:44][CH:45]=5)[NH:40][C:39]3=[O:47])[CH2:37]4)=[O:24])[C:10](=[O:26])[CH:9]([CH:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[NH:8][CH2:13]2)[CH:15]=[C:16]([F:21])[CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)cc(F)c2)N(CC(=O)O)C(=O)C1C1CCOCC1
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)C(C2CCOCC2)NCC1c1cc(F)cc(F)c1)Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
0.10 g (0.22 mmol) 2-(4-(tert-butoxycarbonyl)-6-(3,5-difluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)ethanoic acid (isomer mixture 2,2,2), 60 mg (0.24 mmol) (R)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, 58 mg (0.30 mmol) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-hydrochloride, 41 mg (0.30 mmol) HOBT, 0.03 ml (0.24 mmol) TEA and 1.5 ml DMF were stirred overnight at RT. The reaction mixture was concentrated by rotary evaporation. The residue was stirred with 15 ml of a 1.25M methanolic hydrochloric acid solution for 1 h at 50° C. The mixture was concentrated by rotary evaporation and the residue was purified by HPLC. The product-containing fractions were combined and lyophilised. The product was obtained as a mixture of isomers.