Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Br.[CH3:9][N:10]1[C:14]2[CH2:15][NH:16][CH2:17][CH2:18][C:13]=2[CH:12]=[N:11]1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[N:27]=[C:28]([CH3:40])[N:29]2[C:34]=1[C:33](N1C=NC=N1)=[N:32][CH:31]=[N:30]2>ClCCl>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[N:27]=[C:28]([CH3:40])[N:29]2[C:34]=1[C:33]([N:16]1[CH2:17][CH2:18][C:13]3[CH:12]=[N:11][N:10]([CH3:9])[C:14]=3[CH2:15]1)=[N:32][CH:31]=[N:30]2
Reactant: Cc1nc(-c2ccccc2F)c2c(-n3cncn3)ncnn12
Reactant: Cn1ncc2c1CNCC2
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccccc2F)c2c(N3CCc4cnn(C)c4C3)ncnn12
Temperature: 40 °C

Procedure:
Triethylamine (0.510 mL, 3.66 mmol) and C9 (0.333 g, 1.58 mmol) were added to a solution of C6 (0.360 g, 1.22 mmol) in dichloromethane (10 mL), and the reaction mixture was heated at 40° C. for 18 hours. The mixture was then washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification was effected first via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane), then by reversed phase HPLC (Column: Phenomenex Gemini C18, 5 μm; Mobile phase A: 0.1% ammonium hydroxide in water; Mobile phase B: 0.1% ammonium hydroxide in methanol; Gradient: 5% to 100% B). The product was obtained as a solid. Yield: 202 mg, 0.556 mmol, 46%. LCMS m/z 364.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 7.98 (s, 1H), 7.63 (ddd, J=7.6, 7.5, 1.8 Hz, 1H), 7.52 (dddd, J=8.3, 7.5, 5.2, 1.8 Hz, 1H), 7.35 (ddd, J=7.6, 7.5, 1.1 Hz, 1H), 7.22 (br ddd, J=10.0, 8.3, 1.0 Hz, 1H), 7.16 (br s, 1H), 4.45 (br s, 2H), 3.76-3.84 (m, 2H), 3.43 (s, 3H), 2.67 (s, 3H), 2.35-2.41 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20][CH2:19]1.[Cl:33][C:34]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[C:36]([Cl:49])[C:35]=1[OH:50]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C@H:18]2[CH2:19][CH2:20][C@H:21]([CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH2:22][CH2:23]2)=[CH:3][C:2]([C:38]2[CH:39]=[C:34]([Cl:33])[C:35]([OH:50])=[C:36]([Cl:49])[CH:37]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)CC1

Procedure:
Following general procedure F, tert-butyl {trans-4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexyl}methylcarbamate (62 mg, 0.123 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (53 mg, 0.185 mmol) to afford the crude product (58 mg) as a yellow solid: ESI MS m/z 584 [C31H35Cl2N3O4+H]+.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[F:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([C:36](O)=[O:37])=[CH:28][CH:27]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:20]([O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][CH:2]([NH:1][C:36]([C:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:26]([F:25])=[CH:27][CH:28]=1)=[O:37])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4])[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)COc1cccc(CC(N)C(O)c2cccc(Cl)c2)c1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)COc1cccc(CC(NC(=O)c2ccc(F)c3ccccc23)C(O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-3-[3-(neopentyloxy)phenyl]-1-(3-chlorophenyl)-1-propanol (0.30 g, 0.86 mmol) in N,N-dimethylformamide (5 ml) were added 4-fluoronaphthalene-1-carboxylic acid (0.17 g, 0.90 mmol) and 1-hydroxybenzotriazole monohydrate (0.138 g, 0.90 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.173 g, 0.90 mmol) was finally added. The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give N-[(1RS,2SR)-1-[3-(neopentyloxy)benzyl]-2-(3-chlorophenyl)-2-hydroxyethyl]-4-fluoro-1-naphthamide (0.354 g, 79%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([CH3:23])(=[O:22])=[O:21])[C:3]=1[CH3:24].[O:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[C:33]3[NH:39][CH2:38][C:37]4([CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)[C:34]3=[N:35][CH:36]=2)[CH2:27][CH2:26]1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([N:39]1[C:33]3[C:34](=[N:35][CH:36]=[C:31]([N:28]4[CH2:29][CH2:30][O:25][CH2:26][CH2:27]4)[CH:32]=3)[C:37]3([CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[CH2:38]1)=[C:3]([CH3:24])[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([CH3:23])(=[O:22])=[O:21])=[N:5]2
Reactant: c1nc2c(cc1N1CCOCC1)NCC21CCOCC1
Reactant: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Cl
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y by stirring 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline (50 mg, 0.14 mmol), 6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (44.9 mg, 0.16 mmol), XPhos precatalyst (20.1 mg, 0.027 mmol), sodium tert-butoxide (32.7 mg, 0.34 mmol), and toluene (1.5 mL) at 95° C. for 18 h. Purification by reverse-phase HPLC (0-70% acetonitrile in water) gave 1′-(5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)-4-quinolinyl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro-[pyran-4,3′-pyrrolo[3,2-b]pyridine]. 1H NMR (400 MHz, chloroform-d) δ ppm 7.62-7.76 (1H, m), 7.24-7.33 (1H, m), 7.13-7.23 (1H, m), 6.98-7.09 (2H, m), 6.87-6.98 (1H, m), 6.48-6.60 (1H, m), 5.42-5.51 (1H, m), 3.67-3.76 (1H, m), 3.50-3.67 (2H, m), 3.20-3.28 (4H, m), 2.94-3.14 (2H, m), 2.59-2.65 (1H, m), 2.48-2.59 (6H, m), 1.71-1.88 (2H, m), 1.50-1.55 (1H, m), 1.38-1.46 (2H, m), 1.23-1.38 (1H, m), 1.07-1.19 (1H, m), 0.70-0.75 (1H, m). Mass Spectrum (ESI) m/e=607.0 (M+1).
Reaction SMILES: [CH:1]1[N:9]([C@@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([OH:17])[C@@H:11]2[OH:18])[C:8]2[C:3](=[C:4]([NH2:20])[N:5]=[C:6]([F:19])[N:7]=2)[N:2]=1.[P:21]([O-:25])([O-:24])([O-:23])=[O:22].C(=O)([O-])[O-].[K+:30].[K+].CC(C)=O>O>[CH:1]1[N:9]([C@@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([OH:17])[C@@H:11]2[OH:18])[C:8]2[C:3](=[C:4]([NH2:20])[N:5]=[C:6]([F:19])[N:7]=2)[N:2]=1.[K+:30].[K+:30].[P:21]([OH:25])([O-:24])([O-:23])=[O:22]
Reactant: O=P([O-])([O-])[O-]
Agent: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=P([O-])([O-])O
Temperature: 25 °C

Procedure:
5.0 g of fludarabine-phosphate at a purity of 96.1% is dissolved in 30 ml of water, and 6.5 ml of a potassium carbonate solution (18.5% by weight) is added to this solution below 30° C. It is stirred for 15 more minutes, then solid material is filtered out. The clear solution that is thus obtained is poured into acetone at 50° C., cooled to room temperature and stirred for 2 more hours. The deposited precipitate is filtered and washed twice with acetone. 4.5 g of fludarabine-phosphate dipotassium salt is obtained.
Reaction SMILES: B.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23](O)=[O:24])=[C:10]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]>O1CCCC1>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][CH2:23][OH:24])=[C:10]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)C1=C(COCC(=O)O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Agent: B
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(COCCO)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A 1M solution of borane in tetrahydrofuran (10 ml) was added dropwise over 10 minutes to a stirred, ice-cooled solution of 2-{[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}acetic acid (2.0 g--see preparation 4 of European patent application publication No. 0100189) in tetrahydrofuran (20 ml) and the mixture was allowed to warm to room temperature. The mixture was stirred at room temperature for 3 days, quenched with water (5 ml) and evaporated. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution and the organic layer was dried over MgSO4 and evaporated. The residual oil was purified by chromatography on silica gel (10 g) using hexane plus 20→50% dichloromethane followed by dichloromethane plus 0→1% methanol as eluant. Appropriate fractions were combined and evaporated and the resulting oil was crystallised from hexane to give the title compound (0.6 g), m.p. 125°-130°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:10]=1[CH:11]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.C(Cl)Cl.O>[F:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:10]=1[CH2:11][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=Cc1c(F)cccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: Fc1cccc(F)c1CNc1ccccc1
Temperature: 70 °C
Yield: 53.9 %

Procedure:
A mixture of aniline (2.26 g, 24.3 mmol), 2,6-difluorobenzaldehyde (3.79 g, 26.7 mmol) and glacial acetic acid (3.5 mL, 60.8 mmol) in dichloroethane (50 mL) was heated at 70° C. for 2 h. After cooling to rt, sodium triacetoxyborohydride (5.67 g, 26.8 mmol) was added and the mixture heated at 70° C. for 1.5 h, before cooling to rt, further sodium triacetoxyborohydride (5.67 g, 26.8 mmol) was added and the mixture was heated at 70° C. for a further 75 min before cooling to rt. H2O (50 mL), DCM (25 mL) and 1M aqueous NaOH (100 mL) were added and the phases were separated. The aqueous phase was extracted with DCM (2×50 mL) and the combined organic phases were extracted with DCM (2×50 mL), washed with brine (50 mL) and concentrated in vacuo. Purification by gradient column chromatography eluting with 0-20% EtOAc in heptane yielded the title compound (2.88 g, 13.1 mmol).
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[Cl:12][C:13]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16].N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:15](=[O:16])[C:14]3[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:13]=3[Cl:12])[CH2:2]1)[CH2:8]2
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cccc(Cl)c1Cl

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 2,3-dichlorobenzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.91-1.99 (m, 6H), 2.07 (d, 1H), 2.26 (d, J=13 Hz, 2H), 2.35 (s, 2H), 3.44-3.52 (m, 2H), 3.77-3.89 (m, 1H), 4.43 (s, 1H), 7.36-7.42 (m, 2H), 7.63 (dd, J=6, 4 Hz, 1H); MS (APCI/NH3) m/z 325 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][C@@H:12]([CH:15]([CH3:17])[CH3:16])[CH:13]=O)=[N:7][C:6]=12.[CH3:18][O:19][CH2:20][CH2:21][NH2:22]>>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][C@@H:12]([CH:15]([CH3:17])[CH3:16])[CH2:13][NH:22][CH2:21][CH2:20][O:19][CH3:18])=[N:7][C:6]=12
Reactant: CC(C)[C@@H](C=O)Nc1ccn2ncc(Br)c2n1
Reactant: COCCN
Product: COCCNC[C@@H](Nc1ccn2ncc(Br)c2n1)C(C)C

Procedure:
(S)—N2-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-N1-(2-methoxyethyl)-3-methylbutane-1,2-diamine was prepared by the procedure described in Example 15, Step 4, from (S)-2-(3-bromopyrazolo[1,5-a]pyrimidin-5-ylamino)-3-methylbutanal and 2-methoxyethanamine. LCMS (APCI+) m/z 356, 358 [M+H]+.
Reaction SMILES: C([N:14]1[CH2:17][C:16]([NH:19][C:20]2[CH:21]=[C:22]3[C:31](=[CH:32][CH:33]=2)[O:30][CH2:29][C:28]2[N:23]3[C@H:24]([CH3:35])[C:25](=[O:34])[NH:26][N:27]=2)([CH3:18])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>CO>[CH3:35][C@H:24]1[N:23]2[C:28]([CH2:29][O:30][C:31]3[C:22]2=[CH:21][C:20]([NH:19][C:16]2([CH3:18])[CH2:15][NH:14][CH2:17]2)=[CH:33][CH:32]=3)=[N:27][NH:26][C:25]1=[O:34]
Reactant: C[C@@H]1C(=O)NN=C2COc3ccc(NC4(C)CN(C(c5ccccc5)c5ccccc5)C4)cc3N21
Agent: Cl
Solvent: CO
Product: C[C@@H]1C(=O)NN=C2COc3ccc(NC4(C)CNC4)cc3N21
Temperature: 25 °C
Yield: 139.6 %

Procedure:
A suspension of (R)-6-(1-benzhydryl-3-methyl-azetidin-3-ylamino)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Example #148, Step E, 20 g, 42.8 mmol) and PdOH2/C(10%, 10 g, 71.2 mmol) in MeOH (400 mL) and HCl (2 mL) was stirred at 50° C. under H2 (50 psi) for 48 h. The reaction mixture was cooled to ambient temperature and filtered, washed with hot MeOH (3×100 mL). The combined filtrate was concentrated in vacuo to give (R)-4-methyl-6-(3-methyl-azetidin-3-ylamino)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (18 g, 99%), which was used directly. LC/MS (Table 1, Method 25) Rt=0.525 min.; MS m/z: 302 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH2:37])[CH:29]=3.[N:39]([CH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1)=[C:40]=[O:41]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH:37][C:40]([NH:39][CH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1)=[O:41])[CH:29]=3
Reactant: Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Reactant: O=C=NC1CCCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2)NC1CCCC1
Yield: 39 %

Procedure:
The desired compound was prepared according to the procedure of Example B83, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-11-amine bis(trifluoroacetate) and isocyanatocyclopentane as the starting materials in 39% yield. LCMS for C24H26ClN6O (M+H)+: m/z=449.2.
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][S:7]([NH:10][C:11]([NH:13][C:14]1[N:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[N:15]=1)=[S:12])(=[O:9])=[O:8].BrN1C(=O)CCC1=O>CO>[CH3:21][O:20][C:18]1[CH:17]=[C:16]([O:22][CH3:23])[N:15]2[S:12][C:11](=[N:10][S:7]([CH2:6][C:5]3[CH:24]=[CH:25][CH:26]=[CH:27][C:4]=3[O:3][CH:2]([F:1])[F:28])(=[O:9])=[O:8])[N:13]=[C:14]2[N:19]=1
Reactant: COc1cc(OC)nc(NC(=S)NS(=O)(=O)Cc2ccccc2OC(F)F)n1
Agent: O=C1CCC(=O)N1Br
Solvent: CO
Product: COc1cc(OC)n2sc(=NS(=O)(=O)Cc3ccccc3OC(F)F)nc2n1
Yield: 60.3 %

Procedure:
To a suspension of 0.5 g of N-(2-difluoromethoxybenzyl) sulfonyl-N'-(4,6-dimethoxy-2-pyrimidinyl)thiourea in 20 ml of methanol is added 0.2 g of N-bromosuccinimide with stirring under ice cooling. After stirring for 30 minutes at the same temperature and further for an hour at room temperature, the crystals are collected by filtration, washed with methanol, and recrystallized from acetonitrile to give 0.3 g of the title compound as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:3]=1[CH2:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:6]=1[NH2:7].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([S:29](Cl)(=[O:31])=[O:30])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>O1CCCC1.N1C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:3]=1[CH2:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:6]=1[NH:7][S:29]([C:23]1[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:21]([O:20][CH3:19])[CH:22]=1)(=[O:31])=[O:30]
Reactant: COc1cccc(Cc2c(F)cccc2F)c1N
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)Nc2c(Cc3c(F)cccc3F)cccc2OC)cc1OC
Reaction time: 18 h
Yield: 73 %

Procedure:
3.8 g of 2-(2,6-difluorobenzyl)-6-methoxyaniline are dissolved in 36 ml of tetrahydrofuran and 1.2 ml of pyridine, and then 4.06 g of 3,4-dimethoxybenzene-sulfonyl chloride are then added. After 18 hours at room temperature, the reaction medium is taken up in ethyl acetate and then hydrolyzed, the organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is solidified in a toluene/ethyl acetate mixture (9/1) (v/v) in order to obtain 5 g of expected product.
Reaction SMILES: [CH3:1][P:2]([CH3:10])([CH:4]([OH:9])[C:5]([O:7][CH3:8])=[O:6])=[O:3].[CH3:11][O:12][CH2:13][N:14]=[C:15]=[O:16]>O1CCOCC1.C(N(CC)CC)C>[CH3:1][P:2]([CH3:10])([CH:4]([O:9][C:15](=[O:16])[NH:14][CH2:13][O:12][CH3:11])[C:5]([O:7][CH3:8])=[O:6])=[O:3]
Reactant: COC(=O)C(O)P(C)(C)=O
Reactant: COCN=C=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COCNC(=O)OC(C(=O)OC)P(C)(C)=O
Reaction time: 24 h
Yield: 103.2 %

Procedure:
0.2 g of triethylamine is first added to a solution of 12.5 g (0.075 mol) of methyl 2-(dimethylphosphinoyl)-2-hydroxy-acetate in 50 ml of absolute dioxane, and 6.6 g (0.075 mol) of methoxymethyl isocyanate in 20 ml of absolute dioxane are then added dropwise. The mixture is stirred at 25° for 24 hours, the solvent is stripped off and the residue is recrystallized from diisopropyl ether/ethyl acetate. 19.6 g (98%) of the desired product of melting point 101° are obtained.
Reaction SMILES: [Na+].[CH:2]1([S:8]([O-:11])(=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)(Cl)=O.O.C1(C)C=CC=CC=1.C[N:25](C=O)C>>[CH:2]1([S:8]([NH2:25])(=[O:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CN(C)C=O
Reactant: O=S(=O)([O-])C1CCCCC1
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: NS(=O)(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 29 h

Procedure:
To a suspension of cyclohexanesulfonic acid sodium salt (2.5 g) in DMF (15 mL) was added thionyl chloride (1.96 mL) under ice-cooling, and the mixture was stirred at room temperature for 29 hr. The reaction mixture was added to a mixture of ice-cooled water (100 mL) and toluene (100 mL), and the mixture was extracted. The organic layer was concentrated under reduced pressure. THF (50 mL) was added to the residue, 28% aqueous ammonia (10 mL) was added dropwise to the solution under ice-cooling, and the mixture was stirred at room temperature for 17 hr. After concentration under reduced pressure, water (100 mL) and ethyl acetate (100 mL) were added to extract the residue. The organic layer was concentrated under reduced pressure to give the title compound (760 mg) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>C(NC(C)C)(C)C>[CH2:16]([N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]1=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)NC(C)C
Product: Cc1ccc2c(c1)c1c(n2Cc2ccccc2)CCN(C)C1
Yield: 13.8 %

Procedure:
Preparation of the title compound was carried out according to General Method 5. 2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (Example 1) (100 mg, 0.5 mmol) and benzyl chloride (0.11 ml, 0.9 mmol) in diisopropylamine (2 mL) were heated at 80° C. for 12 h. The contents were basified with 1N NaOH and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The resulting crude product was purified by silica gel chromatography (230-400 mesh) using methanol-dichloromethane gradient followed by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL) to obtain 20 mg of 5-benzyl-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole as a trifluoroacetate salt.
Reaction SMILES: C1(C2C=CC=CC=2)C=CC(C[N:8]2[C:12]3[CH:13]=[C:14]([F:39])[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[CH:29]=[CH:28][C:27]([C:30]([N:32]6[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]6)=[O:31])=[CH:26][CH:25]=5)=[CH:20][CH:19]=4)=[C:16]([F:17])[C:11]=3[N:10]=[C:9]2[O:40][CH:41]2[CH2:46][CH2:45][CH:44]([C:47]([O:49]CC)=[O:48])[CH2:43][CH2:42]2)=CC=1.C1CC=CCC=1.O([Si](C)(C)C)[K]>CCOC(C)=O.CCO.C1COCC1.[OH-].[OH-].[Pd+2]>[F:17][C:16]1[C:11]2[N:10]=[C:9]([O:40][CH:41]3[CH2:46][CH2:45][CH:44]([C:47]([OH:49])=[O:48])[CH2:43][CH2:42]3)[NH:8][C:12]=2[CH:13]=[C:14]([F:39])[C:15]=1[C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([N:32]3[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]3)=[O:31])=[CH:26][CH:25]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)C1CCC(Oc2nc3c(F)c(-c4ccc(-c5ccc(C(=O)N6CCC(O)CC6)cc5)cc4)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)CC1
Agent: [Pd+2]
Agent: C[Si](C)(C)O[K]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1CCC(Oc2nc3c(F)c(-c4ccc(-c5ccc(C(=O)N6CCC(O)CC6)cc5)cc4)c(F)cc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl 4-{[1-(biphenyl-4-ylmethyl)-4,6-difluoro-5-{4′-[(4-hydroxypiperidin-1-yl)carbonyl]biphenyl-4-yl}-1H-benzimidazol-2-yl]oxy}cyclohexanecarboxylate (isomer B, 0.057 g, 0.074 mmol) and Pd(OH)2 (0.014 g, 0.019 mmol) in 0.8 mL of EtOAc and 0.4 mL of EtOH was added 1,4-cyclohexadiene (0.180 mL, 1.91 mmol). The resulting black suspension was microwaved at 130° C. for 2 h, then filtered through a Celite™ pad, and washed with EtOAc. The resulting filtrate was concentrated in vacuo to give a crude residue. The crude residue was dissolved in 2 mL of THF and treated with KOTMS (0.028 g, 0.222 mmol). The reaction mixture was stirred for 18 h at ambient temperature, and then concentrated. The resulting crude residue was purified by reverse phase Gilson™ HPLC (35-100% MeCN/H2O) to provide the title compound as a white solid. LCMS: calculated for C32H31F2N3O5 575.60, observed m/e 576.1 (M+H)+ (Rt 1.99/4 min). 1H NMR (500 MHz, CD3OD): 7.80 (d, 2H), 7.76 (d, 2H), 7.55 (d, 2H), 7.52 (d, 2H), 7.05 (d, 1H), 4.98-4.90 (m, 1H), 4.27-4.16 (m, 1H), 3.95-3.86 (m, 1H), 3.79-3.67 (m, 1H), 3.42-3.33 (m, 1H), 2.43-2.34 (m, 1H), 2.34-2.26 (m, 2H), 2.16-2.06 (m, 2H), 2.03-1.90 (m, 2H), 1.90-1.78 (m, 2H), 1.75-1.42 (m, 5H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16](O)[CH3:17].S(=O)(=O)(O)O>C(N(CC)CC)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCCCOCc1ccccc1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCOCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 61.1 g of 5-benzyloxypentanoic acid, 566 ml of ethanol and 10 ml of concentrated sulfuric acid is refluxed for 15 h. The mixture is cooled to room temperature, 10 ml of triethylamine are added and evaporated. The residue is diluted with 250 ml of ether and the solution is washed in water and brine dried (MgSO4) and evaporated. The residual oil is distilled to give ethyl 5-benzyloxypentanoate, b.p. 110°-113° C. (0.7 mm/Hg).