Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([F:11])[C:8]([O:12][CH3:13])=[C:7]([F:14])[CH:6]=1)=O.[NH2:15][C:16]([NH2:18])=[S:17].C([O-])(O)=O.[Na+]>CCO>[F:14][C:7]1[CH:6]=[C:5]([C:3]2[N:15]=[C:16]([NH2:18])[S:17][CH:2]=2)[CH:10]=[C:9]([F:11])[C:8]=1[O:12][CH3:13]
Reactant: NC(N)=S
Reactant: COc1c(F)cc(C(=O)CBr)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1c(F)cc(-c2csc(N)n2)cc1F
Yield: 85.3 %

Procedure:
A reaction mixture containing 2-bromo-1-(3,5-difluoro-4-methoxyphenyl)ethanone (2.0 g, 7.5 mmol, 1.0 equiv) and thiourea (0.57 g, 7.5 mmol, 1.0 equiv) in EtOH (20.0 mL) was heated at reflux for 3.0 h. The residue was basified with saturated aqueous NaHCO3 (20 mL) and extracted with EtOAc (3×30 mL). The organic layer was separated, dried over MgSO4(s), and concentrated under reduced pressure. The resultant solids were washed with hexanes to give 4-(3,5-difluoro-4-methoxyphenyl)thiazol-2-amine (1.54 g, 6.4 mmol) as white solids in 84% yield: 1H NMR (DMSO-d6, 500 MHz) δ 7.49-7.54 (m, 2H), 7.12-7.14 (m, 3H), 3.92 (s, 3H); ESI-MS: m/z 243.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:26])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[C:15]([NH:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[N:14]=1)[CH:8]=[CH:7][CH:6]=2.[CH2:27]([C@H:31]1[CH2:36][NH:35][CH2:34][CH2:33][N:32]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:28]([CH3:30])[CH3:29]>>[NH2:1][C:2]1[C:3](=[O:26])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[N:14]=[C:15]([NH:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[N:16]=[C:17]([N:35]3[CH2:34][CH2:33][N:32]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[C@@H:31]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:36]3)[CH:18]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: COC[C@H](C)Nc1nc(Cl)cc(Oc2cccc3[nH]c(=O)c(N)nc23)n1
Reactant: CC(C)C[C@H]1CNCCN1C(=O)OC(C)(C)C
Product: COC[C@H](C)Nc1nc(Oc2cccc3[nH]c(=O)c(N)nc23)cc(N2CCN(C(=O)OC(C)(C)C)[C@@H](CC(C)C)C2)n1

Procedure:
The reaction of (S)-3-amino-5-(6-chloro-2-(1-methoxypropan-2-ylamino)pyrimidin-4-yloxy)quinoxalin-2(1H)-one (74 mg, 0.2 mmol, Example 122(b)) with (S)-tert-butyl 2-isobutylpiperazine-1-carboxylate (48 mg, 0.2 mmol, CNH-Tech) under the conditions of Example 34 provided the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 583 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:57][NH:58][CH2:59][C:60]1[CH:73]=[CH:72][C:63]([CH2:64][N:65]2[CH2:70][CH2:69][CH:68]([OH:71])[CH2:67][CH2:66]2)=[CH:62][CH:61]=1>C(Cl)Cl.O>[OH:71][CH:68]1[CH2:69][CH2:70][N:65]([CH2:64][C:63]2[CH:72]=[CH:73][C:60]([CH2:59][N:58]([CH3:57])[C:21]([C:18]3[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH3:24])(=[O:11])=[O:12])[CH3:14])[O:20][CH:19]=3)=[O:22])=[CH:61][CH:62]=2)[CH2:66][CH2:67]1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: CNCc1ccc(CN2CCC(O)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(CN4CCC(O)CC4)cc3)co2)c(C)c1
Reaction time: 0.08 h

Procedure:
5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (30 mg, 0.085 mmol) was dissolved in DCM (10 mL) and EDCI (27 mg, 0.11 mmol), HOBt (17 mg, 0.127 mmol) and DIPEA (0.03 mL, 0.17 mmol) were added. The resulting solution was stirred for 5 min prior to the addition of 1-{4-[(methylamino)methyl]benzyl}piperidin-4-ol dihydrochloride (28 mg, 0.102 mmol) and stirred at ambient temperature for 16 h. The reaction was diluted with water (5 mL) and extracted with EtOAc (2×15 mL). The combined organic extracts were washed with water (2×5 mL) and brine (5 mL), dried over Na2SO4, and concentrated in vacuo. The resulting residue was purified by FCC eluting with 5% MeOH in DCM to afford the title compound.
Reaction SMILES: Br[C:2]1C=C(C=CC=1)C(O)=O.C[Al](C)C.[CH3:15][C:16]([C:18]1[CH:19]=[C:20]([Br:24])[CH:21]=[CH:22][CH:23]=1)=[CH2:17]>CCCCCC>[C:16]([C:18]1[CH:19]=[C:20]([Br:24])[CH:21]=[CH:22][CH:23]=1)([CH3:2])([CH3:15])[CH3:17]
Reactant: O=C(O)c1cccc(Br)c1
Reactant: C=C(C)c1cccc(Br)c1
Agent: C[Al](C)C
Solvent: CCCCCC
Product: CC(C)(C)c1cccc(Br)c1
Temperature: 145 °C
Reaction time: 3 h

Procedure:
A suspension of 4.02 g (20 mmol) of m-bromobenzoic acid (Compound 23) in 10 ml hexane was cooled in an ice-bath under nitrogen and then treated slowly with 40 ml of 2 M (80 mmol) trimethylaluminum in hexane. The hexane was removed by distillation under nitrogen and the apparatus modified for reflux. The reaction mixture was then heated in an oil bath at 140-150 degrees C. for 3 hours. The oil bath was then replaced by an ice-water bath and the reaction mixture was quenched by the slow dropwise addition of water. The mixture was acidified with dilute HCl and mixture heated at reflux until the aluminum salts were dissolved. The reaction mixture was allowed to cool and extracted with 3×8 ml ether. The ether extracts were combined, washed with dil. HCl, water and saturated NaCl and then dried (MgSO4). The solvent was removed in-vacuo and the residue distilled to give a mixture of the title compound and 3-(1-methyl-ethenyl) bromobenzene as a colorless oil. A small portion (200 mg) of this mixture was dissolved in 1 ml of methylene chloride and then treated with a solution of 200 mg of m-chloroperbenzoic acid in 4 ml of methylene chloride. The mixture was stirred at room temperature for 1 hour and the methylene chloride removed invacuo. The residue was dissolved in hexane and filtered through a short silica column and the filtrate concentrated in-vacuo to give pure title compound as a colorless oil. PMR (CDCl3): & 1.30 (9H, s), 7.25 (1H, m), 7.41 (2H, m), 7.65 (H, t, J~2.1 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N+:10]([O-])=[CH:9][CH:8]=[CH:7]2.[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14]>>[C:13]([O:16][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([OH:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: [O-][n+]1cccc2cccc(O)c21
Product: CC(=O)Oc1ccc2cccc(O)c2n1
Temperature: 0 °C
Yield: 84 %

Procedure:
A mixture of 5a (0.81 g, 5 mmol) in acetic anhydride (20 ml) was heated at reflux for 2 h (monitored by TLC). After cooling, it was poured into ice water (100 ml). The resulting solid was collected and crystallized from dichloromethane to give 2-Acetoxy-8-hydroxyquinoline (5b) (0.85 g, 84%) as white crystals. mp: 240°-241° C.; 1H-NMR (DMSO-d6): δ2.55; (s, 3H, CH3), 6.66 (d, 3-H), 7.15-7.23 (m, 3H, Ar--H), 7.78 (d, 4-H), 11.31 (br s, 1H, OH).
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[C:12]([CH2:15][CH3:16])=[N:13][O:14][C:8]=2[C:7]=1[OH:17])=[O:5])C.[NH2:18][CH2:19][C:20]([OH:22])=[O:21].[O-]CC.[Na+].Cl>CN(C=O)C.O.CCOC(C)=O>[CH2:15]([C:12]1[C:9]2[CH:10]=[N:11][C:6]([C:4]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:5])=[C:7]([OH:17])[C:8]=2[O:14][N:13]=1)[CH3:16]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2c(CC)noc2c1O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCc1noc2c(O)c(C(=O)NCC(=O)O)ncc12
Temperature: 25 °C
Yield: 50.3 %

Procedure:
3-Ethyl-7-hydroxy-isoxazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (80 mg, 0.42 mmol) was dissolved in 12 mL of DMF. Glycine (0.51 g, 6.78 mmol) and sodium ethoxide (0.35 g, 5.08 mmol) were added and the mixture was refluxed for 2 h. The mixture was cooled to room temperature and diluted with 60 mL of water. EtOAc (50 mL) was added and the resulting biphasic mixture was stirred vigorously as 4M hydrochloric acid was added dropwise until pH was 3. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. The solvent was evaporated and the solid residue was taken up in 50 mL of saturated sodium bicarbonate solution. The aqueous phase was washed with hexanes and EtOAc. The aqueous layer was then acidified to pH 2 by addition of concentrated hydrochloric acid and extracted with EtOAc (3×50 mL). The combined organic layer was dried over MgSO4 and concentrated to give 56 mg of the title compound. MS: (+) m/z 266.32 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[S:9]([NH:12][O:13][CH3:14])(=[O:11])=[O:10].[N+:15]([C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1Cl)([O-:17])=[O:16].[H-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[S:9]([N:12]([C:19]1[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:18]=1[N+:15]([O-:17])=[O:16])[O:13][CH3:14])(=[O:10])=[O:11]
Reactant: CONS(=O)(=O)c1c(C)nn(C)c1Cl
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CON(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])S(=O)(=O)c1c(C)nn(C)c1Cl
Temperature: 25 °C
Yield: 80.1 %

Procedure:
To a solution of 5-chloro-1,3-dimethyl-N-methoxy-4-pyrazolesulfonamide (0.48 g (2.00 mmol)) and 2,4-dinitrochlorobenzene (0.49 g (2.42 mmol)) in DMF (3.0 ml), sodium hydride (60%, 0.09 g (2.25 mmol)) was added dropwise under cooling with ice and with stirring and the mixture was stirred under cooling with ice for one hour and at room temperature for one hour. Water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with chloroform-hexane (10:1) as eluent to give 0.65 g (87%) of the title compound as pale yellow crystals.
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].[C:14]1(=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[O-][CH2:22][CH3:23].[Na+]>C(O)C>[CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:15]2[CH2:16][CH2:17][CH2:18][C:19](=[CH:8][C:7]3[CH:10]=[CH:11][C:4]([N:3]([CH2:22][CH3:23])[CH2:1][CH3:2])=[CH:5][CH:6]=3)[C:14]2=[O:20])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC[O-]
Reactant: CCN(CC)c1ccc(C=O)cc1
Reactant: O=C1CCCCC1
Agent: [Na+]
Solvent: CCO
Product: CCN(CC)c1ccc(C=C2CCCC(=Cc3ccc(N(CC)CC)cc3)C2=O)cc1

Procedure:
In 25 ml of anhydrous ethanol were dissolved 17.7 g of p-diethylaminobenzaldehyde and 4.9 g of cyclohexanone, and 10 ml of 10% ethanolic solution of sodium ethoxide was added dropwise to the resulting solution, and the resulting mixture was subjected to reaction under reflux for 12 hours. The reaction mixture thus obtained was cooled, and the crystals thus precipitated were collected by filtration and recrystallized from toluene, to obtain 12.8 g of 2,6-bis(4'-diethylaminobenzal)cyclohexanone (m.p. 167° C.).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:15][CH3:16])=[C:11]([F:14])[CH:12]=2)[CH:7]=[C:6]([NH:17][C:18]2[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=2)[N:5]=1.[C:24]([OH:27])(=O)[CH3:25].[CH3:28]OCCOC>>[F:14][C:11]1[CH:12]=[C:13]2[C:8]([CH:7]=[C:6]([NH:17][C:18]3[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=3)[N:5]=[C:4]2[O:27][CH:24]([CH3:25])[CH3:28])=[CH:9][C:10]=1[O:15][CH3:16]
Reactant: CC(=O)O
Reactant: COCCOC
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1F
Agent: [H-]
Agent: [Na+]
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(OC(C)C)c2cc1F
Temperature: 180 °C
Reaction time: 1 h

Procedure:
NaH (155 mg) was added to a solution of ispropanol (500 mg) in DME (2 ml) and stirred for 1 hour. 1-Chloro-7-fluoro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (100 mg) (example 9B) was added to the mixture, and the mixture was heated at 180° C. for 30 minutes under microwave irradiation. The reaction mixture was acidified to PH=7 with acetic acid and purified by preparative LC-MS to give (7-Fluoro-1-isopropoxy-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 331 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl[C:19]1[NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1>CCOC(C)=O.O>[N:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[NH:23][C:19]=1[N:15]1[CH2:16][CH2:17][N:12]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[CH:8][CH:7]=2)[CH2:13][CH2:14]1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1ccc2c(N3CCN(c4nc5ccccc5[nH]4)CC3)ccnc2c1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (247 mg, 1.0 mmol) and 2-chlorobenzimidazole (46 mg, 0.3 mmol) are heated at 150° C. for 1 h. The mixture is dissolved in EtOAc-water. The organic layer is separated, dried (MgSO4), and concentrated. Column chromatography of the residue with hexane-EtOAc furnishes the title product as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([OH:10])=[O:9])[N:3]=1.[ClH:11].O1CCO[CH2:14][CH2:13]1>CCO>[ClH:11].[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10][CH2:13][CH3:14])=[O:9])[N:3]=1
Reactant: C1COCCO1
Reactant: Nc1cccc(C(=O)O)n1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cccc(N)n1

Procedure:
A suspension of 2-aminopyridine-6-carboxylic acid (2 g) in EtOH (10.0 mL) and 4N HCl/dioxane (10.0 mL) was heated to reflux for 16 hours under anhydrous conditions. The reaction mixture was then concentrated to dryness and the residue was dried in a desiccator under vacuum to afford 2-amino-6-carbethoxypyridine hydrochloride as a white powder (1.6 g). 1H-NMR (DMSO-d6) δ 8.3 (br), 7.94 (m, 1H), 7.37 (d, 1H, J=7.2 Hz), 7.22 (dd, 1H, J=8.7 Hz), 4.37 (q, 2H, J=7.2 Hz), 1.32 (t, 3H, J=7.2 Hz); FAB MS m/z 167 (M+H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([Cl:20])=[C:6]([NH:10][C:11](=[O:19])[C@:12]([OH:18])([CH3:17])[C:13]([F:16])([F:15])[F:14])[CH:7]=[CH:8][CH:9]=1)([O-])=O>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[C:5]([Cl:20])=[C:6]([NH:10][C:11](=[O:19])[C@:12]([OH:18])([CH3:17])[C:13]([F:14])([F:15])[F:16])[CH:7]=[CH:8][CH:9]=1
Reactant: C[C@@](O)(C(=O)Nc1cccc([N+](=O)[O-])c1Cl)C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@@](O)(C(=O)Nc1cccc(N)c1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
To a stirred solution of (R)-N-[3-nitro-2-chlorophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 9) (14.3 g) in EtOAc (250 ml) under a hydrogen atmosphere was added 10% palladium on carbon (1.6 g). The reaction mixture was allowed to stir at room temperature overnight; the mixture was filtered through a pad of diatomaceous earth and volatile material was removed by evaporation to give the title compound (13 g) as a brown solid. NMR (CDCl3) 1.75 (s, 3H), 4.00 (s, 1H), 4.10 (brs, 2H), 6.61 (d, 1H), 7.08 (t, 1H), 7.72 (d, 1H), 8.77 (brs, 1H); m/z: 281.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:13].[Cl:14][C:15]1[CH:16]=[C:17]([NH:25][C:26](OC2C=CC=CC=2)=[O:27])[C:18](=[CH:23][CH:24]=1)[C:19]([O:21][CH3:22])=[O:20]>>[NH2:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([S:9]([NH:12][C:26]([NH:25][C:17]2[CH:16]=[C:15]([Cl:14])[CH:24]=[CH:23][C:18]=2[C:19]([O:21][CH3:22])=[O:20])=[O:27])(=[O:11])=[O:10])=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1c(Cl)cc(S(N)(=O)=O)cc1Cl
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Product: COC(=O)c1ccc(Cl)cc1NC(=O)NS(=O)(=O)c1cc(Cl)c(N)c(Cl)c1
Yield: 45.4 %

Procedure:
From 1.06 g (4.40 mmol) of 4-amino-3,5-dichlorobenzenesulfonamide and 1.34 g (4.40 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate in a similar manner to Preparation Example 1, 905 mg (yield 44%) of methyl 2-{[(4-amino-3,5-dichlorobenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate (property: colorless amorphous, PMR (δppm, DMSO-d6): 3.87 (3H, s), 6.59 (2H, br), 7.22 (1H, dd), 7.72 (2H, s), 7.93 (1H, d), 8.24 (1H, d), 10.17 (1H, s) was obtained.
Reaction SMILES: [Cl-].[CH:2]1[C:14]2[CH:13]([CH2:15][OH:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[O:17]1[CH2:21][CH2:20][CH2:19]C1.[CH2:22](N(CC)CC)C>>[C:21]([O:16][CH2:15][CH:13]1[C:14]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:17])[C:20]([CH3:22])=[CH2:19]
Reactant: CCN(CC)CC
Reactant: OCC1c2ccccc2-c2ccccc21
Reactant: C1CCOC1
Agent: [Cl-]
Product: C=C(C)C(=O)OCC1c2ccccc2-c2ccccc21
Yield: 10 %

Procedure:
Methacrloyl chloride (5 ml) was added dropwise to a cooled solution of 9-fluorene methanol (Aldrich Chemical Co. 5.04g, 0.026 moles) in a mixture of dry tetrahydrofuran (15 ml) and dry triethylamine (10 ml). After 1 hour at 0° C. the reaction was quenched with water and extracted with ether. The resultant oil was flash chromatographed to give 0.70g, (10% yield) of (9-fluorenyl)-methyl methacrylate (9 FMMA) as a light yellow oil. The original monomer stored at 0° C. polymerized over a period of 3 days. This material was dissolved in and added dropwise to hexane, yielding a precipitate of poly(9 FMMA) ([η]=0.28 dl/g).
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:9][C:10]([C:12]1[C:13]([OH:21])=[C:14]2[S:20][CH:19]=[CH:18][C:15]2=[N:16][CH:17]=1)=[O:11])[CH3:8].Cl[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24]>ClCCl>[CH:26]([O:25][C:23]([N:16]1[CH:17]=[C:12]([C:10]([O:9][CH2:7][CH3:8])=[O:11])[C:13](=[O:21])[C:14]2[S:20][CH:19]=[CH:18][C:15]1=2)=[O:24])([CH3:28])[CH3:27]
Reactant: CCOC(=O)c1cnc2ccsc2c1O
Reactant: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cn(C(=O)OC(C)C)c2ccsc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Add pyridine (1.20 ml, 14.8 mmol) to a suspension of 7-hydroxy-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (1.10 g, 4.93 mmol) in dichloromethane (50 ml), and then add isopropyl chloroformate (1.0 N in toluene, 14.8 ml). Stir the reaction mixture at room temperature overnight. Wash the mixture with 1 N HCl (50 ml) followed by brine (3×50 ml). Separate the organic layer, dry over sodium sulfate, filter and concentrate. Purify using silica gel column chromatography (gradient eluent, 0-60% ethyl acetate in hexane) to provide 7-oxo-7H-thieno[3,2-b]pyridine-4,6-dicarboxylic acid 6-ethyl ester 4-isopropyl ester (1.37 g, 90%) as a white crystalline solid. MS (ES+): 310 (M+H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[F:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:26]=1[NH:25][C:24](=[O:27])[CH2:23]2>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:23]1[C:22]2[C:26](=[C:18]([F:17])[CH:19]=[CH:20][CH:21]=2)[NH:25][C:24]1=[O:27])([CH3:3])[CH3:2]
Reactant: O=C1Cc2cccc(F)c2N1
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3c(F)cccc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 7-fluoro-2-oxindole to give 0.25 g of 3-(3,5-diisopropyl-4-methoxybenzylidene)-7-fluoro-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [C:1]1([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][N:19](COCC[Si](C)(C)C)[C:20]3[N:24](COCC[Si](C)(C)C)[C:23]4[CH:33]=[CH:34][C:35]([C:37](=[O:40])[CH2:38][CH3:39])=[CH:36][C:22]=4[N:21]=3)[CH2:14][CH2:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(OCC)(=O)C>CN(C)C=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:1]1([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:20]3[NH:24][C:23]4[CH:33]=[CH:34][C:35]([C:37](=[O:40])[CH2:38][CH3:39])=[CH:36][C:22]=4[N:21]=3)[CH2:14][CH2:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCC(=O)c1ccc2c(c1)nc(N(COCC[Si](C)(C)C)CC1CCN(Cc3cccc4ccccc34)CC1)n2COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(=O)c1ccc2[nH]c(NCC3CCN(Cc4cccc5ccccc45)CC3)nc2c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
After dissolving 1-[2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-5-yl]-propan-1-one (32 mg, 0.047 mmol) in anhydrous dimethylformamide (1 ml), tetrabutylammonium fluoride (0.8 ml, 1.0 M tetrahydrofuran solution) and water (5 μl) were added, and the mixture was stirred at 100° C. for 2 hours and 30 minutes. Water and ethyl acetate were added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by thin-layer silica gel chromatography (dichloromethane/methanol/TEA=85/10/1). The purified product was further purified by preparative HPLC and thin-layer silica gel chromatography (dichloromethane/methanol=8/2) to obtain 1-{2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazol-5-yl}-propan-1-one.
Reaction SMILES: [Li+].[OH-:2].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:43][C:44]3[CH:49]=[C:48]([C:50]([F:53])([F:52])[F:51])[C:47]([NH2:54])=[C:46]([Cl:55])[CH:45]=3)[C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH:29]4[CH2:35][CH:34]5[N:36](C(OCC)=O)[C:31](C)([CH2:32][CH2:33]5)[CH2:30]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:56]=[CH:57][CH:58]=[CH:59][C:6]=2[NH:5]1.[CH2:60]1[CH2:64][O:63]CC1>O>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C@H:20]([CH2:43][C:44]3[CH:49]=[C:48]([C:50]([F:52])([F:53])[F:51])[C:47]([NH2:54])=[C:46]([Cl:55])[CH:45]=3)[C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH:29]4[CH2:35][CH:34]5[N:36]([CH2:60][C:64]([OH:2])=[O:63])[CH:31]([CH2:32][CH2:33]5)[CH2:30]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:15][CH2:16]2)[CH2:9][CH2:8][C:7]2[CH:56]=[CH:57][CH:58]=[CH:59][C:6]=2[NH:5]1
Reactant: CCOC(=O)N1C2CCC1(C)CC(N1CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC1)C2
Reactant: [OH-]
Reactant: C1CCOC1
Agent: [Li+]
Solvent: O
Product: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CC4CCC(C3)N4CC(=O)O)CC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.92 mg (0.08 mmol) LiOH in 1 mL water was added to 40.0 mg (0.05 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(8-ethoxycarbonyl-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 1 mL THF and the reaction mixture was shaken overnight at RT. The solvents were eliminated in a nitrogen stream and the residue was purified by HPLC; the fractions containing the product were combined and lyophilised.