Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][C@@H:11]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(=O)=O>CN(C)C=O>[N:1]([CH2:10][C@@H:11]([NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:17])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 12 h

Procedure:
36 mg (0.55 mmol) of sodium azide are added to a solution of 218 mg (0.55 mmol) of (2S)-2,5-bis[(tert-butoxycarbonyl)amino]pentyl methanesulfonate (Example Z7) in 15 ml of dimethylformamide and the mixture is stirred at 70° C. for 12 h. Most of the solvent is distilled off in vacuo, and the residue is diluted with ethyl acetate. The solution is washed several times with a saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness in vacuo. The product is reacted without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]3[CH2:14][CH2:13][CH2:12][C:11]=13)[N:8]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:7]([CH3:23])([CH3:22])[C:6](=[O:24])[CH:5]2[CH3:25].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:36]1COC[CH2:37]1.I[CH:42](C)C>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]3[CH2:14][CH2:13][CH2:12][C:11]=13)[N:8]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:7]([CH3:23])([CH3:22])[C:6](=[O:24])[C:5]2([CH3:42])[CH2:25][CH2:36][CH3:37]
Reactant: C1CCOC1
Reactant: CC(C)I
Reactant: CC1C(=O)C(C)(C)N(C(=O)OC(C)(C)C)c2c1cc(Br)c1c2CCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC1(C)C(=O)C(C)(C)N(C(=O)OC(C)(C)C)c2c1cc(Br)c1c2CCC1
Reaction time: 0.25 h
Yield: 41 %

Procedure:
A solution of tert-butyl 6-bromo-2,2,4-trimethyl-2,3,4,7,8,9-hexahydro-1H-cyclopenta[h]quinolin-3-one-1-carboxylate (300 mg) obtained in Example 1, 7) in toluene (3 ml) was cooled to −20° C., 1.0 M lithiumbis(trimethylsilyl)amide/THF solution (2.9 ml) was added dropwise and the mixture was stirred for 15 min. 2-Iodopropane (293 μl) was added, and the mixture was stirred at 70° C. for 13 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to normal phase chromatography (elution solvent hexane-ethyl acetate=20:1→10:1) to give the title compound (136 mg, 41%).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.C([O-])(=O)C.[Na+].[CH2:15]([O:17][C:18](=[O:30])[C:19](=[N:28]O)[C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:16].ClCCl>C(O)(=O)C.[Zn]>[CH3:5][C:3]1[NH:28][C:19]([C:18]([O:17][CH2:15][CH3:16])=[O:30])=[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:2]=1[C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=NO)C(=O)c1ccccc1
Reactant: CCOC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c(C)c(C(=O)OCC)c1-c1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
A mixture of ethyl acetoacetate (72.5 g, 0.56 mol), zinc dust (98 g, 1.51 mol) and anhydrous sodium acetate (102 g, 1.21 mol) in glacial acetic acid (110 mL) was heated to 60° C. Ethyl-2-hydroxyimino-3-oxo-3-phenyl-propanoate (110 g, 0.5 mol) was added as a solution (some precipitation on standing) in glacial acetic acid (550 mL) in 3 portions with vigorous stirring over a period of 1 h. The temperature increased to 90° C. during the addition and the reaction was then maintained at 60-75° C. for 3 h. Additional zinc dust (49 g, 0.75 mol) was added over 15 min, again causing a temperature rise, and then the reaction mixture was then stirred at 60 to 75° C. for 1 h. After cooling to room temperature the mixture was filtered and the filtrate was evaporated in vacuo to give a residue which was azeotroped with toluene (2×200 mL) to remove residual acetic acid. Water (2 L) and ethyl acetate (300 mL) were added to the residue and the mixture was stirred until two clear phases were obtained. The organic phase was separated and the aqueous phase extracted with ethyl acetate (2×200 mL). The combined organic phases were washed successively with water (2×250 mL), saturated bicarbonate solution (2×250 mL), water (2×100 mL), brine (2×100 mL), dried over anhydrous sodium sulfate and then concentrated to give a gummy residue. A mixture of dichloromethane and petroleum ether (175 mL; 1:6) was added to the solid and it was stirred for 15 min. The resulting free-flowing solid was filtered off and washed with chilled petroleum ether (100 mL) to afford diethyl 5-methyl-3-phenyl-1H-pyrrole-2,4-dicarboxylate (85 g, 57%) as an off-white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([OH:9])=O.N[C@H](CC)C(O)=O.N[C@H](CC)C(OC)=O.CO[C:27]([CH:29]1[CH2:34]OC[CH2:31][NH:30]1)=O.[Cl:35][C:36]1[N:41]=C(Cl)C([N+]([O-])=O)=C[N:37]=1.ClC1N=C(N(C2CCCC2)[C@H](CC)C(OC)=O)C([N+]([O-])=O)=CN=1>>[Cl:35][C:36]1[N:41]=[CH:34][C:29]2[N:30]([CH3:31])[C:7](=[O:9])[CH:2]3[CH2:3][O:4][CH2:5][CH2:6][N:1]3[C:27]=2[N:37]=1
Reactant: COC(=O)C1COCCN1
Reactant: O=C(O)C1COCCN1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: CC[C@@H](N)C(=O)O
Agent: CC[C@@H](N)C(=O)OC
Agent: CC[C@H](C(=O)OC)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Product: CN1C(=O)C2COCCN2c2nc(Cl)ncc21

Procedure:
Intermediate I was prepared in the same manner as Intermediate B, using 3-morpholinecarboxylic acid as the starting material instead of (R)-2-aminobutanoic acid. No reductive amination step, such as that used for the conversion of compound II to compound III, was required. Rather, methylmorpholine-3-carboxylate was reacted directly with 2,4-dichloro-5-nitropyrimidine in the same manner as is described for the conversion of compound III to Intermediate A. LCMS: 254.9 m/z (M+H)+.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH2:5])=[O:4].[CH3:9][C@H:10]([NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C:11](OC1C=CC([N+]([O-])=O)=CC=1)=[O:12]>CN(C)C=O>[NH:23]([C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[C@H:10]([C:11]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH2:5])=[O:4])=[O:12])[CH3:9]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(N)=O
Reaction time: 18 h
Yield: 86.2 %

Procedure:
2.28 g of H-Pro-NH2 and 7.57 g of Z-Ala-ONP are dissolved in 20 ml of dimethylformamide and the yellow solution is left standing at room temperature for 18 hours. It is then evaporated to dryness in a high vacuum, the residue is mixed with ether and the resulting powder is thoroughly triturated. After filtering off and drying, 5.5 g of Z-Ala-Pro-NH2 of melting point 167.5°-168.5° C. are obtained. [α]D20 = -74° (c = 1 in methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28]Cl)[C:26]=2[Cl:27])=[O:21])=[N:6][CH:7]=1.[F:31][C:32]([F:36])([F:35])[CH2:33][NH2:34]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28][NH:34][CH2:33][C:32]([F:36])([F:35])[F:31])[C:26]=2[Cl:27])=[O:21])=[N:6][CH:7]=1
Reactant: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CCl)c1Cl
Reactant: NCC(F)(F)F
Solvent: CN(C)C=O
Product: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CNCC(F)(F)F)c1Cl
Temperature: 75 °C
Yield: 94.5 %

Procedure:
To a solution of N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide (2.1 g, 4.1 mmol) in DMF (20 mL) was added a 2,2,2-trifluoroethylamine (3.2 mL, 41 mmol). The mixture was heated at 75° C. for 18 hours, then cooled to ambient temperature and concentrated in vacuo to remove excess 2,2,2-trifluoroethylamine. Water was added and the mixture was extracted with methylene chloride. The organic layer was dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 2.2 g (95% yield) of N-(5-chloropyridin-2-yl)-2-[((4-(((2,2,2-trifluoroethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; NMR (DMSO-d6/TFA) 10.8 (s, 1) 9.4 (s, 1), 8.2 (d, 1), 8.1 (d, 1), 8.0 (s, 1), 7.8 (dd, 1), 7.2 (d, 2), 4.2 (s, 2), 4.1 (q, 2), 3.8 (s, 3) ppm.
Reaction SMILES: C1([C@H](CC(O)=O)C(O)=O)C=CC=CC=1.[NH2:15][C@H:16]1[C@H:20]([F:21])[CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1.CCN(C(C)C)C(C)C.[C:38](Cl)([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39]>C(Cl)Cl>[CH2:41]([O:40][C:38]([NH:15][C@H:16]1[C@H:20]([F:21])[CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1)=[O:39])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](F)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C(O)C[C@H](C(=O)O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@@H](F)[C@H](NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Yield: 95.6 %

Procedure:
A solution of (2S)-2-phenylbutanedioic acid-tert-butyl (3R,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate (1:1) (500 mg, 1.2 mmol) in DCM (20 mL) was cooled in an ice/water bath. DIPEA (0.69 mL, 4 mmol, 3.3 mol eq) was added, followed by CBZ-Cl (185 μL, 1.26 mmol, 1.05 mol eq). The resulting reaction solution was capped, stirred in the cold bath and allowed to warm to rt and stirred for 2 hr. The reaction was diluted with DCM (30 mL) and washed with sat. aq. NaHCO3 (10 mL). The organic layer was separated, dried over Na2SO4, and evaporated to give a colorless residue that was purified via flash chromatography (eluting with a gradient of 100% heptane to 50 ethyl acetate-50% heptane) to give the title compound as a colorless oil (388 mg, 96 yield). 1H NMR (400 MHz, chloroform-d) δ ppm 7.30-7.42 (m, 5 H) 5.12 (br. s., 2 H) 4.74-5.04 (m, 1 H) 4.28 (br. s., 1 H) 3.28-3.80 (m, 4 H) 1.47 (s, 9 H). 19F NMR (376 MHz, chloroform-d) δ ppm −180.76-−178.52 (m, 1 F). m/z (APCI+) for C17H23FN2O4 239.2 (M+H)+. Chiral purity was determined as below (using the racemic material to compare):
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH2:6].[Cl:12][C:13]1[S:17][C:16]([S:18](Cl)(=[O:20])=[O:19])=[CH:15][CH:14]=1.C(N(CC)CC)C>>[CH3:2][O:3][C:4](=[O:11])[C@H:5]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH:6][S:18]([C:16]1[S:17][C:13]([Cl:12])=[CH:14][CH:15]=1)(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CC[C@H](C)[C@H](N)C(=O)OC
Agent: Cl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](NS(=O)(=O)c1ccc(Cl)s1)C(=O)OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
To a solution of L-isoleucine methyl ester hydrochloride (1.82 g, 10 mmol) and 5-chlorothiophene-2-sulfonyl chloride (1.82 g, 10 mmol) was added triethylamine (4.18 mL, 30 mmol). The mixture was stirred at 60° C. overnight, then filtered and concentrated. The crude product was purified by flash chromatography over silica gel using 10% ethyl acetate in hexane to give 5-chlorothiophene-2-sulfonyl isoleucine methyl ester 2.53 g.
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21](OC(F)(F)F)=[CH:20][CH:19]=3)[N:15]([CH:29]3[CH2:31][CH2:30]3)[C:14]=2[C:32]([N:34]2[CH2:39][CH2:38][CH:37]([N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[CH2:36][CH2:35]2)=[O:33])[CH:10]=[N:9]1)C1C=CC=CC=1.C(OC(=O)CN(C1CC1)C(=O)C1C=CC=C([O:58][C:59]([F:62])([F:61])[F:60])C=1)C>[Pd]>[CH:29]1([N:15]2[C:14]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([N:40]4[CH2:41][CH2:42][CH2:43][CH2:44]4)[CH2:38][CH2:39]3)=[O:33])=[C:13]([C:11]3[CH:10]=[N:9][NH:8][CH:12]=3)[N:17]=[C:16]2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:58][C:59]([F:62])([F:61])[F:60])[CH:19]=2)[CH2:31][CH2:30]1
Reactant: O=C(c1c(-c2cnn(Cc3ccccc3)c2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1)N1CCC(N2CCCC2)CC1
Reactant: CCOC(=O)CN(C(=O)c1cccc(OC(F)(F)F)c1)C1CC1
Agent: [Pd]
Product: O=C(c1c(-c2cn[nH]c2)nc(-c2cccc(OC(F)(F)F)c2)n1C1CC1)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described in example 95, the title compound has been obtained from [5-(1-benzyl-1H-pyrazol-4-yl)-3-cyclopropyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (prepared in analogy to the sequence described for the preparation of intermediate 13, but using [cyclopropyl-(3-trifluoromethoxy-benzoyl)-amino]-acetic acid ethyl ester instead of [cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-acetic acid ethyl ester in step 13A) by hydrogenation with 10% palladium on charcoal to give the title compound as colorless amorphous solid. MS: 515.2 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH:5]=O)([CH3:4])[CH3:3].[CH3:7][O:8][C:9]1[C:10]([CH3:19])=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([NH:14][NH2:15])=[O:13]>CO.C(O)(=O)C>[CH3:4][C:2]([CH3:1])([CH3:3])[CH:5]=[N:15][NH:14][C:12](=[O:13])[C:11]1[CH:16]=[CH:17][CH:18]=[C:9]([O:8][CH3:7])[C:10]=1[CH3:19]
Reactant: COc1cccc(C(=O)NN)c1C
Reactant: CC(C)(C)C=O
Solvent: CO
Solvent: CC(=O)O
Product: COc1cccc(C(=O)NN=CC(C)(C)C)c1C
Yield: 66.6 %

Procedure:
Pivaldehyde (13.45 g, 156 mmoles) was dissolved in 300 mL methanol in a round bottom flask. 3-methoxy-2-methyl-benzoic acid hydrazide (26.6 g, 147.6 mmoles) and 150 drops glacial acetic acid were added, and the mixture was heated at reflux for ca. 8 hours, while monitoring by TLC. Upon completion of the reaction, the solvent was removed in vacuo, and the product was slurried in cold hexanes and filtered on a Büchner funnel to provide 24.4 g (66%) of 3-methoxy-2-methyl-benzoic acid (2,2-dimethyl-propylidene)-hydrazide. Rf=0.19, (2:1 hexanes:ethyl acetate); 1H NMR (400 MHz, DMSO-d6) δ 7.42+7.41 (3 s, 1H), 7.1 (t, 1H), 6.9 (d, 1H), 6.82 (d, 1H), 3.78 (s, 3H), 2.2+2.1 (2 s, 3H), 1.07+1.0 (3 s, 9H), multiple conformations, possibly E/Z mixture.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[OH:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]2[O:31][CH:32]=[CH:33][CH:34]=2)=[O:29])=[CH:23][CH:22]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[O:31]1[CH:32]=[CH:33][CH:34]=[C:30]1[C:28]([NH:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=2)=[CH:26][CH:25]=1)=[O:29]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: O=C(Nc1ccc(O)cc1)c1ccco1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccc(NC(=O)c3ccco3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and furan-2-carboxylic acid (4-hydroxy-phenyl)-amide via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1) to produce a white solid. MS (ES) for C23H23NO7 [M+H]+: 426.3.
Reaction SMILES: C(OCC)C.O[CH:7]([C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20])[CH2:8][C:9]([CH2:12][Si](C)(C)C)=[C:10]=[CH2:11].[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.O>CCOC(C)=O>[CH2:11]=[C:10]1[C:9](=[CH2:12])[CH2:8][CH:7]2[O:20][CH:19]1[CH:18]1[C:17]2=[C:24]=[CH:23][CH:22]=[CH:21]1
Reactant: C=C=C(CC(O)c1ccccc1C=O)C[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: C=C1CC2OC(C1=C)C1C=CC=C=C21
Temperature: -78 °C
Yield: 77.2 %

Procedure:
5.2 mL of diethyl ether was added to 2-(1-hydroxy-3-trimethylsilanylmethyl-penta-3,4-dienyl)-benzaldehyde (358 mg, 1.30 mmol) under nitrogen atmosphere. While stirring at −78° C., TMSOTf (235 μL, 1.30 mmol) was added. While stirring the reaction mixture, the reaction temperature was slowly increased to room temperature for 3 hours. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed, H2O was added. After stirring for about 5 minutes, the reaction mixture was diluted with EtOAc and washed with water and saturated brine. The organic layer was separated from the reaction mixture and dried with anhydrous MgSO4. The solvent was removed under reduced pressure and the remaining material was purified with column chromatography (EtOAc/n-hexane=1/6) to obtain 185 mg of the product (77%).
Reaction SMILES: C(O)(=O)C.[C:5]([C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=1)#[N:6].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:5]([C:7]1[CH:12]=[C:11]([CH2:13][Br:14])[CH:10]=[CH:9][N:8]=1)#[N:6]
Reactant: Cc1ccnc(C#N)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: N#Cc1cc(CBr)ccn1
Temperature: 50 °C
Yield: 24.6 %

Procedure:
0.146 ml of acetic acid is added to a solution of 0.236 g of 2-cyano-4-methylpyridine in 5 ml of carbon tetrachloride, under an inert atmosphere of argon at a temperature in the region of 20° C. The mixture is brought, with stirring, to a temperature of 50° C. 0.712 g of N-bromosuccinimide and 0.096 g of benzoyl peroxide are successively added at this temperature. The mixture is maintained at 80° C. for about 18 hours. After cooling, the reaction medium is placed on a cartridge 27 mm in diameter packed with 25 g of 20-40 μm silica not conditioned beforehand, and then eluted with dichloromethane at a flow rate of 10 ml/minute. The fractions between 140 and 175 ml are concentrated to dryness under reduced pressure. 0.097 g of 2-cyano-4(bromomethyl)pyridine is thus obtained.
Reaction SMILES: [OH:1][C:2]1[CH2:3][C:4]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:5][C:6](=[O:8])[CH:7]=1.C1C(=O)N([Br:29])C(=O)C1>>[Br:29][C:7]1[C:6](=[O:8])[O:5][C:4]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3][C:2]=1[OH:1]
Reactant: O=C(O)CCCCC1(c2ccccc2)CC(O)=CC(=O)O1
Reactant: O=C1CCC(=O)N1Br
Product: O=C(O)CCCCC1(c2ccccc2)CC(O)=C(Br)C(=O)O1

Procedure:
The title compound was prepared as described in General Method 3 using 1.4 mmol of 5-[4-hydroxy-6-oxo-2-phenyl-3,6-dihydro-2H-pyran-2-yl]pentanoic acid (prepared in Example J1) and 1.4 mmol of NBS. 1H NMR (DMSO-d6) δ 0.94 (m, 1 H), 1.22-1.40 (m, 3 H), 1.92 (m, 2 H), 2.13 (t, 2 H), 3.28 (q, 2 H), 7.16-7.52 (m, 5 H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:6][C@@H:5]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]1([CH3:19])[CH3:18].I([O-])(=O)(=O)=[O:21].[Na+].C(#N)C>C(Cl)(Cl)(Cl)Cl.O.O.[Ru](Cl)(Cl)Cl>[CH2:10]([O:9][C:8]([NH:7][C@@H:5]1[CH2:6][C@H:3]([C:2]([OH:21])=[O:1])[C:4]1([CH3:19])[CH3:18])=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC1(C)[C@@H](CO)C[C@H]1NC(=O)OCc1ccccc1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CC#N
Product: CC1(C)[C@@H](C(=O)O)C[C@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a solution of benzyl ((1R,3S)-3-(hydroxymethyl)-2,2-dimethylcyclobutyl)carbamate (2.75 g, 10.4 mmol) in carbon tetrachloride (14 mL) was added sodium periodate (6.68 g, 31.2 mmol), water (21 mL) and acetonitrile (14 mL), followed by ruthenium(III) chloride hydrate (52 mg, 0.2 mmol, in 0.5 mL of water) at room temperature. The resulting biphasic mixture was stirred vigorously at room temperature for 1 h. The reaction mixture was diluted with water and extracted with DCM (2×150 mL). The combined organic layers was dried over sodium sulfate and concentrated to afford the title compound (2.6 g, crude), which was used directly in the next step without further purification. MS (ESI) m/z 278.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9](NC(OC(C)(C)C)=O)[C:10](=[O:29])[N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:23]3[CH:27]=[CH:26][NH:25][C:24]3=[O:28])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl.[N:39]1([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41][C@H:40]1[C:49](O)=[O:50].C(Cl)CCl.C1C=CC2N(O)N=[N:69]C=2C=1>CCOC(C)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:69][C:49]([C@@H:40]2[CH2:41][C:42]3[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:48][N:39]2[C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])=[O:50])[C:10](=[O:29])[N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:23]3[CH:27]=[CH:26][NH:25][C:24]3=[O:28])[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2-n2cc[nH]c2=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2-n2cc[nH]c2=O)CC1
Yield: 81.2 %

Procedure:
The title compound was prepared according to the procedure described in Example 10 (Step b) using N-((1R)-1-[(4-chlorophenyl)methyl]-2 oxo-2-{4-[2-(2-oxo(4-imidazolinyl))phenyl]-piperidyl}ethyl)(tert butoxy)carboxamide (Step b) (0.283 g, 0.54 mmol) and satd anhydrous HCl in EtOAc, followed by Boc-L-TicOH (Advanced ChemTech) (0.18 g, 0.65 mmol), EDC (Advanced ChemTech) (0.155 g, 0.81 mmol), HOBT (Novabiochem) (0.073 g, 0.54 mmol) and TEA (Aldrich) (0.075 mL, 0.54 mmol) in CH2Cl2 (10 mL). Purification by silica gel chromatography (100% EtOAc then 1:9 MeOH:EtOAc) provided the title compound as a white foam (0.3 g). MS (ESI, pos. ion) m/z: 684 (M+1). Calc'd for C38H42ClN5O5: 683.29.
Reaction SMILES: C(#N)C.[Na].[CH2:5]([C:12]1[O:13][C:14](=O)[C:15](=[CH:17][OH:18])[N:16]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.[C:21]([NH2:29])(=[NH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[C:22]1([C:21]2[NH:29][C:17](=[O:18])[C:15]([NH:16][C:12](=[O:13])[CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)=[CH:14][N:28]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1OC(Cc2ccccc2)=NC1=CO
Reactant: N=C(N)c1ccccc1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CC#N
Product: O=C(Cc1ccccc1)Nc1cnc(-c2ccccc2)[nH]c1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
Acetonitrile (6 ml) was added to 2-benzyl-4-hydroxymethylene-5-oxazolone sodium salt (0.50 g, 2.22 mmol) and benzamidine hydrochloride (0.35 g, 2.22 mmol), and the mixture was stirred overnight at 80° C. Water (3 ml) was added, and the mixture was stirred. The precipitate was collected by filtration, and the obtained crystals were washed with water and vacuum dried to give 2-phenyl-6-oxo-5-phenylacetylamino-1,6-dihydropyrimidine (0.51 g, 1.67 mmol).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[N:10]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH:9]=1)([OH:7])=O>CN(C)C=O>[ClH:3].[Cl:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:18]1[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=1)[CH:9]=[C:8]2[C:5]([Cl:3])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cn(-c2ccnc3ccccc23)c2ccc(Cl)cc12
Solvent: CN(C)C=O
Product: Cl
Product: O=C(Cl)c1cn(-c2ccnc3ccccc23)c2ccc(Cl)cc12

Procedure:
45 cm3 of sulphinyl chloride and one drop of dimethylformamide are added to 2.1 g (6.51 mmol) of 3-carboxy-5-chloro-1-(quinolin-4-yl)-1H-indole at a temperature in the region of 20° C. under an argon atmosphere. After stirring at reflux for 1 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), giving 2.5 g of 5-chloro-3-chlorocarbonyl-1-(quinolin-4-yl)-1H-indole hydrochloride in the form of a cream-colored solid, which is used directly in the following step.