Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([C:14]1([CH3:22])[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:23].[Cl:24][C:25]1[CH:26]=[C:27]([N:32]=[C:33]=[O:34])[CH:28]=[CH:29][C:30]=1[CH3:31].C(N(CC)CC)C.Cl>C1COCC1>[Cl:24][C:25]1[CH:26]=[C:27]([NH:32][C:33]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:13])[N:8]([C:14]2([CH3:22])[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:7]3=[O:23])=[O:34])[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: Cc1ccc(N=C=O)cc1Cl
Reactant: CC1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)NCc2ccc3c(c2)C(=O)N(C2(C)CCC(=O)NC2=O)C3=O)cc1Cl
Reaction time: 2 h
Yield: 56.9 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.50 g, 1.50 mmol) and 3-chloro-4-methyl-phenyl isocyanate (0.25 g, 1.50 mmol) in THF (25 mL), was added triethylamine (0.42 mL, 3.00 mmol) at room temperature under nitrogen. After 2 h, 2% aq. HCl (75 mL) was added. The product was extracted with EtOAc (75 mL) and the organic layer was separated and washed with water (2×75 mL), dried (MgSO4) and concentrated in vacuo to give 1-(3-chloro-4-methyl-phenyl)-3-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.40 g, 58% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, 4.37 min (98.73%); mp: 232-234° C.; 1H NMR (DMSO-d6) δ 1.89 (s, 3H), 1.98-2.13 (m, 1H), 2.23 (s, 3H), 2.52-2.79 (m, 3H), 4.44 (d, J=6.0 Hz, 2H), 6.89 (t, J=5.9 Hz, 1H), 7.08-7.21 (m, 2H), 7.64 (d, J=1.9 Hz, 1H), 7.72-7.88 (m, 3H), 8.82 (s, 1H), 11.01 (s, 1H); 13C NMR (DMSO-d6) δ 18.74, 21.02, 28.58, 29.11, 442.65, 58.76, 116.53, 117.74, 121.37, 123.13, 127.53, 129.49, 131.02, 131.37, 132.97, 133.21, 139.49, 148.47, 155.10, 167.77, 167.93, 172.13, 172.21; LCMS: MH=469/471; Anal Calcd for C23H21ClN4O5: C, 58.91; H, 4.51; N, 11.95. Found: C, 58.63; H, 4.40; N, 11.82.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[C@H:10]([N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])[CH2:9][CH2:8][N:7]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:6]1)=[N+]=[N-]>[Pd].C(O)C>[NH2:1][CH2:4][C@H:5]1[C@H:10]([N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])[CH2:9][CH2:8][N:7]([CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH2:6]1
Reactant: CN(Cc1ccccc1)[C@@H]1CCN(CCc2ccc(F)cc2)C[C@H]1CN=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: CN(Cc1ccccc1)[C@@H]1CCN(CCc2ccc(F)cc2)C[C@H]1CN
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
A mixture of crude trans-{3-azidomethyl-1-[2-(4-fluoro-phenyl)-ethyl]-piperidin-4-yl}-benzyl-methylamine (106 mg, 278 μmol) and 10% palladium on charcoal (20 mg) in ethanol (5 mL) was stirred at room temperature under a hydrogen atmosphere. After 1.75 hours, the mixture was filtered through Celite and the solids were rinsed with ethanol. The filtrate was concentrated to provide a gum (98 mg, quantitative). 1H NMR (300 MHz, CDCl3) δ7.33 (m, 5H), 7.15 (m, 2H), 6.98 (t, J=9 Hz, 2H), 3.72 (d, J=13 Hz, 1H), 3.55 (d, J=13 Hz, 1H), 3.07 (m, 2H), 2.9-2.7 (m, 4H), 2.55 (m, 2H), 2.37 (m, 1H), 2.23 (s, 3H), 2.19 (m, 2H), 2.0-1.6 (m, 5H). Mass spec (AP+) m/z 356.2 (M+H+).
Reaction SMILES: [CH2:1]([Mg]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)[C:12]1[S:16][C:15]2[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:14]=2[C:13]=1[C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:27][CH:26]=1)=[O:24]>C1COCC1>[CH2:1]([C:12]1[S:16][C:15]2[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:14]=2[C:13]=1[C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:27][CH:26]=1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(N(C)C)sc2c1
Reactant: Br[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(Cc3ccccc3)sc2c1
Reaction time: 0.5 h

Procedure:
Add benzylmagnesium bromide (1.5 mL, 3M) to a stirred solution of (2-dimethylamino-6-methoxy-benzo[b]thiophen-3-yl)-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (1.0 g, 2.28 mmol) in THF (10 mL) at room temperature (r.t.). Stir the mixture for 30 min. and quench with sat. NaHCO3. Dilute the reaction mixture with CH2Cl2 and wash with water and brine, dry over MgSO4, filter and concentrate. Use the crude product without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:15][CH3:16])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([Br:10])[C:7]=1[CH2:8][OH:9].[H-].[Na+].[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>O1CCCC1>[Si:19]([O:9][CH2:8][C:7]1[C:6]([Br:10])=[C:5]([C:11]([F:14])([F:13])[F:12])[N:4]=[C:3]([O:15][CH3:16])[C:2]=1[Br:1])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1nc(C(F)(F)F)c(Br)c(CO)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc(C(F)(F)F)c(Br)c(CO[Si](C)(C)C(C)(C)C)c1Br
Reaction time: 0.5 h

Procedure:
To a solution of the compound from Step D above (880 mg, 2.41 mmol) in tetrahydrofuran (3 mL) was added sodium hydride (60 weight % dispersion in oil; 107 mg, 2.65 mmol). After 30 min at room temperature, a solution of tert-butyl(dimethyl)silyl chloride (434 mg, 2.89 mmol) was added and the reaction was then stirred for an additional 1 h. The solvent was evaporated and residue was purified by flash chromatography (silica gel; 20% ethyl acetate/hexanes as eluant) to yield the title compound. 1H NMR (400 MHz, CDCl3) δ 5.03 (s, 2H), 4.05 (s, 3H), 0.95 (s, 9H), 0.19 (s, 6H). LC/MS: 480 (M+H+2).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:10](#[N:13])[CH:11]=[CH2:12].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1>[N:1]1([CH2:12][CH2:11][C:10]#[N:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: C=CC#N
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Product: N#CCCn1cnc2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 15.8 grams of 1H-benzimidazole, 8 grams of acrylonitrile and 0.2 ml of benzyltrimethylammonium hydroxide (40% solution in methanol) in 200 ml of dioxane was stirred at room temperature for 24 hours. The solvent was evaporated from the resulting yellow solution under reduced pressure and the residual yellow solid was triturated first with ether and then with water to give 1H-benzimidazole-1-propionitrile melting at about 108°-110° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C@:6]12[CH2:14][C@H:13]1[C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)=[N:20][NH:21]2)=[CH:17][CH:16]=1.[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]>C(Cl)Cl>[F:46][C:45]([F:48])([F:47])[C:43]([OH:49])=[O:44].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C@:6]12[CH2:14][C@H:13]1[C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[CH:26][CH:25]=3)=[N:20][NH:21]2)=[CH:17][CH:16]=1
Reactant: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)n[nH]c3c1)C(=O)N2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(-c4ccc(C5CCNCC5)cc4)n[nH]c3c1)C(=O)N2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 19.1 %

Procedure:
To a solution of tert-butyl 4-(4-(6-((1R,2S)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-2-yl)-1H-indazol-3-yl)phenyl)piperidine-1-carboxylate (102 mg, 0.181 mmol) in CH2Cl2 (5 mL) was added TFA (0.4 mL, 5.4 mmol). The resulting reaction mixture was stirred at rt for 2.5 h. The crude reaction mixture was concentrated under reduced pressure to dryness, and purified by preparative HPLC to give the title compound as a yellow solid (20 mg, 72%). 1H NMR (400 MHz, MeOD) δ 7.89 (d, J=8.2 Hz, 3H), 7.47 (s, 1H), 7.41 (d, J=8.2 Hz, 2H), 7.01 (d, J=8.6 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 6.91 (dd, J=8.4, 2.4 Hz, 1H), 5.60 (d, J=2.3 Hz, 1H), 3.56-3.50 (m, 2H),), 3.39-3.32 (m, 1H), 3.25 (s, 3H), 3.17 (t, J=11.9 Hz, 2H), 3.02-2.92 (m, 1H), 2.25-2.22 (m, 1H), 2.19-2.01 (m, 3H), 2.02-1.91 (m, 2H); MS ESI 465.3 [M+H]+, calcd for [C29H28N4O2+H]+ 465.22.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=4[C:26]([F:29])([F:28])[F:27])[CH2:15][CH2:14]3)=[O:12])=[N:9][N:10]=2)[CH:7]=1.[CH3:30][N:31](C=O)C>C(=O)(O)[O-].[Na+].[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:25][C:21]1[C:20]([C:26]([F:29])([F:28])[F:27])=[C:19]([CH:16]2[CH2:17][CH2:18][N:13]([C:11]([C:8]3[N:6]4[CH:7]=[C:2]([C:30]#[N:31])[CH:3]=[CH:4][C:5]4=[N:10][N:9]=3)=[O:12])[CH2:14][CH2:15]2)[CH:24]=[CH:23][CH:22]=1
Reactant: CN(C)C=O
Reactant: O=C(c1nnc2ccc(Br)cn12)N1CCC(c2cccc(F)c2C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [C-]#N
Product: N#Cc1ccc2nnc(C(=O)N3CCC(c4cccc(F)c4C(F)(F)F)CC3)n2c1
Temperature: 130 °C
Yield: 67 %

Procedure:
A solution of (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (87 mg, 0.19 mmol) and zinc cyanide (43 mg, 037 mmol) in DMF (2.0 mL) was sparged with Ar for 10 min. To the solution was added Pd(PPh3)4 (21 mg, 0.019 mmol) the vessel was sealed and heated to 130° C. with microwaves for 30 min. The mixture was diluted with saturated sodium bicarbonate solution (30 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were concentrated to dryness under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 70% EtOAc in hexanes) and freeze dried to provide 3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile as a white solid (52 mg, 67%): mp 188-190° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.54-9.51 (m, 1H), 8.13 (dd, J=9.5, 1.0 Hz, 1H), 7.81 (dd, J=9.5, 1.5 Hz, 1H), 7.71-7.65 (m, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.32 (dd, J=12.5, 8.5 Hz, 1H), 5.17-5.09 (m, 1H), 4.78-4.70 (m, 1H), 3.44-3.28 (m, 2H, overlaps with H2O), 3.09-3.00 (m, 1H), 1.97-1.75 (m, 4H); ESI MS m/z 418 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2=[N:15][C:16](S(C)(=O)=O)=[N:17][C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])=[C:13]2[CH2:12][NH:11][C:10]1=[O:31].[CH2:32]([OH:35])[CH2:33][OH:34]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2=[N:15][C:16]([O:34][CH2:33][CH2:32][OH:35])=[N:17][C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])=[C:13]2[CH2:12][NH:11][C:10]1=[O:31]
Reactant: OCCO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Product: Cc1cc(F)ccc1-c1nc(OCCO)nc2c1CNC(=O)N2c1c(F)cccc1F

Procedure:
The product of Example 3 (0.0658 g, 0.147 mmol) was suspended in ethylene glycol (1 mL) and stirred under argon. NaH, dry, 95%, (8.0 mg, 0.32 mmol) was added. After 30 min the solvent was removed in vacuo, and the residue partitioned between EtOAc and H2O. The organic phase was washed with H2O (2×), satd aq NaCl (1×), dried over anhydrous Na2SO4, filtered, and evaporated to give the crude product. Flash chromatography on silica gel eluted with 0-10% EtOAc/CH2Cl2 gave the title compound as a white-amorphous solid. mp 172-175° C., LC MS m/z=431 (MH+) Rt=1.7 min.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][N:16]([C:17]4[N:22]=[C:21]([N:23]5[C:28](=[O:29])[CH2:27][CH2:26][C@H:25]([NH:30]C(=O)OC(C)(C)C)[CH2:24]5)[CH:20]=[CH:19][CH:18]=4)[C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1.O1CCOCC1>Cl.O>[NH2:30][C@@H:25]1[CH2:24][N:23]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([N:16]3[C:10]4[CH:9]=[C:8]([C:6]5[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=5)[N:13]=[CH:12][C:11]=4[CH:14]=[N:15]3)[N:22]=2)[C:28](=[O:29])[CH2:27][CH2:26]1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3C[C@@H](NC(=O)OC(C)(C)C)CCC3=O)n2)n1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3C[C@@H](N)CCC3=O)n2)n1
Yield: 18.3 %

Procedure:
A solution of tert-butyl N-[(3S)-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-6-oxo-3-piperidyl]carbamate (45 mg, 0.15 mmol) in hydrogen chloride (4 mol/l) in 1,4-dioxane (2.0 ml, 8.0 mmol) and 1,4-dioxane 2.0 mL was stirred at RT 18 h. The reaction was diluted with water then wash with EtOAc. The aqueous layer was basified with 1M NaOH to pH 10 and extracted with EtOAc. The organic layers was dried with sodium sulfate, filtered, and concentrated in vacuum. The crude product was submitted for reverse phase HPLC to give 202 (11 mg) in 18% yield. MS (ESI) m/z: 401.1. 1H NMR (400 MHz, DMSO) δ 9.61 (s, 1H), 9.47 (s, 1H), 9.35 (s, 1H), 8.73 (s, 1H), 8.63 (s, 1H), 8.04 (t, J=8.1 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.76 (d, J=8.1 Hz, 1H), 4.24 (dd, J=12.2, 3.8 Hz, 1H), 3.94 (dd, J=12.3, 6.3 Hz, 1H), 3.49 (s, 1H), 2.75 (dd, J=12.2, 5.3 Hz, 1H), 2.69 (s, 3H), 2.63-2.55 (m, 1H), 2.10 (dd, J=13.0, 4.3 Hz, 1H), 1.85-1.72 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].C1(C)C=CC=CC=1.[Cl:19][CH2:20][CH:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22](Cl)=[O:23]>O.[OH-].[Na+].C1COCC1>[Cl:19][CH2:20][CH:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:23]
Reactant: CC(C)CC(CCl)C(=O)Cl
Reactant: NCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)CC(CCl)C(=O)NCCCCCCCC(=O)O
Temperature: 5 °C
Reaction time: 16 h

Procedure:
8-Amino caprylic acid (4.3 g) is dissolved in 20 ml of water containing 1.1 g of sodium hydroxide. To this is added 20 ml of THF, and 5 ml of toluene, and the solution is cooled to 5° C. 2-(Chloromethyl)-4-methylvaleryl chloride is dissolved in 10 ml of THF and added dropwise to the above solution. The pH of the reaction mixture is maintained between 8 and 9 during the reaction time by the addition of a total of 1.1 g of sodium hydroxide in 20 ml of water, as needed. After stirring at room temperature for about 16 hours, the aqueous layer is separated and acidified with 10% hydrochloric acid. Product is extracted with ethyl acetate and the ethyl acetate is dried with magnesium sulfate, filtered and concentrated in vacuo to yield 5.6 g of product.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:22]=[C:21]3[C:17]([N:18]([CH:24]([CH3:26])[CH3:25])[C:19](=[O:23])[NH:20]3)=[C:16](I)[N:15]=2)=[N:6]1.[H][H]>CN(C)C=O.[Pd]>[F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:22]=[C:21]3[C:17]([N:18]([CH:24]([CH3:26])[CH3:25])[C:19](=[O:23])[NH:20]3)=[CH:16][N:15]=2)=[N:6]1
Reactant: [H][H]
Reactant: CC(C)n1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Agent: [Pd]
Solvent: CN(C)C=O
Product: CC(C)n1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc21
Reaction time: 8 h

Procedure:
330 mg (0.57 mmol) of the compound from example 116 were initially charged in dimethylformamide (10.0 ml), then 66 mg of palladium (10% w/w on charcoal) were added and the mixture was hydrogenated at standard hydrogen pressure for two days. Subsequently, another 66 mg of palladium (10% w/w on charcoal) were added and hydrogenation was continued overnight.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=4)[NH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:7]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:43](Cl)(=[O:45])[CH3:44]>C(#N)C>[C:43]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=4)[NH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:7]=1)(=[O:45])[CH3:44]
Reactant: Cc1ccc(N)cc1CCN1CCC(c2c[nH]c3ccc(F)cc23)CC1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(C)c(CCN2CCC(c3c[nH]c4ccc(F)cc34)CC2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Polymer bound 3-[1-(2-{5-amino-2-methylphenyl}ethyl)piperidin-4-yl]-5-fluoro-1H-indole (100 mg, 100 μmol), triethylamine (90 μL), and dimethylaminopyridine (0.50 mL of an 0.2 M solution in dry acetonitrile) were mixed in a reactor tube. The mixture was cooled to 0° C. and treated with acetyl chloride (0.50 mL of an 1M solution in dry acetonitrile). The reaction mixture was left at 0° C. for 2 h. The resin was filtered off and washed with dry acetonitrile (3×1 mL). The resin was treated for 1 h with 1 mL of a mixture of sodium methoxide (2 mL, 5 N sodium methoxide in methanol), methanol (50 mL) and tetrahydrofuran (50 mL). After filtration, the resin was washed with methanol (1 mL). The combined filtrates were loaded on a pre-conditioned ion exchange column (500 mg SCX column, commercially available from Analytical Instruments, part no. 1210-2040), washed with acetonitrile (1 mL) and methanol (1 mL). The product was eluted with 4 M ammonia in methanol. Evaporation of volatile solvents afforded the title compound as a yellow oil (6 mg, 15 μmol). LC/MS (m/z) 394 (MH+), RT=1.98, purity: 88%.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10]([CH:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[S:20](=[O:28])(=[O:27])[NH:19]2)=[CH:9]1)(C)(C)C.[OH-].[Na+]>CCO>[Cl:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:6]([OH:29])=[O:5])[CH:9]=[C:10]2[CH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[S:20](=[O:28])(=[O:27])[NH:19]1
Reactant: CC(C)(C)OC(=O)Cn1cc(C2NS(=O)(=O)c3ccccc32)c2cc(Cl)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cn1cc(C2NS(=O)(=O)c3ccccc32)c2cc(Cl)ccc21
Temperature: 50 °C

Procedure:
The product from step c) (100 mg) was dissolved in 3 mL EtOH and treated with 0.5 mL of 1 M NaOH. The reaction was heated to 50° C. for 2 h. Upon cooling, the reaction was washed with DCM, acidified with 1 M HCl, and extracted into DCM. The organic layer was washed twice with water, dried over MgSO4, and concentrated to give the title compound as a solid. MS: ESI (negative): 375, 377 (M−H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[C:11](O)=[O:12])[CH2:8]2.S(Cl)(Cl)=O.[NH2:18][N:19]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(C(C)C)CC)(C)C>>[O:29]=[C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:19]1[NH:18][C:11]([CH:2]1[CH:1]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]1[CH2:4]3)[CH2:8]2)=[O:12]
Reactant: O=C(O)C1C2CC3CC(C2)CC1C3
Reactant: Nn1c(-c2ccccc2)nc2ccccc2c1=O
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nn1c(-c2ccccc2)nc2ccccc2c1=O)C1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
A solution of adamantane-2-carboxylic acid (110 mg, 0.61 mmol, prepared as described in J. Med. Chem, (2007), 50(1), 149-164) in thionyl chloride (1.5 mL, 20.6 mmol) was heated at 80° C. for 90 minutes and then cooled to room temperature and concentrated under vacuum. The residue was dissolved in CH2Cl2 (3 mL) and 3-amino-2-phenylquinazolin-4(3H)-one (145 mg, 0.61 mmol, Aldrich) and diisopropylethylamine (0.2 mL, 1.14 mmol) were added. The mixture was stirred at room temperature for 2 hours and concentrated under vacuum. The residue was purified by flash chromatography (SiO2, eluted with hexanes-EtOAc, 90:10-70:30), then by preparative HPLC on a Waters Nova-Pak® HR C18 6 μm 60 {acute over (Å)} Prep-Pak® cartridge column (40 mm×100 mm) using a gradient of 10% to 100% acetonitrile in 10 mM aqueous ammonium acetate over 12 minutes at a flow rate of 70 mL/min to provide the title compound as a white powder (56 mg, 23%): 1 H NMR (300 MHz, CD3OD) δ ppm 1.21 (br. d, J=12.9 Hz, 1 H), 1.31 (br. d, J=12.9 Hz, 1 H), 1.51 (br. d, J=12.7 Hz, 1 H), 1.58-1.72 (m, 3 H), 1.73-1.91 (m, 5 H), 1.90-2.01 (m, 2 H), 2.21 (br. s, 1 H), 2.61 (br. s, 1 H), 7.44-7.56 (m, 3 H), 7.56-7.65 (m, 3 H), 7.76 (d, J=8.3 Hz, 1 H), 7.89 (ddd, J=8.4, 7.0, 1.6 Hz, 1 H), 8.27 (dd, J=7.9, 1.6 Hz, 1 H); MS (DCI) m/z 400 (M+H); Elemental analysis calculated for C25 H25N3O2.0.7 H2O: C, 72.86; H, 6.46; N, 10.20. Found: C, 72.72; H, 6.30; N, 10.06.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([N:16]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])[S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:45](I)[CH3:46]>CN(C)C=O>[CH2:1]([O:8][C:9]([C:11]1([N:16]([CH2:34][CH2:35][C:36]([O:38][CH2:45][CH3:46])=[O:37])[S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:18])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCN(C1(C(=O)OCc2ccccc2)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(C1(C(=O)OCc2ccccc2)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.4 %

Procedure:
To a solution of 1{(2-carboxyethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentanecarboxylic acid benzyl ester (147 grams) in N,N-dimethyl formamide (3 L) at room temperature was added potassium carbonate (150 grams, 1.08 mole) and ethyl iodide (32.4 mL, 0.405 mole). The mixture was stirred for 16 hours at room temperature. After filtration, most of the solvent was removed under vacuum. The residue was taken up in water and acidified using 6N aqueous hydrogen chloride solution. The resulting mixture was extracted with diethyl ether. The organic extract was washed with water and brine, dried over magnesium sulfate, and concentrated to yield 1{(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentane carboxylic acid benzyl ester as a yellow semi-solid (149.1 grams, 96%).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:6][CH2:5][CH2:4]1.[ClH:7].Cl.[CH:9]1[CH:18]=[CH:17][C:16]2[CH2:19][CH2:20][CH2:21][N:14]3[C:15]=2[C:10]=1[C@H:11]1[CH2:24][NH:23][CH2:22][C@H:12]1[CH2:13]3>>[ClH:7].[ClH:7].[CH:3]1([CH2:2][N:23]2[CH2:24][C@H:11]3[C@H:12]([CH2:13][N:14]4[CH2:21][CH2:20][CH2:19][C:16]5[CH:17]=[CH:18][CH:9]=[C:10]3[C:15]4=5)[CH2:22]2)[CH2:6][CH2:5][CH2:4]1
Reactant: BrCC1CCC1
Reactant: c1cc2c3c(c1)[C@H]1CNC[C@H]1CN3CCC2
Agent: Cl
Product: c1cc2c3c(c1)[C@H]1CN(CC4CCC4)C[C@H]1CN3CCC2

Procedure:
Using bromomethylcyclobutane and following the procedures described in EXAMPLE 104, (±)-cis-5,6,8,8a,9,10,11,11a-octahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline free base from EXAMPLE 11 was converted into the title compound of EXAMPLE 105 as an off-white powder. 1H NMR (dmso-D6) δ: 11.10 (broad s, 1H), 6.90-6.78 (m, 2H), 6.65-6.55 (m, 1H), 3.90-3.80 (m, 1H), 3.79-3.70 (m, 1H), 3.60-3.30 (m, 3H), 3.20-2.95 (m, 4H), 2.90-2.65 (m, 5H), 2.08-1.98 (m, 2H), 1.95-1.70 (m, 7H). LRMS (ES)+: 283.2 (M+H)+.