Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C@H]1[C@H]2CN[C@@H]1[C@@H](O2)OC)C1C=CC=CC=1.[CH2:18]([O:25][C@H:26]1[C@H:32]2[CH2:33][N:34]([C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])[C@@H:27]1[C@@H:28]([O:31]2)[O:29][CH3:30])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[CH2:18]([O:25][C@H:26]1[C@H:32]2[CH2:33][N:34]([C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])[C@@H:27]1[CH:28]([O:31]2)[O:29][CH3:30])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CO[C@@H]1O[C@@H]2CN(C(=O)OCc3ccccc3)[C@H]1[C@H]2OCc1ccccc1
Agent: CO[C@@H]1O[C@@H]2CN[C@H]1[C@H]2OCc1ccccc1
Solvent: ClC(Cl)Cl
Product: COC1O[C@@H]2CN(C(=O)OCc3ccccc3)[C@H]1[C@H]2OCc1ccccc1

Procedure:
Methyl 3-O-benzyl-2,5-dideoxy-2,5-imino-α-D-lyxofuranoside (13α) (870 mg, 3.70 mmol) was stirred with a 3:2 mixture of ether and saturated aqueous sodium bicarbonate (60 ml). Benzyl chloroformate (1.57 ml, 11.1 mmol) was added to the mixture which was stirred at room temperature for 12 hours. The ether layer was separated and the aqueous phase further extracted with ether (4×25 ml). The combined extracts were dried, filtered and the solvent removed. Purification by flash chromatography (ether-hexane 1:10-1:3) afforded methyl 3-O-benzyl-N-benzyloxycarbonyl-2,5-dideoxy-2,5-imino-α-D-lyxofuranoside (1.04 g, 76%) as a white crystalline solid, m.p. 74°-75° C., Rf 0.2 (ether-hexane 1:3); [α]20D +12.0° (c, 0.98 in chloroform); νmax (chloroform) 2940, 1695 (C=O), 1420, 1260, 1230, 1090 and 750 cm-1 ; 1H NMR δ 3.38, 3.41 (3H, 2× s, CH3); 3.3-3.7 (2H, m, 5,5'-H); 4.05-4.90 (5H, m, H-3, H-2, H-4, CH2Ph); 5.12-5.20 (3H, m, H-1, CH2 -Z); 7.2-7.4 (10H, m, 2×H-Ph). 13C NMR δ 50.71 (t, C-5); 55.15, 55.33 (2×q, Me); 59.63, 60.17 (2×d, C-2); 66.95, 67.08 (2×t, CH2 -Z); 72.28 (t, CH2Ph); 75.09, 75.49, 77.93, 78.48 (4×d, C-3, C-4); 105.67, 105.90 (d, C-1); 127.83, 127.92, 128.15, 128.64 (4×d, HC-Ph); 136.68, 137.46 (2×s, C-Ph); 155.68, 155.81 (2×s, C=O). m/z: 91 (100%), 108 (25%), 158 (20%), 370 (M+H+, 10%). (Found C, 67.98; H, 6.39; N, 3.60. C21H23NO5 requires C, 68.28; H, 6.28; N, 3.79). Methyl 3-O-benzyl-2,5-dideoxy-2,5-imino-β-D-lyxofuranoside (13β) (829 mg, 3.53 mmol) was treated likewise giving methyl 3-O-benzyl-N-benzyloxycarbonyl-2,5-dideoxy-2,5-imino-β-D-lyxofuranoside (1.18 g, 90%) as a clear oil, Rf 0.35 (ether-hexane 1:3); [α]20D -75.2° (c, 0.83 in chloroform); νmax (film) 2930, 1705 (C=O), 1425, 1275, 1255, 1105 and 750 cm-1 ; 1H NMR δ 3.36, 3.42 (3H, 2×s, CH3); 3.50 (1H, 2×d 5-H); 3.67 (1H, 2×d, H-5'); 4.02-4.06 (1H, m, H-3); 4.29 (1H, bs, H-2); 4.49, 4.54 (1H, bs and dd, H-4); 4.52-4.65 (2H, m, CH2Ph); 5.0-5.2 (2H, 2×dd, CH2Ph); 5.21 (1H, s, H-1); 7.28-7.38 (10H, m, H-Ph). 13C NMR δ 50.02 (t, C-5); 55.70, 55.89 (2×q, Me); 60.17, 59.52 (2×d, C-2); 66.79 (t, CH2 -Z); 72.00, 72.10 (t, CH2Ph); 77.56, 78.08, 78.52, 79.18 (4×d, C-3, C-4); 104.71, 105.11 (2×d, C-1); 128.79, 127.96, 128.33, 128.61, 128.78 (5×d, HC-Ph); 137.09, 137.22 (2×s, C-Ph); 156.20, 156.45 (2×s, C=O). m/z: 91 (100%), 370 (M+H+, 60%), 202 (30%). (Found C, 68.08; H, 6.39; N, 3.40. C21H 23 NO5 requires C, 68.28; H, 6.28; N, 3.79).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([O:13]C2C=CC=CC=2)=O)[N:7]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH2:39][CH2:40][O:41][CH3:42])[N:34]=[CH:33][N:32]=[C:31]2[S:43][C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][CH:50]=1)[NH2:47].C(N(CC)C(C)C)(C)C>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:47][C:46]2[CH:48]=[CH:49][CH:50]=[C:44]([S:43][C:31]3[C:30]4[C:35](=[CH:36][C:37]([O:38][CH2:39][CH2:40][O:41][CH3:42])=[C:28]([O:27][CH3:26])[CH:29]=4)[N:34]=[CH:33][N:32]=3)[CH:45]=2)=[O:13])[N:7]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CCOC(=O)Cn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cn1nc(C(C)(C)C)cc1NC(=O)Nc1cccc(Sc2ncnc3cc(OCCOC)c(OC)cc23)c1
Yield: 29 %

Procedure:
Using the procedure described in Example 159B, ethyl 2-[3-tert-butyl-5-(phenoxycarbonylamino)-1H-pyrazol-1-yl]acetate described in Example 166A (0.138 g, 0.4 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described in Example 231A (0.143 g, 0.4 mmol), and N,N-diisopropylethylamine (0.5 mL) in THF (6 mL) at 50° C. for 7 hours, to afford ethyl 2-[3-tert-butyl-5-(3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}ureido)-1H-pyrazol-1-yl]acetate as solid (0.071 g, 29%). 1H NMR (300 MHz, DMSO-d6) δ 8.98 (br, 1H), 8.74 (s, 1H), 8.60 (s, 1H), 7.83 (s, 1H), 7.34-7.52 (m, 4H), 7.26 (d, 1H), 6.12 (s, 1H), 4.85 (s, 2H), 4.33 (m, 2H), 4.15 (q, 2H), 4.00 (s, 3H), 3.77 (m, 2H), 3.34 (s, 3H), 1.20 (s and t, 12H); LC-MS (ESI) m/z 609 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([C:15]([O:17][CH3:18])=[O:16])[C:9]([CH3:19])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>O1CCOCC1.O>[CH3:18][O:17][C:15]([C:10]1[C:9]([CH3:19])=[CH:8][C:3]([C:4]([OH:6])=[O:5])=[C:2]([CH3:1])[C:11]=1[N+:12]([O-:14])=[O:13])=[O:16]
Reactant: COC(=O)c1cc(C)c(C(=O)OC)c([N+](=O)[O-])c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1c(C)cc(C(=O)O)c(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2.25 h

Procedure:
Dimethyl 2,5-dimethyl-3-nitroterephthalate (2.27 g, 8.50 mmol) was dissolved in 1,4-dioxane (20 mL) and was cooled in an ice bath. 1N Sodium hydroxide (8.5 mL) was added dropwise, and the mixture was stirred at ambient temperature for 2.25 h. Additional 1N sodium hydroxide (0.5 mL) was added drop-wise and the mixture was stirred at ambient temperature for a further 1 h at which point another 0.5 mL aliquot of 1N aqueous sodium hydroxide was added and stirring was continued for an additional 1 h. The reaction mixture was diluted with water and was washed with ether. The aqueous portion was acidified with 1N hydrochloric acid to pH ˜2 and then was extracted with ethyl acetate (2×). The combined ethyl acetate portion was dried over sodium sulfate, then filtered and concentrated to provide 4-(methoxycarbonyl)-2,5-dimethyl-3-nitrobenzoic acid (quantitative yield). 1H NMR (400 MHz, d6-DMSO): δ 13.8 (br s, 1H), 7.93 (d, 1H), 3.81 (s, 3H), 2.38 (s, 3H), 2.37 (s, 3H); MS (EI) for C11H11NO6: 252 (M−H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[F:21][C:4]1[CH:3]=[C:2]([C:27]2[CH:26]=[CH:25][C:24]([C:23]([F:34])([F:33])[F:22])=[CH:29][CH:28]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Product: O=C(c1ccc(-c2ccc(C(F)(F)F)cc2)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 3-Trifluoromethyl benzene boronic acid. MS (M+H) 421.1
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[C:9]2[CH2:8][CH2:7][C:6]3[O:25][C@H:26]4[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]4[C:5]=3[C:4]=2[N:3]=1.FC(F)(F)C(O)=O>>[N:12]1([C:10]2[C:9]3[CH2:8][CH2:7][C:6]4[O:25][C@H:26]5[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]5[C:5]=4[C:4]=3[N:3]=[C:2]([NH2:1])[N:11]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N)nc3c2CCC2=C3[C@@H]3CCCC[C@@H]3O2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc2c(c(N3CCNCC3)n1)CCC1=C2[C@@H]2CCCC[C@@H]2O1

Procedure:
The product from Example 3A (179 mg, 0.419 mmol) was cooled with an ice bath and treated with trifluoroacetic acid (6.5 mL, 84 mmol) for 1 minute, then concentrated under reduced pressure for about 2 minutes to remove excess trifluoroacetic acid. The residue was cooled with an ice bath, taken up in dichloromethane (50 mL) and basified with sodium hydroxide (10%). The organic layer was separated, dried with magnesium sulfate, and concentrated under reduced pressure. The resulting residue was chromatographed on a silica gel column eluting with ammonium hydroxide/methanol/dichloromethane (0.8/8/92) to provide the title product in enantiomerically enriched form: 1H NMR (CDCl3) δ 1.20-1.31 (m, 2H), 1.44-1.53 (m, 1H), 1.53-1.61 (m, 2H), 1.71-1.85 (m, 1H), 2.08-2.16 (m, 2H), 2.42 (t, 2H), 2.67-2.78 (m, 2H), 2.93-3.00 (m, 4H), 3.03-3.10 (m, 1H), 3.10-3.16 (m, 4H), 4.62-4.69 (m, 3H); MS (DCl/NH3) m/z 328 (M+H)+; [α]58920−106° (c 0.0038, methanol).
Reaction SMILES: N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.[C:25]([N:32]([CH3:38])[C@@H:33]([C:35]([OH:37])=O)[CH3:34])([O:27]C(C)(C)C)=[O:26].C(N(CC)C(C)C)(C)C.C(O)=O.[NH2:51][CH2:52][C:53]1[CH:54]=[C:55]([CH2:59][N:60]2[C:68]3[C:63](=[C:64]([OH:69])[CH:65]=[CH:66][CH:67]=3)[C:62]([NH:70][S:71]([C:74]3[S:75][C:76]([Cl:79])=[CH:77][CH:78]=3)(=[O:73])=[O:72])=[N:61]2)[CH:56]=[CH:57][CH:58]=1.Cl>CN(C=O)C.O1CCOCC1.CO.CO.CS(C)=O>[CH:25]([OH:27])=[O:26].[Cl:79][C:76]1[S:75][C:74]([S:71]([NH:70][C:62]2[C:63]3[C:68](=[CH:67][CH:66]=[CH:65][C:64]=3[OH:69])[N:60]([CH2:59][C:55]3[CH:54]=[C:53]([CH2:52][NH:51][C:35](=[O:37])[C@@H:33]([CH3:34])[NH:32][CH3:38])[CH:58]=[CH:57][CH:56]=3)[N:61]=2)(=[O:72])=[O:73])=[CH:78][CH:77]=1
Reactant: C[C@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: NCc1cccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(O)cccc32)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=CO
Solvent: CN(C)C=O
Solvent: CO
Product: CN[C@H](C)C(=O)NCc1cccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(O)cccc32)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a solution of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate (39.7 mg, 0.064 mmol) in anhydrous DMF (1 mL) was added at room temperature N-Boc-N-methyl-D-alanine (11.91 mg, 0.059 mmol), followed by N,N-diisopropylethylamine (0.0306 mL, 0.176 mmol) and finally a solution of N-(1-{[3-(aminomethyl)phenyl]methyl}-4-hydroxy-1H-indazol-3-yl)-5-chloro-2-thiophenesulfonamide formate salt (for a preparation see Intermediate 15) (29 mg, 0.059 mmol) in anhydrous DMF (1 mL). The reaction mixture was stirred at room temperature for 1 hour and then was partitioned between saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was separated, washed with brine-water (1:1), passed through a hydrophobic frit, and evaporated in-vacuo to yield a colourless oil. LCMS (System B) RT=3.01 min, ES+ve m/z 634/636 (M+H)+ for desired BOC protected product. This product was suspended in a solution of hydrogen chloride in 1,4-dioxane (4M, 0.5 mL) and methanol was added until the reaction was in solution. The mixture was stirred at room temperature for 18 hours and then evaporated in-vacuo to yield a colourless oil. The residual oil was dissolved in MeOH-DMSO (0.5 mL) and purified by MDAP) on OA MDAP on Sunfire C18 column, eluting with solvents A/B (A: 0.1% v/v solution of formic acid in water, B: 0.1% v/v solution of formic acid in acetonitrile) (25 min run). The appropriate fractions were combined and evaporated in-vacuo to yield the title compound as a colourless oil (15 mg, 44%). LCMS (System B) RT=1.63 min, ES+ve m/z 534/536 (M+H)+
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[CH3:19][CH:20]([OH:22])[CH3:21]>>[CH:20]([O:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1)([CH3:21])[CH3:19]
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: CC(C)O
Product: Cc1cc(Nc2cc3ccccc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from propan-2-ol, (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (1-isopropoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 283 (MH+).
Reaction SMILES: [CH2:1]([N:3]([C:7]1[CH2:12][CH:11]([CH3:13])[CH2:10][CH2:9][C:8]=1[C:14]([O-:16])=O)[C:4](=[O:6])[CH3:5])[CH3:2].C[O-].[Na+]>O1CCOCC1>[CH2:1]([N:3]1[C:7]2[CH2:12][CH:11]([CH3:13])[CH2:10][CH2:9][C:8]=2[C:14]([OH:16])=[CH:5][C:4]1=[O:6])[CH3:2]
Reactant: CCN(C(C)=O)C1=C(C(=O)[O-])CCC(C)C1
Agent: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCn1c2c(c(O)cc1=O)CCC(C)C2

Procedure:
The reaction of a 1:9 mixture of the methyl and ethyl esters of 2-(N-ethyl-acetamido)-4-methyl-cyclohex-1-ene-1-carboxylate (36.3 g; 0.144 mole) with dry sodium methoxide in dioxan as described in Example 8 gave the title product as a white crystalline solid; m.p. (EtOH) 335° - 338° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:18]=[CH:17][C:7]2[O:8][CH2:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[NH:12][C:6]=2[CH:5]=1.Cl[C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)[CH2:21]1.C(=O)([O-])O.[Na+]>CCCCCC.CS(C)=O.C(OCC)(=O)C>[Cl:3][C:4]1[CH:18]=[CH:17][C:7]2[O:8][CH2:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]([CH2:24][C@H:23]3[CH2:25][CH2:20][CH2:21][N:22]3[CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]4[O:34][CH2:35][O:36][C:30]=4[CH:29]=3)[C:6]=2[CH:5]=1
Reactant: Clc1ccc2c(c1)Nc1ccccc1CO2
Reactant: Cl[C@@H]1CCCN(CCc2ccc3c(c2)OCO3)C1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Clc1ccc2c(c1)N(C[C@H]1CCCN1CCc1ccc3c(c1)OCO3)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% sodium hydride (48 mg, 1.2 mmol) was washed with hexane in argon gas stream and then suspended in dimethyl sulfoxide (8 ml). The obtained suspension was stirred at room temperature for 30 minutes. 7-Chloro-5,11-dihydrodibenzo[b,e][1,4]oxazepine (232 mg, 1 mmol) was added to the suspension, and they were stirred at room temperature for 30 minutes and then at 50° C. for 30 minutes. A solution of (R)-3-chloro-1-(3,4-methylenedioxyphenethyl)piperidine (308 mg, 1.15 mmol) in dimethyl sulfoxide (3 ml) was added dropwise to the obtained solution, and they were stirred at 50° C. for 4 hours. The reaction mixture was distributed into saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (10:1) as the eluent, suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain (R)-7-chloro-5,11-dihydro-5-[1-(3,4-methylenedioxyphenethyl)pyrrolidin-2-ylmethyl]-dibenzo[b,e][1,4]oxazepine in the form of a light yellow solid (362 mg, 78%).
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C@H:4]1[C:6]([CH3:8])([CH3:7])[C@H:5]1[C:9]([OH:11])=[O:10].[Br-].[Br-].[Br-].[Al+3]>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:12])=[CH:3][CH:4]1[C:6]([CH3:7])([CH3:8])[CH:5]1[C:9]([OH:11])=[O:10]
Reactant: CC(C)=C[C@@H]1[C@H](C(=O)O)C1(C)C
Agent: [Al+3]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CC(C)=CC1C(C(=O)O)C1(C)C
Reaction time: 0.17 h
Yield: 98.5 %

Procedure:
To a solution of cis chrysanthemic acid (2.0 g) in toluene (20 ml) was added a solution of aluminum tribromide (32 mg) in toluene (2.2 ml) at room temperature under a nitrogen atmosphere. Irradiation with a xenon lamp (500 W) was made for 10 minutes under stirring. After the irradiation was over, similar after-treatment as in Example 30 was applied to obtain chrysanthemic acid (1.97 g). The isomer ratio of the product was cis, 6.8%; and trans, 93.2%.
Reaction SMILES: [C:1]([NH:7][C@H:8]([C:13]([O-:15])=O)[CH2:9][C:10]([O-:12])=[O:11])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Na+].[Na+].P(Cl)(Cl)Cl.C(N[C@@H]1C(=O)OC(=O)C1)(=O)CC(C)=O.[CH3:36][O:37][C:38](=[O:48])[C@H:39]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH2:40]>O1CCOCC1.C(O)(=O)C.C(OCC)(=O)C>[CH3:36][O:37][C:38](=[O:48])[C@H:39]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH:40][C:13](=[O:15])[C@H:8]([CH2:9][C:10](=[O:11])[OH:12])[NH:7][C:1](=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(=O)CC(=O)N[C@@H](CC(=O)[O-])C(=O)[O-]
Agent: CC(=O)CC(=O)N[C@H]1CC(=O)OC1=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClP(Cl)Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)CC(C)=O
Reaction time: 20 h

Procedure:
Crude disodium N-acetoacetylaspartate, 28.51 parts, was stirred with 200 parts by volume of ethyl acetate and 11.7 parts by volume of acetic acid at 0°-5° C. under argon while 4.37 parts by volume of phosphorous trichloride was added dropwise. The resulting mixture was allowed to warm to ambient temperatures while stirring for 20 hours. To the resulting solution which contains N-acetoacetyl-L-aspartic anhydride was added dropwise over a 2 hour period 122 parts by volume of 0.9 M L-phenylalanine methyl ester in dioxane. After continued stirring for 20 hours, the solvent was evaporated under vacuum at 35°-40° C. Toluene, 200 parts by volume, was added to the residue and the evaporation was repeated, giving crude N-acetoacetyl-L-aspartyl-L-phenylalanine methyl ester as a semi-solid yellow residue.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[CH:34][CH:33]=1>>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[CH:36][CH:37]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(CCCC(=O)O)cc1
Reactant: O=Cc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(O)CCCc1ccc(NCc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from 3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]benzaldehyde and 4-(4-amino-phenyl)-butyric acid according to the procedure of Example 66. MS (ES) m/z 567.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[C@H:7]([CH2:9][CH:10]([CH3:12])[CH3:11])[NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH:14](=O)[CH3:15].S([O-])([O-])(=O)=O.[Na+].[Na+]>>[CH3:14][CH:15]=[N:8][CH:7]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13]
Reactant: CC=O
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: CC=NC(CC(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of leucine tert-butyl ester (2.0 g, 8.9 mmol) and acetaldehyde (999 ul, 17.9 mmol) was stirred at room temperature for 5 minutes. Anhydrous sodium sulphate was added and the mixture stirred at room temperature for 18 hours. The solid was removed by filtration and the solvent evaporated in vacuo to afford the title compound as an oil.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:16][C@@H:17]2[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[CH2:18]2)=[N:7][C:8]=1[NH:9][C:10]1[S:14][N:13]=[C:12]([CH3:15])[CH:11]=1)#[N:2].Cl.CC#N.C(O)(C(F)(F)F)=[O:34]>OS(O)(=O)=O.O.CO>[C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:16][C@@H:17]2[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]([N:26]([CH3:27])[CH3:28])=[O:25])[CH2:18]2)=[N:7][C:8]=1[NH:9][C:10]1[S:14][N:13]=[C:12]([CH3:15])[CH:11]=1)(=[O:34])[NH2:2]
Reactant: Cc1cc(Nc2nc(N[C@@H]3CCCCN(C(=O)N(C)C)C3)cnc2C#N)sn1
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: CO
Solvent: O
Product: Cc1cc(Nc2nc(N[C@@H]3CCCCN(C(=O)N(C)C)C3)cnc2C(N)=O)sn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
(R)-3-(5-Cyano-6-(3-methylisothiazol-5-ylamino)pyrazin-2-ylamino)-N,N-dimethylazepane-1-carboxamide (510) (20 mg, 0.050 mmol) was dissolved in 5 mL TFA, and the solution was heated to 80° C. Concentrated H2SO4 (7 drops) was added dropwise, and the reaction was allowed to stir for 30 min Additional H2SO4 (15 drops) was added dropwise and the reaction was allowed to stir for 30 minutes. The reaction was cooled to RT, and diluted with 2 mL water and 2 mL methanol. The mixture was then directly subjected to reverse phase preparative HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases, and lyophilized to give (R)-3-(5-carbamoyl-6-(3-methylisothiazol-5-ylamino)pyrazin-2-ylamino)-N,N-dimethylazepane-1-carboxamide (511) (16 mg, 0.038 mmol, 76% yield). LC-MS (ESI): m/z (M+1) 419.6. Proton NMR (DMSO-d6): δ 12.27 (1H, s), 8.05 (1H, s), 7.81 (1H, s), 7.48-7.44 (2H, m), 6.85 (1H, s), 4.46 (1H, m), 3.35 (4H, m), 2.70 (6H, s), 2.30 (3H, s), 2.02 (1H, m), 1.79 (2H, m), 1.70 (1H, m), 1.57 (2H, m) ppm.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].[CH3:31][N:32]1[CH2:37][CH2:36][CH:35]([O:38][C:39]2[CH:46]=[CH:45][C:42]([CH:43]=O)=[CH:41][CH:40]=2)[CH2:34][CH2:33]1>>[CH2:1]([N:3]([CH2:43][C:42]1[CH:45]=[CH:46][C:39]([O:38][CH:35]2[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]2)=[CH:40][CH:41]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN1CCC(Oc2ccc(C=O)cc2)CC1
Product: CCN(Cc1ccc(OC2CCN(C)CC2)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 82 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (35 mg) and 4-(1-methylpiperidin-4-yloxy)benzaldehyde (94 mg) according to an analogous synthetic method to Example 264 and purified by LC-MS, the title compound (37 mg) was obtained.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[C:9]([F:21])[CH:8]=1.CN(C)[CH:24]=[O:25]>O1CCCC1>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([CH:8]=[C:9]([F:21])[CH:10]=1)[CH:24]=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Fc1cc(Br)cc(OCc2ccccc2)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc(F)cc(OCc2ccccc2)c1
Reaction time: 0.5 h
Yield: 32 %

Procedure:
Add n-butyl lithium (35 mL, 1.6M, 55.96 mmol) over 15 minutes to 1-bromo-3-fluoro-5-benzyloxy-benzene (14.30 g, 50.87 mmol) in tetrahydrofuran (300 mL) cooled in a dry ice/acetone bath, maintaining the internal temperature <−70°. Stir 30 minutes and add N,N-dimethylformamide (7.44 g, 101.74 mmol). Stir 30 minutes and remove cold bath. After 1 hour, quench with saturated aqueous ammonium chloride. Wash organic layer with water and saturated aqueous sodium chloride. Dry (sodium sulfate), filter and concentrate to an oil. Purify on 120 g silica gel eluting with 100:0 to 90:10 hexanes:ethyl acetate to give 3.75 g (32%) of the desired compound as an oil.
Reaction SMILES: [C:1]1([C:7]2([CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][C:31]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)([C:34]([NH2:36])=[O:35])[CH2:30][CH2:29]3)[CH2:11][CH2:10][N:9]([C:12](=[O:25])[C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:43]CCl>>[ClH:43].[C:1]1([C:7]2([CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][C:31]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)([C:34]([NH2:36])=[O:35])[CH2:30][CH2:29]3)[CH2:11][CH2:10][N:9]([C:12](=[O:25])[C:13]3[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCl
Agent: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Product: Cl

Procedure:
Prepared by the method of example 3.3A using 1-[2-[3-phenyl-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylic acid amide (710 mg, 1.24 mmol) and dichloromethane saturated with HCl(gas) (20 mL). The solution was concentrated in vacuo to obtain a residue. The residue was dried under high vacuum at 56° C. for 18 h to afford the title compound: