Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([N:13]1[CH2:17][C@@H:16]([CH3:18])[CH2:15][C@H:14]1[C:19]1[NH:20][C:21]([C:24]2[CH:29]=[C:28]3[CH2:30][O:31][C:32]4[CH:59]=[C:58]5[C:35]([CH:36]=[CH:37][C:38]6[N:42]=[C:41]([C@@H:43]7[CH2:47][C@H:46]([CH2:48][O:49][CH3:50])[CH2:45][N:44]7[C:51](OC(C)(C)C)=[O:52])[NH:40][C:39]=65)=[CH:34][C:33]=4[C:27]3=[CH:26][CH:25]=2)=[CH:22][N:23]=1)=[O:12])[C@@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].[CH3:60][O:61][C:62]([NH:64][C@H:65]([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)C(O)=O)=[O:63].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>Cl.CCO>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@H:7]([CH3:8])[CH2:9][CH3:10])[C:11]([N:13]1[CH2:17][C@@H:16]([CH3:18])[CH2:15][C@H:14]1[C:19]1[NH:20][C:21]([C:24]2[CH:29]=[C:28]3[CH2:30][O:31][C:32]4[CH:59]=[C:58]5[C:35]([CH:36]=[CH:37][C:38]6[N:42]=[C:41]([C@@H:43]7[CH2:47][C@H:46]([CH2:48][O:49][CH3:50])[CH2:45][N:44]7[C:51](=[O:52])[C@H:65]([NH:64][C:62](=[O:63])[O:61][CH3:60])[C:69]7[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=7)[NH:40][C:39]=65)=[CH:34][C:33]=4[C:27]3=[CH:26][CH:25]=2)=[CH:22][N:23]=1)=[O:12])=[O:4]
Reactant: CC[C@@H](C)[C@H](NC(=O)OC)C(=O)N1C[C@@H](C)C[C@H]1c1ncc(-c2ccc3c(c2)COc2cc4c(ccc5nc([C@@H]6C[C@H](COC)CN6C(=O)OC(C)(C)C)[nH]c54)cc2-3)[nH]1
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC[C@@H](C)[C@H](NC(=O)OC)C(=O)N1C[C@@H](C)C[C@H]1c1ncc(-c2ccc3c(c2)COc2cc4c(ccc5nc([C@@H]6C[C@H](COC)CN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]c54)cc2-3)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
A solution of tert-butyl (2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-alloisoleucyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (218 mg, 0.27 mmol) in 1.25 N HCl in EtOH (3 mL) was heated to 50° C. for 3 h. The reaction was concentrated and the crude material dissolved in DMF (3 mL). To this solution was added a solution of (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (73 mg, 0.35 mmol) and COMU (127 mg, 0.30 mmol). To the resulting solution was added diisopropylethylamine (0.141 mL, 0.81 mmol). After stirring for 2 h at room temperature, the reaction was quenched with 1N HCl (0.200 mL) and purified by HPLC. After lyophilization, the TFA salt was dissolved in EtOAc and washed with saturated NaHCO3. The organic phase was dried over Na2SO4 and concentrated. The free base was then dissolved in MeCN/H2O and lyophilized to afford methyl {(1R)-2-[(2S,4S)-2-(9-{2-[(2S,4S)-1-{(2S,3R)-2-[(methoxycarbonyl)amino]-3-methylpentanoyl}-4-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate (121 mg, 50%). LCMS-ESI+: calculated for C50H56N8O8: 896.4; observed [M+1]+: 897.5.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:15]([O:19][CH2:20][CH2:21][CH2:22][OH:23])([CH3:18])([CH3:17])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:44]1[C:48](=[O:49])[C:47]2=[CH:50][CH:51]=[CH:52][CH:53]=[C:46]2[C:45]1=[O:54]>C1COCC1>[C:15]([O:19][CH2:20][CH2:21][CH2:22][O:23][N:44]1[C:48](=[O:49])[C:47]2[C:46](=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:45]1=[O:54])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OCCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OCCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.2 %

Procedure:
Diisopropyl azodicarboxylate (13.4 mL, 68 mmol) was added dropwise at 0° C. to a stirred suspension of 3-tert-butoxy-propan-1-ol (9.0 g, 68 mmol), triphenylphosphine (17.8 g, 68 mmol), and N-hydroxyphthalimide (11.1 g, 68 mmol) in THF (150 mL), and the reaction stirred for 16 h at room temperature. The solution was concentrated in vacuo and purified by silica gel chromatography (20% Et2O/hexanes) to give 15.5 g (82%) of 2-(3-tert-Butoxy-propoxy)-isoindole-1,3-dione as a faintly yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.72-7.84 (m, 4H), 4.30 (t, 2H, J=4.8 Hz), 3.58 (t, 2H, J=4.8 Hz), 1.94-2.00 (m, 2H), 1.20 (s, 9H). MS (ES) [m+H] calc'd for C15H19NO4, 278; found 278.
Reaction SMILES: CCCCCC.C(OCC)(=O)C.[F:13][C:14]1[CH:15]=[C:16]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][C:21]2=[O:29])[CH:17]=[CH:18][CH:19]=1>CCOCC.CCCCC>[F:13][C:14]1[CH:15]=[C:16]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[CH:16][N:20]([CH3:28])[CH3:21])[C:21]2=[O:29])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C1Cc2ccccc2N1c1cccc(F)c1
Solvent: CCCCCC
Solvent: CCCCC
Solvent: CCOC(C)=O
Product: CN(C)C=C1C(=O)N(c2cccc(F)c2)c2ccccc21

Procedure:
By the procedure of Example Al, but using 13:7 hexane:ethyl acetate and then 3:7 hexane:ethyl acetate as eluant and ether/pentane for crystallization, 1-(3-fluorophenyl)-2(1H,3H)-indolone (0.80 g, 3.5 mmoles) was converted to title product, 0.53 g, m.p. 87°-88.5°.
Reaction SMILES: [N:1]1([C@H:5]2[CH2:8][C@H:7]([C:9]3[S:10][C:11]4[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:12]=4[N:13]=3)[CH2:6]2)[CH2:4][CH2:3][CH2:2]1.BrC1C=CC2N=C([C@H]3[CH2:30][C@H:29]([N:31]4[CH2:35][CH2:34][CH2:33][C@H:32]4[CH3:36])C3)SC=2C=1.CC1C(B2OC(C)(C)C(C)(C)O2)=CC=C(C)N=1.N1C=C(B(O)O)C=NC=1>>[N:1]1([C@H:5]2[CH2:8][C@H:7]([C:9]3[S:10][C:11]4[CH:17]=[C:16]([C:35]5[C:29]([CH3:30])=[N:31][C:32]([CH3:36])=[CH:33][CH:34]=5)[CH:15]=[CH:14][C:12]=4[N:13]=3)[CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: Brc1ccc2nc([C@H]3C[C@H](N4CCC4)C3)sc2c1
Agent: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)n1
Agent: OB(O)c1cncnc1
Product: Cc1ccc(-c2ccc3nc([C@H]4C[C@H](N5CCC5)C4)sc3c2)c(C)n1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, except for substituting the product of Example 61A for the product of Example 1E, and substituting Example 2A (2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine) for pyrimidine-5-boronic acid. 1H NMR (300 MHz, CDCl3) δ ppm 8.01 (d, J=8.48 Hz, 1H) 7.75 (d, J=1.36 Hz, 1H) 7.45 (d, J=7.80 Hz, 1H) 7.39 (dd, J=8.48, 1.70 Hz, 1H) 7.06 (d, J=7.80 Hz, 1H) 3.96-4.08 (m, 1H) 3.19-3.40 (m, 5H) 2.59 (s, 3H) 2.49 (s, 3H) 2.37-2.56 (m, 4H) 2.07-2.19 (m, 2H). MS: (M+H)+=350.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11](F)[CH:10]=2)=[N:7][CH:8]=1.Br.[CH:21]1([CH2:24][S:25]C(=N)N)[CH2:23][CH2:22]1.[OH-].[Na+]>CN(C)C=O>[CH:21]1([CH2:24][S:25][C:11]2[CH:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:8][N:7]=3)[CH:16]=[CH:15][C:12]=2[C:13]#[N:14])[CH2:23][CH2:22]1
Reactant: N#Cc1ccc(-c2ccc(C(F)(F)F)cn2)cc1F
Reactant: N=C(N)SCC1CC1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccc(C(F)(F)F)cn2)cc1SCC1CC1
Yield: 96.8 %

Procedure:
1.8 g (6.8 mmol) of 4-(5-trifluoromethylpyridin-2-yl)-2-fluorobenzonitrile, 1.6 g (7.6 mmol) of S-cyclopropylmethylisothiourea hydrobromide salt and 50 ml of N,N-dimethylformamide were put into a round-bottomed flask and stirred together with 1.6 g (8 mmol) of 20% aqueous sodium hydroxide overnight. The solvent was distilled off under reduced pressure, and the reaction mixture was separated with 50 ml of water and 50 ml of ethyl acetate. The organic layer was washed with 50 ml of water twice and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 2.2 g of 2-cyclopropylmethylthio-4-(5-trifluoromethylpyridin-2-yl)benzonitrile (yield 96%) as pale yellow feathery crystals (m.p. 135-136° C.).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[C:7]([O:15][CH3:16])[CH:8]=[C:9]([C:12]([O-:14])=[O:13])[CH:10]=2)[NH:5][N:4]=1)[CH3:2].[Li+].[OH-]>C1COCC1>[CH2:1]([C:3]1[C:11]2[C:6](=[C:7]([O:15][CH3:16])[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[NH:5][N:4]=1)[CH3:2]
Reactant: CCc1n[nH]c2c(OC)cc(C(=O)[O-])cc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1n[nH]c2c(OC)cc(C(=O)O)cc12
Yield: 91.1 %

Procedure:
To a solution of 3-ethyl-7-methoxy-1H-indazole-5-carboxylate (1.05 g, 4.23 mmol) in THF (35 mL) was added 1 M LiOH (8.46 mL, 8.46 mmol) and the mixture was heated at reflux overnight. The mixture was concentrated and the residue was triturated with 1 N HCl. The precipitates were washed with water and air dried. The solids were then taken up in hot methanol, filtered, concentrated and dried overnight under high vacuum to provide the title compound as an off-white solid (849 mg, 91%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[N:7]2.[F:18][C:19]1[CH:24]=[CH:23][C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][C:20]=1[C:34]1[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:3]3[C:8](=[N:7][C:6]([C:12]4[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=4)=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[CH:21][C:20]=1[C:34]1[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Reactant: Clc1ccnc2nc(-c3cccnc3)ccc12
Product: N#Cc1ccccc1-c1cc(-c2ccnc3nc(-c4cccnc4)ccc23)ccc1F
Yield: 88 %

Procedure:
This was prepared in 88% yield from 5-chloro-2-(pyridin-3-yl)-[1,8]naphthyridine (from step a) and 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (from Example 2, step e) using a similar procedure to that described in Example 55, step a. δH (400 MHz, CDCl3) 7.44-7.52 (3H, m), 7.55 (1H, td, J 7.4, 1.2), 7.61-7.65 (3H, m), 7.71 (1H, td, J 7.4, 1.2), 7.85 (1H, dd, J 7.8, 1.2), 8.06 (1H, d, J 9.0), 8.59 (1H, d, J 8.6), 8.71-8.75 (2H, m), 9.20 (1H, d, J 4.7), 9.46 (1H, d, J 1.6). m/z (ES+) 403 [MH]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9].[NH2:10][C:11]([C@@H:13]1[CH2:17][CH2:16][C@H:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[N:14]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:12].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C.O>[NH2:10][C:11]([C@@H:13]1[CH2:17][CH2:16][C@H:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[F:9])=[CH:20][CH:19]=2)[N:14]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:12]
Reactant: Fc1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(O)cc2)CC[C@H]1C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3F)cc2)CC[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
1-(Bromomethyl)-2-fluorobenzene (30 μl, 0.220 mmol) was added to a solution of 1,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-5-(4-hydroxyphenyl)-1-pyrrolidinecarboxylate (D9, 45 mg, 0.146 mmol) and potassium carbonate (30 mg, 0.217 mmol) in acetonitrile (2 ml). The mixture was stirred overnight at room temperature. After the reaction was finished, as shown by TLC, ethyl acetate and water were added. The organic phase was then washed with brine, dried (Na2SO4), filtered and evaporated. The crude material was purified by chromatography on silica gel using cyclohexane/ethyl acetate (7:3 to 6:4) to afford the title compound (51 mg, 85%); Rt (HPLC): 5.56 min; Rf (cyclohexane:ethyl acetate=1:1): 0.28; 1H NMR (300 MHz, CDCl3) δ(ppm): 7.56-7.48 (m, 1H); 7.37-7.28 (m, 1H); 7.24-7.06 (m, 5H); 6.93 (d, 2H); 5.45-5.37 (br. s, 1H); 5.15 (s, 2H); 4.73-4.60 (m, 1H); 4.53-4.45 (m, 1H); 2.58-2.48 (m, 1H); 2.34-2.25 (m, 1H); 2.09-1.93 (m, 2H); 1.28-1.13 (br. s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[CH:6]=[N:5]2.[H-].[Na+].CS(O[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24]1)(=O)=O.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(OC)C=3)C=CC2=O)CC1)(C)(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:33]([O:32][C:30](=[O:31])[NH:29][CH:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][N:8]2[C:9]3[C:4](=[CH:3][C:2]([F:1])=[C:11]([F:12])[CH:10]=3)[N:5]=[CH:6][C:7]2=[O:13])[CH2:24][CH2:25]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: O=c1cnc2cc(F)c(F)cc2[nH]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3cc(F)c(F)cc32)CC1
Yield: 22.3 %

Procedure:
6,7-Difluoroquinoxalin-2(1H)-one (Intermediate 152, 1.0 g, 5.50 mmol) was deprotonated with sodium hydride (60% in oil, 0.26 g, 6.60 mmol) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (6.6 mmol) as described for Intermediate 2. Chromatography on silica gel with 5% toluene/ethyl acetate gave 500 mg (23%) of the product as a colorless solid.
Reaction SMILES: Br[C:2]1[C:7]2[N:8]=[C:9]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[N:10]=[CH:11][C:6]=2[C:5](=[O:18])[N:4]([CH3:19])[CH:3]=1.[CH:20]1([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:26]=2B2OC(C)(C)C(C)(C)O2)[CH2:22][CH2:21]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:20]1([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:26]=2[C:2]2[C:7]3[N:8]=[C:9]([C:12]4[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=4)[N:10]=[CH:11][C:6]=3[C:5](=[O:18])[N:4]([CH3:19])[CH:3]=2)[CH2:21][CH2:22]1
Reactant: Cn1cc(-c2ncc3c(=O)n(C)cc(Br)c3n2)cn1
Reactant: CC1(C)OB(c2cc(S(C)(=O)=O)ccc2OCC2CC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2ncc3c(=O)n(C)cc(-c4cc(S(C)(=O)=O)ccc4OCC4CC4)c3n2)cn1
Yield: 35.8 %

Procedure:
The title compound of step 4 (200 mg, 0.627 mmol), the title compound of Example 90, step 1 (266 mg, 0.752 mmol), K3PO4 (400 mg, 1.881 mmol) and Pd(dppf)Cl2 (10 mg) in dioxane (4 mL) and H2O (1 mL) were heated at 70° C. for 18 h under N2. After preparative HPLC, the title compound (104.5 mg, 35.8%) was obtained as an off white solid. 1H NMR (CDCl3, 400 MHz) δ 9.64 (s, 1H), 8.24-8.18 (m, 2H), 8.07 (s, 1H), 7.96 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.77 (s, 1H), 7.10 (d, J=8.8 Hz, 1H), 3.95 (s, 3H), 3.91 (d, J=7.2 Hz, 2H), 3.68 (s, 3H), 3.12 (s, 3H), 1.13-1.01 (m, 1H), 0.54-0.44 (m, 2H), 0.21-0.14 (m, 1H). LCMS: 466.1 (M+1)+
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]3=[O:30])[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH2:34][CH2:35][CH2:36][CH3:37].O>CN(C=O)C>[CH2:34]([N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:9][CH2:10]2)[C:15]1=[O:30])[CH2:35][CH2:36][CH3:37]
Reactant: CCCCI
Reactant: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCN(CC2CCCCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCN1C(=O)N(C2CCN(CC3CCCCC3)CC2)C(c2ccccc2)c2ccccc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 100 mg (0.25 mmol) of 3-[1-(cyclohexylmethyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone in 2 ml of DMF, 22 mg (0.55 mmol) of sodium hydride (60%) were added at room temperature and stirred at about 60° C. for one hour. After allowing the reaction mixture to stand cool, a solution of 69 mg (0.38 mmol) of 1-iodobutane in 1 ml of DMF was added thereto at room temperature and stirred at about 60° C. for 2 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform—10% methanol/chloroform) to give 88 mg (0.19 mmol) of the title compound as colorless oil.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[C:22]2[N:21]=[CH:20][CH:19]=[N:18][C:17]=2[C:16]([C:23](O)=[O:24])=[CH:15][CH:14]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[N:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[NH:26][C:23]([C:16]1[C:17]2[N:18]=[CH:19][CH:20]=[N:21][C:22]=2[C:13]([C:3]2[C:2]([F:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=2[F:12])=[CH:14][CH:15]=1)=[O:24]
Reactant: COc1cc(OC)c(F)c(-c2ccc(C(=O)O)c3nccnc23)c1F
Reactant: Nc1ccccn1
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccccn3)c3nccnc23)c1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (Step 88.1), 2-aminopyridine, and stirring the reaction mixture for 72 h at rt. The crude product was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 96:3:1), followed by trituration in Et2O, a second silica gel column chromatography (Hex/EtOAc, 1:4) and an additional trituration in Et2O. Title compound: ESI-MS: 423.1 [M+H]+; tR=4.21 min (System 1); TLC: Rf=0.19 (Hex/EtOAc, 1:4).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:7]([CH2:12][OH:13])=[C:8]([CH2:10][OH:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C(Cl)Cl.CN(C)C1C=CN=CC=1.O>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:7]([CH2:12][OH:13])=[C:8]([CH2:10][O:11][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCc1nc(CO)c(CO)n1Cc1ccccc1Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1nc(CO[Si](C)(C)C(C)(C)C)c(CO)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.6 %

Procedure:
A solution of 2-n-butyl-1-(2-chlorophenyl)methyl-4,5-bis (hydroxy)methyl-1H-imidazole (Example 1 (ii)) (310 mg, 1 mmol) in methylene chloride (5 mL) was treated with 4-dimethylaminopyridine (5.2 mg), triethylamine (1.5 mmol) and t-butyl dimethylsilyl chloride (192 mg, 1.24 mmol). The mixture was stirred at 25° C. for 20 hours, diluted with water and the organic layer was washed well with water, dried, concentrated and chromatographed over silica gel with an ethyl acetate/methanol gradient to afford 127 mg (24%) of the bis (4,5-t-butyldimethylsilyl) ether and 252 mg (59%) of 2-n-butyl-1-(2-chlorophenyl)methyl-4-t-butyldimethysilyloxymethyl-5-hydroxymethyl-1H-imidazole. This monoether (252 mg) was oxidized to the 5-carbox-aldehyde using manganese dioxide as described in Example 1 (iii) to provide 170 mg of 2-n-butyl-1-(2-chlorophenyl)-methyl-4-(t-butyldimethylsilyloxy)methyl-1H-imidazol-5-carboxaldehyde as an oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:13](C(C)(C)C)[O:14][SiH](C)C)[CH:6]=[C:7]([C:9]([SH:12])([CH3:11])[CH3:10])[CH:8]=1>C(O)(=O)C.C1COCC1.O>[OH:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([SH:12])([CH3:10])[CH3:11])[CH:6]=[C:5]([CH2:13][OH:14])[CH:4]=1
Reactant: C[SiH](C)OC(c1cc(CO)cc(C(C)(C)S)c1)C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(S)c1cc(CO)cc(CO)c1
Yield: 64.4 %

Procedure:
A solution of 43 mg of 5-hydroxymethyl-1-(1-mercapto-1-methylethyl)-3-[(tert-butyl)dimethylsilanyloxymethyl]benzene in 1 ml of an acetic acid/THF/water (3/1/1) mixture is stirred at AT for 4.5 h and concentrated under RP, and then the residue is taken up in 3 ml of water. The pH of the aqueous phase is brought to 7 by addition of a 10% aqueous Na2CO3 solution and then the aqueous phase is extracted with AcOEt. The organic phase is dried over MgSO4 and concentrated under RP. 18 mg of 3,5-bis(hydroxymethyl)-1-(1-mercapto-1-methylethyl)benzene are thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:56]=[CH:55][CH:54]=[CH:53][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40][CH2:41]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[NH:57]1[CH2:61][CH2:60][CH2:59][C:58]1=[O:62]>>[CH3:1][O:2][C:3]1[CH:56]=[CH:55][CH:54]=[CH:53][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40][CH2:41][N:57]2[CH2:61][CH2:60][CH2:59][C:58]2=[O:62])=[CH:15][CH:16]=1
Reactant: O=C1CCCN1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCOS(=O)(=O)c2ccc(C)cc2)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCN2CCCC2=O)cc1

Procedure:
Analogously to Example 27a, 0.20 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-(2-{2-[2-(toluene-4-sulphonyloxy)ethyl]phenoxy}ethoxy)piperidine-1-carboxylate (Example 26b) and 0.19 ml of pyrrolidin-2-one are reacted. The title compound is obtained as a colourless oil. Rf=0.10 (2:1 EtOAc-heptane); Rt=5.88.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[S:51][C:52]2[CH:58]=[CH:57][CH:56]=[CH:55][C:53]=2[N:54]=1.N1C=CC=CC=1>C(Cl)Cl.O>[S:51]1[C:52]2[CH:58]=[CH:57][CH:56]=[CH:55][C:53]=2[N:54]=[C:50]1[NH:49][C:40](=[O:42])[CH:39]([C:31]1[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:36])=[O:37])=[C:29]([Cl:28])[CH:30]=1)[CH2:43][CH:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: Nc1nc2ccccc2s1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc3ccccc3s2)cc1Cl
Temperature: 0 °C
Yield: 75.8 %

Procedure:
A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirred at 0° C. until it became homogeneous. The resulting light purple reaction mixture was then treated with 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 16, 200 mg, 0.61 mmol). The resulting reaction mixture was stirred at 0° C. for 20 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminobenzothiazole (136 mg, 0.91 mmol) and pyridine (0.15 mL, 1.8 mmol) and was stirred at 25° C. for 16 h. The reaction was then diluted with water (15 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 60/40 hexanes/ethyl acetate) afforded N-benzothiazol-2-yl-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (214 mg, 77%) as an off-white foam: EI-HRMS m/e calcd for C22H23ClN2O3S2 (M+) 462.0839, found 462.0833.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH:14]([CH3:18])[C:15](O)=[O:16])[CH:8]=[CH:7]2.C(Cl)(=O)C(Cl)=O.[NH3:25]>C1C=CC=CC=1>[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH:14]([CH3:18])[C:15]([NH2:25])=[O:16])[CH:8]=[CH:7]2
Reactant: N
Reactant: CC(C(=O)O)c1ccc2cc(F)ccc2c1
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C(N)=O)c1ccc2cc(F)ccc2c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A suspension of 2.4 g. of sodium hydride and 50 ml. of benzene is added to a mixture of 23 g. of 6-fluoro-2-naphthyl-α-methylacetic acid and 450 ml. of benzene. The resulting mixture is stirred for four hours. The mixture is cooled to 0° C and 19 g. of oxalyl chloride are added; after the addition, the mixture is allowed to stand for 4 hours. The resulting mixture is then saturated with ammonia and allowed to stand for 8 hours. This mixture is then evaporated under reduced pressure. The residue is taken up in methylene chloride, washed with water to neutrality, dried, filtered, and evaporated to give 6-fluoro-2-naphthyl-α-methylacetamide.