Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH2:28][CH2:29][C@H:30]([O:41][C:42]1[N:47]=[CH:46][N:45]=[C:44]2[N:48]([C:51]3[C:56]([Cl:57])=[CH:55][CH:54]=[CH:53][N:52]=3)[N:49]=[CH:50][C:43]=12)[C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]=1)=[O:32])(C(C)(C)C)(C)C>C1COCC1>[Cl:57][C:56]1[C:51]([N:48]2[C:44]3[N:45]=[CH:46][N:47]=[C:42]([O:41][C@@H:30]([CH2:29][CH2:28][CH2:27][OH:26])[C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]=4)=[O:32])[C:43]=3[CH:50]=[N:49]2)=[N:52][CH:53]=[CH:54][CH:55]=1
Reactant: Cc1ccc(NC(=O)[C@H](CCCO[Si](C)(C)C(C)(C)C)Oc2ncnc3c2cnn3-c2ncccc2Cl)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)[C@H](CCCO)Oc2ncnc3c2cnn3-c2ncccc2Cl)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.4 %

Procedure:
A solution of tetrabutylammonium fluoride 2M in THF (0.449 mL, 0.45 mmol) was added in one portion to a stirred solution of (2S)-5-(tert-butyldimethylsilyloxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyridin-2-yl)pentanamide (Intermediate O1) (170 mg, 0.30 mmol) in THF (5 mL). The resulting solution was stirred at ambient temperature for 4 hours, evaporated and the residue dissolved in ethyl acetate (30 mL). This was washed with water (20 mL) and brine (20 mL), dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, eluting with 0 to 10% MeOH in ethyl acetate to afford the product (100 mg, 73%). 1H NMR (400 MHz, CDCl3) δ 1.61-1.68 (1H, m), 1.84-1.88 (2H, m), 2.23-2.36 (2H, m), 2.30 (3H, s), 3.72-3.82 (2H, m), 5.94-5.98 (1H, m), 7.46 (1H, dd), 7.54 (1H, dd), 8.01 (1H, dd), 8.08-8.10 (1H, m), 8.12-8.15 (1H, m), 8.45 (1H, s), 8.61-8.62 (2H, m), 8.63 (1H, s); m/z (ESI+)(M+H)+=454; HPLC tR=1.51 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH:23]1C=CC=CC=1>>[CH3:23][O:17][C:16](=[O:18])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: O=C(O)Cc1ccc(Sc2ccc(Cl)cc2)cc1
Reactant: c1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(Sc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 21 g of [p-(p-chlorophenylthio)phenyl]acetic acid and 11.9 g of thionyl chloride are stirred overnight at room temperature. To the resulting greenish yellow solution is added 20 ml of benzene and the solvent is evaporated at reduced pressure. This procedure is repeated once. The residue is added dropwise to 300 ml of methanol, maintained at 0° C., and the resulting solution is stirred overnight. The solvent is evaporated at reduced pressure and the mixture is dissolved in 200 ml of ether. The ether layer is washed with 100 ml of water, 100 ml of saturated NaHCO3, 100 ml of saturated brine and dried over MgSO4. Evaporation of the solvent and distillation of the residue affords the product as a light yellow oil.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:18][CH:19]=[CH:20][N:21]=3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][N:27]2[C@H:32]([CH3:36])[C:33](O)=[O:34].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O.CC#N.CN(C=O)C>[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][N:27]2[C@H:32]([CH3:36])[C:33]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:18][CH:19]=[CH:20][N:21]=3)(=[O:14])=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5]1)=[O:34]
Reactant: C[C@H](C(=O)O)n1ccc2c(F)cccc21
Reactant: O=S(=O)(Nc1nccs1)c1ccc(N2CCNCC2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: C[C@H](C(=O)N1CCN(c2ccc(S(=O)(=O)Nc3nccs3)cc2)CC1)n1ccc2c(F)cccc21

Procedure:
Synthesized according to general procedure 5, method A. The reaction was set up with 0.08 mmol 4-(piperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide, 0.08 mmol (2R)-2-(4-fluoro-indol-1-yl)-propionic acid, 0.08 mmol BOP reagent, 0.08 mmol triethylamine and 200 μL DMF. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=514.50; tR=3.03 min.
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]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28].C(N(CC)CC)C.Cl>CN(C)C=O>[O:21]=[C:15]1[CH:14]([N:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][CH:32]=[C:24]([C:23]([F:22])([F:33])[F:34])[CH:25]=4)[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCC(N2Cc3cc(CNC(=O)c4cccc(C(F)(F)F)c4)ccc3C2=O)C(=O)N1
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a stirred mixture of 3-(5-Aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (1.00 g, 3.20 mmol) and 3-(trifluoromethyl)benzoyl chloride (0.67 g, 3.20 mmol) in N,N-dimethylformamide (25 mL), was added triethylamine (0.90 mL, 6.40 mmol) at room temperature under nitrogen. After 1 h, 1N aq. HCl (50 mL) was added and the mixture was stirred for 10 min. The product was isolated by filtration, washed with 1N aq. HCl (50 mL) and water (50 mL). The solids were dissolved in EtOAc (75 mL) and washed with water (75 mL). The organic layer was separated, dried (MgSO4) and concentrated in vacuo to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-trifluoromethyl-benzamide as an off-white solid (0.95 g, 66% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.69 min (98.71%); mp: 244-246° C.; 1H NMR (DMSO-d6) δ 1.94-2.06 (m, 1H), 2.27-2.46 (m, 1H), 2.53-2.68 (m, 1H), 2.80-3.04 (m, 1H), 4.32 (d, J=17.4 Hz, 1H), 4.45 (d, J=17.4 Hz, 1H), 4.63 (d, J=5.9 Hz, 2H), 5.11 (dd, J=5.0, 13.3 Hz, 1H), 7.49 (d, J=7.7 Hz, 1H), 7.57 (s, 1H), 7.66-7.82 (m, 2H), 7.94 (d, J=7.7 Hz, 1H), 8.16-8.34 (m, 2H), 9.42 (t, J=5.8 Hz, 1H), 10.98 (s, 1H); 13C NMR (DMSO-d6) δ 22.50, 31.19, 42.90, 47.14, 51.59, 122.21, 122.99, 123.86 (q, J=3.6 Hz), 123.90 (q, J=270 Hz), 127.18, 127.94 (q, J=3.5 Hz), 129.2 (q, J=32 Hz), 129.71, 130.47, 131.44, 134.97, 142.42, 143.50, 164.79, 167.91, 170.98, 172.85. LCMS: MH=446; Anal Calcd for C22H18N3O4F3+0.6H2O: C, 57.92; H, 4.24; N, 9.21. Found: C, 57.87; H, 4.08; N, 9.16.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][CH:27]([O:34][CH3:35])[CH2:28][NH:29][CH2:30][CH2:31][CH2:32][CH3:33].[CH:36]([C:39]1[S:40][CH:41]=[C:42]([C:44]([N:46]2[CH2:51][C:50]3([CH2:56][CH2:55][N:54]([CH2:57][CH2:58][O:59][C:60]4[CH:73]=[CH:72][CH:71]=[CH:70][C:61]=4[CH2:62][CH2:63][O:64][CH2:65][CH2:66][C:67](O)=[O:68])[CH2:53][CH2:52]3)[O:49][CH2:48][CH2:47]2)=[O:45])[N:43]=1)([CH3:38])[CH3:37].CCN(C(C)C)C(C)C>CN(C)C=O>[CH2:30]([N:29]([CH2:28][CH:27]([O:26][CH3:25])[O:34][CH3:35])[C:67](=[O:68])[CH2:66][CH2:65][O:64][CH2:63][CH2:62][C:61]1[CH:70]=[CH:71][CH:72]=[CH:73][C:60]=1[O:59][CH2:58][CH2:57][N:54]1[CH2:53][CH2:52][C:50]2([O:49][CH2:48][CH2:47][N:46]([C:44]([C:42]3[N:43]=[C:39]([CH:36]([CH3:38])[CH3:37])[S:40][CH:41]=3)=[O:45])[CH2:51]2)[CH2:56][CH2:55]1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCNCC(OC)OC
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCOc4ccccc4CCOCCC(=O)O)CC3)C2)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCN(CC(OC)OC)C(=O)CCOCCc1ccccc1OCCN1CCC2(CC1)CN(C(=O)c1csc(C(C)C)n1)CCO2
Reaction time: 1 h

Procedure:
HATU (0.337 g) was added to a stirred solution of N-(2,2-dimethoxyethyl)butan-1-amine (0.105 g), 3-(2-(2-(4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-acid (0.390 g) (example 178 step d) and Hunig's Base (0.516 mL) in N,N-dimethylformamide (3 mL). After 1 h, the solution was partitioned between ethyl acetate and brine. The ethyl acetate layer was washed with brine (×3) and evaporated in vacuo. Purification was silica gel chromatography eluting with 10% triethylamine in ethyl acetate. Yield 0.4 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[CH:15][CH:16]=3)[C:11](=[O:24])[C:10]([CH3:26])([CH3:25])[CH2:9]2)=[CH:4][CH:3]=1.[H-].[Li+].[Al+3].[H-].[H-].[H-]>CCOCC.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][N:21]([CH3:22])[CH3:23])=[CH:15][CH:16]=3)[CH:11]([OH:24])[C:10]([CH3:26])([CH3:25])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: CN(C)CCOc1ccc2c(c1)C(=O)C(C)(C)CC2c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CN(C)CCOc1ccc2c(c1)C(O)C(C)(C)CC2c1ccc(Cl)cc1

Procedure:
A solution of 4-(4-chlorophenyl)-2,2-dimethyl-7-(2-dimethylaminoethoxy)-1-tetralone (13.6 g) in dry ether (75 ml) was added to a stirred suspension of aluminium lithium hydride (1.3 g) in dry ether (75 ml) over 40 min. The mixture was heated under reflux a further 45 min., cooled, a few drops of dilute sodium hydroxide solution added, and the ether solution decanted off. The remaining pasty mass was extracted with hot ether, and the combined ether solutions were dried (MgSO4). Removal of the solvent gave 4-(4-chlorophenyl)-1-hydroxy-2,2-dimethyl-7-(2-dimethylaminoethoxy)tetralin as a white foam. (13.3 g, 98%). The hydrochloride salt formed white prisms from ethanol-ether, m.p. 235°-7°.
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:14][CH2:13][C:9]2[N:10]=[CH:11][S:12][C:8]=2[CH2:7]1)=[O:5])C.[CH3:15][CH2:16]OCC>>[CH2:15]([C:11]1[S:12][C:8]2[CH2:7][CH:6]([CH2:4][OH:5])[CH2:14][CH2:13][C:9]=2[N:10]=1)[CH3:16]
Reactant: CCOCC
Reactant: CCOC(=O)C1CCc2ncsc2C1
Product: CCc1nc2c(s1)CC(CO)CC2
Yield: 86 %

Procedure:
The compound is prepared by reduction of the above derivative (III) with AlLiH4 within ether, at room temperature. B.p.0.5 =142°-144° C. Yield: 86%.
Reaction SMILES: C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][C@H:35]1[C@@H:40]([NH:47][C:48]1[C:57]2[C:52](=[C:53]([O:58][CH2:59][CH2:60][NH:61][S:62]([CH3:65])(=[O:64])=[O:63])[CH:54]=[CH:55][CH:56]=2)[N:51]=[C:50]([CH3:66])[CH:49]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)C=C.SC1C=CC=CC=1C(O)=O.[OH-].[Na+].C(O)(C)C.O.[ClH:84]>C1COCC1>[ClH:84].[ClH:84].[CH3:66][C:50]1[CH:49]=[C:48]([NH:47][C@@H:40]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C@@H:35]2[CH2:36][CH2:37][CH2:38][CH2:39][NH:34]2)[C:57]2[C:52](=[C:53]([O:58][CH2:59][CH2:60][NH:61][S:62]([CH3:65])(=[O:63])=[O:64])[CH:54]=[CH:55][CH:56]=2)[N:51]=1
Reactant: C=CCN1CCCC[C@H]1[C@@H](Nc1cc(C)nc2c(OCCNS(C)(=O)=O)cccc12)c1ccccc1
Agent: Cl
Agent: O=C(O)c1ccccc1S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: Cc1cc(N[C@@H](c2ccccc2)[C@@H]2CCCCN2)c2cccc(OCCNS(C)(=O)=O)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
Tris-(dibenzylidenaceton)-dipalladium(0) (19.0 mg, 0.021 mmole) and 1,4-bis(diphenylphosphino)butane (9 mg, 0.021 mmole) were mixed with THF (10 mL). N-[2-(4-{[(S)—((S)-1-Allylpiperidin-2-yl)-phenylmethyl]-amino}-2-methylquinolin-8-yloxy)-ethyl]-methanesulfonamide (example 35, 130 mg, 0.256 mmole) in THF (5 mL) and 2-mercaptobenzoic acid (86.7 mg, 0.562 mmole) in THF (5 mL) were added and the mixture was stirred at RT for 2 hrs. The content of the flask was mixed with 1N NaOH and extracted with dichloromethane. The organic layer was washed with water and saturated NaCl solution and concentrated. The residue thus obtained was cystallized from isopropanol/water/HCl to obtain a white solid (42 mg, 30%).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:12]=[CH:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][N:14]=2)[CH:9]=1)=[O:7]>O1CCCC1.O>[C:6]([C:8]1[CH:12]=[CH:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][N:14]=2)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1ccn(-c2nccc3ccccc23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccn(-c2nccc3ccccc23)c1
Yield: 107.7 %

Procedure:
0.237 g (5.65 mmol) of lithium hydroxide monohydrate is added at 20° C. to 0.57 g (2.26 mmol) of 3-methoxycarbonyl-1-(isoquinol-1-yl)-1H-pyrrole dissolved in 15 mL of tetrahydrofuran and 15 mL of water. After stirring at reflux for 2 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 5 mL of water and then triturated with 5.65 mL of N hydrochloric acid for 1 hour. The aqueous phase is filtered and the solid residue is washed with twice 5 mL of water and then air-dried to give 0.58 g of 3-carboxy-1-(isoquinol-1-yl)-1H-pyrrole in the form of a white solid. Mass spectrum (EI): m/e 238 (M+.), m/e 193.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:36])(=[O:35])[N:20]=1.[OH-].[Na+:38]>O>[CH2:33]([S:30]([NH:29][C:27]1[CH:26]=[CH:25][C:23]2[NH:24][C:19]([C:3]3[C:4](=[O:18])[C@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2]=3[O-:1])=[N:20][S:21](=[O:36])(=[O:35])[C:22]=2[CH:28]=1)(=[O:31])=[O:32])[CH3:34].[Na+:38]
Reactant: CCS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3[C@@](C)(CCC(C)C)C1=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C([O-])c3ccccc3[C@@](C)(CCC(C)C)C1=O)N2
Yield: 87.6 %

Procedure:
A mixture of Example 102A (70.4 mg, 0.132 mmol) and 0.998 M sodium hydroxide (0.133 mL, 0.132 mmol) in 3 mL water was stirred at rt for 16 h. The reaction mixture was concentrated in vacuo to give the title compound (64 mg, 87% yield). 1H NMR (300 MHz, DMSO-d6) δ 0.46 (m, 1H) 0.68 (d, J=6.62 Hz, 3H) 0.70 (d, J=6.62 Hz, 3H) 0.79 (m, 1H) 1.19 (t, J=7.35 Hz, 3H) 1.29 (m, 1H) 1.38 (s, 3H) 1.72 (m, 1H) 2.15 (m, 1H) 3.02 (m, 2H) 7.23 (d, J=7.72 Hz, 1H) 7.31 (m, 2H) 7.44 (m, 3H) 8.04 (d, J=7.35 Hz, 1H) 9.96 (s, 1H) 15.43 (s, 1H). MS (ESI+) m/z 532.0 (M+H−Na)+, 549.0 (M−Na+NH4)+, (ESI−) m/z 530.0 (M−H−Na)−.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:15](=[O:16])[CH2:14][C:13](=[O:17])[NH:12][C:11]3[C:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C:23]=4[CH:24]=[CH:25][C:10]2=3)=[CH:5][CH:4]=1.B(Br)(Br)Br.ClCCl>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:15](=[O:16])[CH2:14][C:13](=[O:17])[NH:12][C:11]3[C:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C:23]=4[CH:24]=[CH:25][C:10]2=3)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2C(=O)CC(=O)Nc3c2ccc2c3CCCC2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1CC(=O)N(c2ccc(O)cc2)c2ccc3c(c2N1)CCCC3
Yield: 64 %

Procedure:
5-(4-Methoxyphenyl)-1,5,8,9,10,11-hexahydronaphtho[1,2-b][1,4]diazepine-2,4-dione (200 mg, 0.59 mmol) obtained in Example 13 was dissolved in dry dichloromethane (5 mL) while stirring in ice-bath. To the solution was dropwise added 1M boron tribromide-dichloromethane (1.2 mL). The mixture was stirred at room temperature for 16 hours and at 50° C. for 3 hours. The solvent was removed by evaporation under reduced pressure. To the residue was added cold water. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/1) to give the titled compound as a white amorphous form (124 mg, yield 64%).
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:41][O:42][C:43]1[C:44]2[N:57]=[C:56]([NH2:58])[S:55][C:45]=2[C:46]([CH:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)=[N:47][CH:48]=1>C1COCC1>[CH3:41][O:42][C:43]1[C:44]2[N:57]=[C:56]([NH:58][C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[O:9])[S:55][C:45]=2[C:46]([CH:49]2[CH2:50][CH2:51][O:52][CH2:53][CH2:54]2)=[N:47][CH:48]=1
Reactant: COc1cnc(C2CCOCC2)c2sc(N)nc12
Reactant: O=C(O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cnc(C2CCOCC2)c2sc(NC(=O)C3CCCCC3)nc12

Procedure:
From cyclohexanecarboxylic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-(tetrahydro-pyran-4-yl)-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 376 (M+H+, 100).
Reaction SMILES: FC1C=CC(F)=C[C:3]=1[CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].BrCC1[N:25]=[C:24]([Cl:26])[CH:23]=[CH:22][N:21]=1.O.C(O)(C(F)(F)F)=O>CC#N>[CH2:10]([O:9][P:5]([CH2:4][C:3]1[N:25]=[C:24]([Cl:26])[CH:23]=[CH:22][N:21]=1)(=[O:12])[O:6][CH2:7][CH3:8])[CH3:11]
Reactant: CCOP(=O)(Cc1cc(F)ccc1F)OCC
Reactant: Clc1ccnc(CBr)n1
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(Cc1nccc(Cl)n1)OCC

Procedure:
Prepared according to the same procedure as diethyl 2,5-difluorobenzylphosphonate, starting with 2-(bromomethyl)-4-chloropyrimidine. Analytical HPLC method: Phenomenex LUNA C18, 50×2 3μ, A=90% H2O/10% CH3CN, B=90% CH3CN/10% H2O, Modifier 0.1% TFA, 0.00 min=0% B, 4.0 min=100% B, 5.0 min=100% B, Flow rate=0.8 mL/min. Mass spec.: 265.1 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[OH:24][C:25]([CH3:30])([CH3:29])[C:26](O)=[O:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:26](=[O:27])[C:25]([OH:24])([CH3:30])[CH3:29])=[C:16]2[N:15]=1
Reactant: CC(C)(O)C(=O)O
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(O)C(=O)Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a mixture of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 25 mg, 0.079 mmol), 2-hydroxy-2-methylpropanoic acid (10 mg, 0.095 mmol), and HATU (36 mg, 0.095 mmol) was added 0.6 mL acetonitrile to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.041 mL, 0.24 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred overnight. The reaction mixture was concentrated, re-dissolved in methanol, and purified by reverse-phase column chromatography, eluting with 5 to 55% acetonitrile/water to yield the final product as an off-white solid (21 mg, 66% yield). MS (apci) m/z=402.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[C:4]([O:10][CH3:11])[CH:3]=1.B(Br)(Br)Br.Cl[CH2:17]Cl>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]2[N:9]=[C:11]([CH3:17])[O:10][C:4]=2[CH:3]=1
Reactant: COc1cc(Br)cc(C)c1N
Reactant: ClCCl
Agent: BrB(Br)Br
Product: Cc1nc2c(C)cc(Br)cc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.50 g (2.31 mmol) 4-Bromo-2-methoxy-6-methyl-phenylamine in 5 mL dichloromethane is cooled with ice/ethanol and 0.24 mL (2.49 mmol) boron tribromide in 5 mL dichloromethane is added slowly. Stirring is continued for 30 under cooling and 2 h at rt. The mixture is poured onto ice, allowed to stand for 30 min and the aq. layer is extracted with dichloromethane. The aq. phase is treated with NaHCO3 until the mixture shows basic pH, followed by extraction with dichloromethane. The combined organic phases are dried and concentrated to yield the desired product which is used without further purification.
Reaction SMILES: BrC1C=CC=CC=1[C:8]1[C:9]2[C:14]([C:15](C3C=CC=CC=3Br)=[C:16]3[C:21]=1C=CC=C3)=[CH:13][CH:12]=[CH:11][CH:10]=2.BrC1C2C(=CC=CC=2)C(C2C3C(=CC=CC=3)C(C3C4C(C(Br)=C5C=3C=CC=C5)=CC=CC=4)=CC=2)=C2C=1C=CC=C2.OC(C(O)(C)C)(C)C.C1(C(=CC=CC=1)O)O>>[CH:13]1[C:14]2[C:9](=[CH:8][CH:21]=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: Brc1ccccc1-c1c2ccccc2c(-c2ccccc2Br)c2ccccc12
Agent: Brc1c2ccccc2c(-c2ccc(-c3c4ccccc4c(Br)c4ccccc34)c3ccccc23)c2ccccc12
Agent: CC(C)(O)C(C)(C)O
Agent: Oc1ccccc1O
Product: c1ccc2ccccc2c1

Procedure:
Preparation analogous to Example 3b. Instead of 19.5 g (40 mmol) of 9,10-bis(2-bromophenyl)anthracene, 25.5 g (40 mmol) of 1,4-bis(10-bromoanthracen-9-yl)naphthalene are used, and instead of 10.6 g (90 mmol) of pinacol, 9.9 g (90 mmol) of pyrocatechol are used. Sublimation at p=1×10−5 mbar, T=330° C. Yield: 17.7 g (25 mmol), 61.8% of theory; purity: 99.7% according to 1H-NMR.
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[CH:9][N:10]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:11]3[CH:12]=[CH:13][CH:14]=[C:6]([C:7]=32)[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32].[BH4-].[Na+].C(O)(=O)C>C(Cl)Cl>[F:34][C:33]([F:36])([F:35])[C:31]([OH:37])=[O:32].[C:18]1([S:15]([N:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:6]4[CH2:5][NH:4][CH2:3][CH:2]([OH:1])[C:8]([C:7]=34)=[CH:9]2)(=[O:17])=[O:16])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC(=O)c2cn(S(=O)(=O)c3ccccc3)c3cccc(c23)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccccc1)n1cc2c3c(cccc31)CNCC2O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
tert-Butyl 3-oxo-1-(phenylsulfonyl)-1,3,4,6-tetrahydro-5H-azepino[5,4,3-cd]indole-5-carboxylate Intermediate 18 (11 mg, 0.03 mmol) was dissolved in DCM (1 ml). TFA (0.5 ml) was added and the solution was heated to boiling, and then evaporated. The residue was dissolved in EtOH (3 ml). Sodium borohydride (7.5 mg, 0.2 mmol) was added. The reaction mixture was stirred at room temperature for 45 min. The solution was acidified with acetic acid, and evaporated. The evaporation procedure was repeated twice with the addition of methanol. The crude product was purified by preparative HPLC (ACE C8 5 mm, water containing 0.1% TFA-CH3CN) to give the title compound, 7 mg.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:24]=[C:22]([OH:23])[C:20]([OH:21])=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:27](Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29].Cl>O.C(OCC)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:24]=[C:22]([OH:23])[C:20]([OH:21])=[CH:19][CH:18]=1)[C:13]([O:15][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)C(=O)OC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
N-benzyloxycarbonyl-L-dopa (3.30 g) was dissolved in a mixture of 50 ml of water and 10 ml of ethyl ether. Under stirring with ice cooling, 10 ml of a 1N sodium hydroxide aqueous solution and 10 ml of an ethyl ether solution of 1.20 g pivaloyl chloride were added dropwise at the same time over a period of 30 minutes while keeping pH at 6.0 to 8.0 After the addition was over, the mixture was stirred at room temperature for 1 hour, and diluted with 50 ml of ethyl acetate. Subsequently, 2N hydrochloric acid was added to adjust pH to 2.0. An organic layer was taken out, water-washed and dried over anhydrous magnesium sulfate. After the drying agent was separated by filtration, the solvent was evaporated under reduced pressure. When the residue was purified by silica gel column chromatography (Wakogel C-100, 120 g, eluted with methylene chloride/methanol=5/1), 2.60 g (yield 62.6%) of N-benzyloxycarbonyl-mono-O-pivaloyl-L-dopa was obtained as a pale yellow glass solid.