Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C(C2SC3CCOC4C=C(C5CN([CH2:27][C:28]([NH2:30])=[O:29])C5)C=CC=4C=3N=2)=NC=N1)(C)C.[NH:31]1[CH2:34][CH:33]([C:35]2[CH:36]=[CH:37][C:38]3[O:47][CH2:46][CH2:45][C:44]4[S:43][C:42]([C:48]5[N:49]([CH:53]([CH3:55])[CH3:54])[N:50]=[CH:51][N:52]=5)=[N:41][C:40]=4[C:39]=3[CH:56]=2)[CH2:32]1.BrCC(N)=O>CN(C=O)C>[CH:53]([N:49]1[C:48]([C:42]2[S:43][C:44]3[CH2:45][CH2:46][O:47][C:38]4[CH:37]=[CH:36][C:35]([CH:33]5[CH2:34][N:31]([CH2:27][C:28]([NH2:30])=[O:29])[CH2:32]5)=[CH:56][C:39]=4[C:40]=3[N:41]=2)=[N:52][CH:51]=[N:50]1)([CH3:54])[CH3:55]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(N)=O)C3)ccc1-2
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CNC3)cc1-2
Agent: NC(=O)CBr
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CN(CC(N)=O)C3)cc1-2
Yield: 53 %

Procedure:
Following the procedure of 319, 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene and bromoacetamide were reacted in DMF to give 371 (111 mg, 53%). LCMS: RT=6.96 min, [M+H]+=425. 1H NMR δ (ppm) (CDCl3): 8.31 (1 H, d, J=2.35 Hz), 7.90 (1 H, s), 7.17 (1 H, dd, J=8.28, 2.36 Hz), 7.03 (1 H, d, J=8.26 Hz), 7.01-6.85 (1 H, m), 5.91-5.83 (1 H, m), 5.41 (1 H, s), 4.37 (2 H, t, J=5.06 Hz), 3.89 (2 H, t, J=7.36 Hz), 3.81-3.73 (1 H, m), 3.43-3.34 (4 H, m), 3.22 (2 H, s), 1.63 (6 H, d, J=6.65 Hz)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH3:12])=[C:6]([NH2:13])[CH:5]=1.[NH2:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=2[N:20]=1.[C:26](N1C=CN=C1)(N1C=CN=C1)=S.C(Cl)CCl>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH2:11][CH3:12])[C:26]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:13][C:6]=2[CH:5]=1)=[O:14]
Reactant: Nc1nc2ccc(Cl)cc2s1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CCNc1ccc(C(=O)OC)cc1N
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)OC)ccc21
Yield: 44.2 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylic acid methyl ester (926.0 mg) was prepared by following General Procedure D starting from 3-amino-4-ethylamino-benzoic acid methyl ester (1.06 g), 2-amino-6-chloro-benzothiazole (1.0 g), 1,1′-thiocarbonyldiimidazole (979.0 mg), and EDC (1.05 g) in DMF (5.0 mL).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.CS(O)(=O)=O.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:38][CH2:37][N:36]([CH2:39][C@H:40]([OH:45])[C:41]([F:44])([F:43])[F:42])[CH2:35][CH2:34]2)=[CH:29][C:28]=1[O:46][CH3:47].FC(F)(F)C(O)=O>COCC(O)C>[F:44][C:41]([F:42])([F:43])[C@@H:40]([OH:45])[CH2:39][N:36]1[CH2:35][CH2:34][CH:33]([C:30]2[CH:31]=[CH:32][C:27]([NH:26][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=5[O:19][CH3:20])[N:6]4[N:5]=3)=[C:28]([O:46][CH3:47])[CH:29]=2)[CH2:38][CH2:37]1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: COc1cc(C2CCN(C[C@H](O)C(F)(F)F)CC2)ccc1N
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: COCC(C)O
Product: COc1cc(C2CCN(C[C@H](O)C(F)(F)F)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Temperature: 135 °C
Reaction time: 48 h
Yield: 18 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (50.00 mg, 0.174 mmol), methanesulfonic acid (0.034 mL, 0.52 mmol) and (S)-3-[4-(4-amino-3-methoxy-phenyl)-piperidin-1-yl]-1,1,1-trifluoro-propan-2-ol (109 mg, 0.342 mmol) were combined in 1-methoxy-2-propanol (1.02 mL) in a capped tube and the reaction was stirred at 135° C. for 48 h. The product was isolated by reverse phase preparative hplc (Gilson) followed by neutralization of the trifluoroacetic acid salt to afford (S)-1,1,1-trifluoro-3-(4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-propan-2-ol as a brown solid (17 mg, 18%). MP: 77-94° C.; 1H-NMR (CDCl3) δ 8.69 (s, 1H), 8.30 (d, J=8.1 Hz, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.44 (m, 2H), 7.14 (m, 1H), 7.08 (d, J=8.4 Hz, 1H), 7.02 (4.4 Hz, 1H), 6.83 (d, J=4.5 Hz, 1H), 6.71 (m, 2H), 4.08 (m, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.02 (m, 2H), 2.67 (m, 2H), 2.52 (m, 2H), 2.23 (m, 1H), 1.77 (m, 3H); LC/MS (ESI+): 542.3 (M+H).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[H-].[Na+].[H][H].F[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[N:20][N:21]([CH3:23])[N:22]=2)=[CH:14][C:13]=1[N+:24]([O-:26])=[O:25].Cl>CN(C=O)C>[C:1]([CH:3]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[N:20][N:21]([CH3:23])[N:22]=2)=[CH:14][C:13]=1[N+:24]([O-:26])=[O:25])[C:4]([NH2:6])=[O:5])#[N:2]
Reactant: Cn1nnc(-c2ccc(F)c([N+](=O)[O-])c2)n1
Reactant: N#CCC(N)=O
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccc(C(C#N)C(N)=O)c([N+](=O)[O-])c2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
A solution of 2-cyanoacetamide (0.888 g, 10.56 mmol) in DMF (2.268 mL) was added to a suspension of sodium hydride 60% wt. in mineral oil (0.443 g, 11.08 mmol) in DMF (5.67 mL) to give a grey suspension. After cooling to 0° C. (Note: Hydrogen Gas evolution) the resulting mixture was stirred at 0° C. for 30 minutes. Then a solution of 5-(4-fluoro-3-nitrophenyl)-2-methyl-2H-tetrazole (1.15 g, 5.15 mmol) in DMF (2.3 mL) was added to give a deep purple solution. After 3 hours, the reaction mixture was slowly poured into an ice-water mixture (33.0 mL) and conc.HCl (0.952 mL). The resulting yellow slurry was stirred for 30 minutes, the solid was filtered, washed with water (3×5 mL) and then with Hexane (2×5 mL), dried at 40° C. under high vacuum until constant weight to give 2-cyano-2-(4-(2-methyl-2H-tetrazol-5-yl)-2-nitrophenyl)acetamide (1.41 g, 95% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 4.49 (s, 3H) 5.77 (s, 1H) 7.77 (s, 1H) 7.95 (d, J=8.2 Hz, 1H) 8.03 (s, 1H) 8.51 (dd, J=8.2, 1.8 Hz, 1H) 8.70 (d, J=1.8 Hz, 1H); MS m/z 288.1 (M+H)+; HPLC 96.4% @ 220 nm, RT=1.31 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([S:22](Cl)(=[O:24])=[O:23])[CH2:19][CH2:20][CH3:21].N1C=CC=CC=1.CN(C=O)C>CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:4]3[CH:3]=[C:2]([NH:1][S:22]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:24])=[O:23])[CH:7]=[CH:6][CH:5]=3)[N:9]=[CH:10][C:11]=12
Reactant: CCCCS(=O)(=O)Cl
Reactant: Nc1cccc(-n2ncc3c(N)ncnc32)c1
Solvent: CO
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCCS(=O)(=O)Nc1cccc(-n2ncc3c(N)ncnc32)c1
Temperature: 25 °C
Reaction time: 42 h
Yield: 55.6 %

Procedure:
Title compound 11B, 1-(3-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (40 mg, 1.0 eq, 0.18 mmol), 1-butanesulphonylchloride (23 μl, 1.0 eq, 0.18 mmol) and pyridine (14 μl, 1.0 eq, 0.18 mmol) were added to DMF (1 ml) and the mixture was stirred for 42 hours at room temperature under an inert atmosphere. Methanol was then added (1 ml) and the solvents were removed in vacuo. The resultant residue was absorbed onto silica and purified by column chromatography using DCM/MeOH (96:4) as eluent to yield the title compound as a white solid (35 mg, 0.10 mmol, 57%). LCMS: [M+H]+=347, Rt=1.62 min, 100% purity.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:40])[C@@H:16]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:17][C:18]2[CH:23]=[CH:22][C:21](OS(C(F)(F)F)(=O)=O)=[CH:20][CH:19]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:41]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])(=[O:44])[CH:42]=[CH2:43].C(N(CC)CC)C>CN(C=O)C.C(O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]1([CH:7]([O:14][C:15](=[O:40])[C@@H:16]([NH:32][C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([CH:43]=[CH:42][C:41]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[CH:22][CH:23]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)C(=O)OC(c1ccccc1)c1ccccc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)C=Cc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(c2ccccc2)c2ccccc2)cc1
Temperature: 90 °C
Yield: 53.8 %

Procedure:
Bis(triphenylphosphine) palladium dichloride (120 mg, 0.2 mmol) was added to a deoxygenated mixture of (S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-3-[4-[[(trifluoromethyl)sulfonyl]oxy]phenyl]propanoic acid diphenylmethyl ester (3.0 g, 5.2 mmol), t-butyl acrylate (1.5 mL, 10.2 mmol) and triethylamine (4.0 mL, 30.0 mmol) in DMF (50 mL) and the well-stirred suspension was then heated at 90° C. (24 h). The solvent was removed in vacuo and the resulting residue was purified by flash chromatography on silica gel eluting with a mixture of dichloromethane and hexanes (8:1) to give the (S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-3-[4-[3-(1,1-dimethylethoxy)-3-oxo-1-propenyl]phenyl]propanoic acid diphenylmethyl ester (1.6 g, 2.8 mmol) in 54% yield, mp. 135°-137° C., [α]D -5.35° (0.97 % in ethanol).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].C([N:9](CC)CC)C.[N:14]1([CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3([CH2:35][NH:36][CH2:37][CH3:38])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1>ClCCl>[NH3:9].[CH2:37]([N:36]([CH2:35][C:29]1([C:26]2[CH:25]=[CH:24][C:23]([O:22][CH2:21][CH2:20][CH2:19][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:28][CH:27]=2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH3:38]
Reactant: CCS(=O)(=O)Cl
Reactant: CCN(CC)CC
Reactant: CCNCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: ClCCl
Product: CCN(CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1)S(=O)(=O)CC
Product: N
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
Ethanesulfonyl chloride (26 μL, 0.28 mmol) was added dropwise to a solution of triethylamine (35 μL, 0.25 mmol) and N-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)ethanamine (78 mg, 0.23 mmol) in dichloromethane (0.5 mL) at 0° C. allowed to warm to ambient temperature and stirred overnight. The reaction was quenched with NaHCO3 (10 mL), extracted using dichloromethane (3×10 mL), dried using Na2SO4 and concentrated in vacuo. The compound was purified by column chromatography on Biotage® silica gel, eluting with dichloromethane:methanol:ammonia, 96.5:3.5:0.35 to 95:5:0.5 to give the title compound as a pale brown oil (55 mg, 54%). 1H NMR (400 MHz, CDCl3) δ 7.24 (d, 2H), 6.90 (d, 2H), 4.02 (t, 2H), 3.84-3.72 (m, 2H), 3.48 (t, 2H), 3.32 (s, 2H), 2.76 (quartet, 2H), 2.72-2.60 (m, 4H), 2.60-2.48 (m, 4H), 2.20-2.08 (m, 2H), 2.04 (pentet, 2H), 1.98-1.90 (m, 2H), 1.86-1.76 (m, 4H), 1.30 (t, 3H), 0.88 (t, 3H). HRMS (ESI+) 439.2625 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15](Cl)=[O:16])=[CH:10]3)[C:6]=2[CH:18]=1.[NH3:19]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]([NH2:19])=[O:16])=[CH:10]3)[C:6]=2[CH:18]=1
Reactant: O=C(Cl)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Temperature: 8 °C
Reaction time: 5 h
Yield: 69 %

Procedure:
Into a 20 L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 9-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carbonyl chloride (460 g, 1.40 mol, 1.00 equiv) in tetrahydrofuran (4.5 L), followed by the addition ammonia (0° C.) (9 L) in one portion. The resulting solution was stirred at 0=8° C. for 5 h. The reaction progress was monitored by LCMS. The precipitates were collected by filtration, washed with 5×500 mL of water and 3×500 mL of EA, and dried in a vacuum oven to afford 300 g (69%) of 9-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide as an off-white solid. LC-MS: 308 [M+H]+1H-NMR (300 MHz, DMSO, ppm): δ 4.48 (4H, s), 6.99-7.02 (1H, d), 7.16 (1H, s), 7.43-7.47 (1H, m), 7.59 (1H, s), 7.80 (1H, s), 8.62-8.63 (1H, d).
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=3)[CH:34]=2)([O:31]C)[O:11][C:10]1([CH2:52]O)[CH2:50][OH:51])C1C=CC=CC=1.O.[C:55]1([CH3:65])[CH:60]=[CH:59][C:58](S(O)(=O)=O)=[CH:57][CH:56]=1>ClCCl>[CH2:65]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@:12]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:11][C@@:10]1([CH2:50][OH:51])[CH2:52][O:31]2)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)OC(CO)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Solvent: O
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a solution of [(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 1i (2.49 g, 3.37 mmol) in dichloromethane (300 mL) was added p-toluenesulfonic acid monohydrate (0.32 g, 1.69 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour and quenched with 30 mL of saturated aqueous sodium bicarbonate. The resulting mixture was extracted with dichloromethane (20 mL×2). The combined organic layers were washed with saturated aqueous sodium chloride (20 mL×2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=7/1 to give the title compound 1j as pale yellow oil (1.06 g, 44.5%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ (ppm): 7.45 (d, 1H), 7.40 (m, 12H), 7.30 (m, 3H), 7.09 (m, 2H), 6.91 (m, 2H), 6.78 (m, 2H), 4.88 (m, 3H), 4.78 (d, 1H), 4.29 (m, 2H), 4.11-3.96 (m, 6H), 3.88 (d, 1H), 3.80 (m, 2H), 3.71 (m, 2H), 1.85 (t, 1H), 1.41 (t, 3H).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:12][CH2:11][C@H:10]([O:13][C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[CH:20]=[C:19]([C@:24]3([CH3:30])[CH2:28][O:27][C:26](=[O:29])[NH:25]3)[CH:18]=[CH:17]4)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:31]N1C(=O)CCC1=O.C(Cl)Cl>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[C:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([O:13][C:14]3[C:15]([I:31])=[C:16]4[C:21](=[CH:22][CH:23]=3)[CH:20]=[C:19]([C@:24]3([CH3:30])[CH2:28][O:27][C:26](=[O:29])[NH:25]3)[CH:18]=[CH:17]4)[CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@@]1(c2ccc3cc(O[C@H]4CC[C@@H](c5ccccc5)CC4)ccc3c2)COC(=O)N1
Reactant: O=C1CCC(=O)N1I
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: C[C@@]1(c2ccc3c(I)c(O[C@H]4CC[C@H](c5ccccc5)CC4)ccc3c2)COC(=O)N1

Procedure:
A mixture of (R)-4-(6-(cis-4-phenyl-cyclohexyloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one (Example 30, 71.4 mg 0.000178 mol), N-iodosuccinimide (44.8 mg, 0.000199 mol) and zirconium tetrachloride (6.2 mg, 0.000027 mol) in methylene chloride (1.46 mL, 0.0228 mol) was heated to reflux under Ar in a vial for 6 h. LCMS showed the reaction to be completed. The precipitate was filtered off and the residue was purified with Isco column eluted with EtOAc in hexane from 0 to 40% to give (R)-4-(6-(trans-4-phenyl-cyclohexyloxy)-5-iodonaphthalen-2-yl)-4-methyloxazolidin-2-one as a solid (81.0 mg, 86% yield). LCMS 528.27 ([M+1], 80%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[C:47](Cl)(=[O:51])[CH2:48][CH2:49][CH3:50].C(N(CC)CC)C>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:51])[CH2:48][CH2:49][CH3:50])[CH:43]=[CH:44][CH:45]=2)=[N:8]1
Reactant: CCCC(=O)Cl
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.200 g, 0.33 mmol) in 4 mL of tetrahydrofuran was added butanoyl chloride (0.052 mL, 0.49 mmol) followed by triethyl amine (0.230 mL, 0.167 mmol). The reaction was stirred at room temperature for 15 hours. The reaction mixture was partitioned between water and ethyl acetate. The residue was not purified (yield not calculated). ES-MS (m/z) 673 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[O:21])=[CH:16][CH:15]=1.I[CH3:38]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([N:22]([CH3:38])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[O:21])=[CH:18][CH:19]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccc(Oc5ccccc5)cc4)cc3)c2)o1
Reactant: CI
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)N(C)Cc4ccc(Oc5ccccc5)cc4)cc3)c2)o1

Procedure:
2′-Methyl-N-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(4-phenoxybenzyl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(4-phenoxybenzyl)-1,1′-biphenyl-4-carboxamide and iodomethane using method L. NMR; δH [2H6]—DMSO 7.89,(1H, d), 7.76,(1H, s), 7.55-7.48,(5H, m), 7.40-7.36,(3H, m), 7.23,(1H, b), 7.13,(1H, t), 7.01,(4H, m), 4.684.52,(2H, m), 2.91,(3H, s), 2.55,(3H, s), 2.32,(3H, s). LCMS; retention time 3.85 min, MH+ 490.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:7]=[CH:6]2.[CH:19]1([CH2:22][O:23][C:24]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][C:25]=2[C:26](O)=[O:27])[CH2:21][CH2:20]1.C(OCC)(=O)C>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:14][CH2:15][N:16]([C:26]([C:25]3[CH:29]=[C:30]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=[CH:32][C:24]=3[O:23][CH2:22][CH:19]3[CH2:21][CH2:20]3)=[O:27])[CH2:17][CH2:18]1)[CH:7]=[CH:6]2
Reactant: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)O)c1
Reactant: Clc1ccc2nc(N3CCNCC3)ccc2c1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)N2CCN(c3ccc4cc(Cl)ccc4n3)CC2)c1

Procedure:
Prepared in analogy to example 1.1 b) from 6-chloro-2-piperazin-1-yl-quinoline hydrochloride (Example 1.20b) and 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (Example 2.6) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid. MS (m/e): 500.3 (M+H+; 100%)
Reaction SMILES: P([O-])([O-])([O-])=[O:2].[OH:6][C@H:7]([CH2:59][CH2:60][O:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[CH2:8][C:9](SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(O)(=O)OP(O)(=O)OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1OP(O)(O)=O)=[O:10]>>[OH:6][CH:7]([CH2:59][CH2:60][O:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[CH2:8][C:9]([OH:10])=[O:2]
Reactant: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@H](O)CCOc1ccccc1
Reactant: O=P([O-])([O-])[O-]
Product: O=C(O)CC(O)CCOc1ccccc1

Procedure:
Then, the pellet was suspended in 480 parts of a 0.1M phosphate buffer (pH 7.0), and 5 parts of (R)-3-hydroxy-5-phenoxyvaleryl CoA (prepared by a method described in Eur. J. Biochem., 250, 432–439 (1997) after obtaining 3-hydroxy-5-phenoxyvaleric acid by hydrolyzing 3-hydroxy-5-phenoxylvaleric acid ester obtained by a Reformatsky reaction using zinc, in which 3-phenoxypropanal synthesized by a method described in J. Org. Chem., 55, 1490–1492 (1990) and ethyl bromoacetate were used as raw materials) and one part of bovine serum albumin (Sigma) were added to the suspension before moderately shaking the suspension for 30 minutes at 30° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:10]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]([NH:27][C:28]1[CH:36]=[C:35]2[C:31]([CH2:32][C:33](=[O:37])[NH:34]2)=[CH:30][CH:29]=1)(=[O:26])[CH3:25].N1CCCCC1>C(O)C.C(OCC)(=O)C>[CH:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:10]=[C:32]2[C:31]3[C:35](=[CH:36][C:28]([NH:27][C:24](=[O:26])[CH3:25])=[CH:29][CH:30]=3)[NH:34][C:33]2=[O:37])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(OCCN2CCOCC2)c(C2CCCCC2)c1
Reactant: CC(=O)Nc1ccc2c(c1)NC(=O)C2
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)Nc1ccc2c(c1)NC(=O)C2=Cc1ccc(OCCN2CCOCC2)c(C2CCCCC2)c1
Reaction time: 6 h
Yield: 34.6 %

Procedure:
A mixture of 3-cyclohexyl-4-morpholinoethoxybenzaldehyde (3 g, 9.45 mmol), 6-acetamido-2-oxindole (3.5 g, 18.9 mmol) and piperidine (5 ml, 50 mmol) in ethanol (35 ml) was held in a sealed tube at 100° C. for 6 hours. The reaction mixture was cooled, diluted with ethyl acetate (500 ml) and filtered to remove excess 6-acetamido-2-oxindole. The filtrate was extracted with 0.5N hydrochloric acid (200 ml) and brine (2×200 ml). The acid wash was basified with solid sodium bicarbonate to pH 9 and extracted with ethyl acetate (2×200 ml). The combined organic layers were washed with brine (200 ml), dried over magnesium sulfate and concentrated. The combined solids were dissolved in dichloromethane (25 ml) and precipitated with diethyl ether (500 ml) to afford 1.6 g of a mustard yellow solid. The solid was dissolved in methanol (100 ml) and filtered, affording a yellow solid (which was set aside) and then precipitated with water (400 ml) and filtered. The solid residue was redissolved in methanol and concentrated to a solid. This process was repeated twice to afford ˜82% pure isomer 1 by HPLC. The filtered yellow solid was 77% isomer 2 by HPLC.