Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[CH:24]([OH:27])[CH2:25][CH3:26].C1CCN2C(=NCCC2)CC1.[Cl-].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[C:24](=[O:27])[CH2:25][CH3:26]
Reactant: CCC(O)c1cc(OC)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCC(=O)c1cc(OC)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
Under an argon atmosphere, 1-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methoxyphenyl}-1-propanol (compound 11) (65.9 mg) was dissolved in methylene chloride (2 ml) to prepare a solution. 1,8-Diazabicyclo[5.4.0]-7-undecene (72 mg) was then added to the solution, and the mixture was cooled to −78° C. N-Tert-butylbenzenesulfineimidoyl chloride (71.4 mg) was dissolved in methylene chloride to prepare a solution, and the solution was added to the reaction solution. The mixture was stirred at −78° C. for 30 min and at 0° C. for 30 min. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (56.2 mg, yield 86%).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][O:9][C:10]([NH:12][CH2:13][CH2:14][C@H:15]([OH:19])[C:16]([OH:18])=O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.COC1C=CC(COC([N:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)=O)=CC=1.C(N(CC)CC)C>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([NH:12][CH2:13][CH2:14][C@H:15]([OH:19])[C:16]([N:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)=[O:18])=[O:11])=[CH:20][CH:21]=1)([O-:3])=[O:2]
Reactant: COc1ccc(COC(=O)N2CCNCC2)cc1
Reactant: O=C(NCC[C@H](O)C(=O)O)OCc1ccc([N+](=O)[O-])cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCC[C@H](O)C(=O)N1CCNCC1)OCc1ccc([N+](=O)[O-])cc1

Procedure:
To 0.9 g of (2S)-4-(p-nitrobenzyloxycarbonyl)amino-2-hydroxybutyric acid dissolved in tetrahydrofuran were added, with cooling on an ice bath, 0.36 g of N-hydroxysuccunimide and 0.65 g of dicyclohexylcarbodiimide, followed by overnight reaction with stirring. To the solution were added 0.75 g of 1-(p-methoxybenzyloxycarbonyl)piperazine and 0.31 g of triethylamine, followed by 2 hours of reaction. After removal of insoluble material from the reaction mixture by filtration and subsequent concentration of the filtrate, a residue was mixed with ethyl acetate, washed with sodium bicarbonate aqueous solution, citric acid aqueous solution and sodium chloride aqueous solution in that order and then dried over sodium sulfate, followed by evaporation of the solvent under a reduced pressure. Thereafter, the resulting residue was subjected to a silica gel column chromatography to yield 1.33 g of 1-(p-methoxybenzyloxycarbonyl)-4-((2S)-(4-(p-nitrobenzyloxycarbonyl) amino-2-hydroxybutyryl)piperazine.
Reaction SMILES: [CH:1]([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][CH:24]([CH3:26])[CH3:25])=[CH:16][CH:15]=3)=[CH:13][C:8]=2[CH:7]=[C:6]([C:27]([O:29]C)=[O:28])[CH2:5][CH2:4]1)=[O:2].[OH-].[Na+].Cl>C1COCC1.C(O)C>[CH:1]([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][CH:24]([CH3:25])[CH3:26])=[CH:16][CH:15]=3)=[CH:13][C:8]=2[CH:7]=[C:6]([C:27]([OH:29])=[O:28])[CH2:5][CH2:4]1)=[O:2]
Reactant: COC(=O)C1=Cc2cc(-c3ccc(OCCOC(C)C)cc3)ccc2N(C=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)OCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 100.1 %

Procedure:
In a mixture of THF and ethanol (1:1, v/v, 30.0 ml) was dissolved methyl 1-formyl-7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (445 mg). To the solution was added 1N sodium hydroxide solution (11.0 ml), and the mixture was stirred at room temperature for 13 hours. The mixture was a little concentrated, and to the residue was added 1N hydrochloric acid to convert weakly acidic solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give 1-formyl-7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (430 mg) as white crystals.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[C:15]([C:17]1[S:29][C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]([CH2:30][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:20](=[O:39])[C:19]=2[C:18]=1[O:40][CH3:41])=[O:16])(C)(C)C.C(OC(=O)C)C.[ClH:49]>C(OCC)(=O)C>[ClH:49].[NH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[C:15]([C:17]1[S:29][C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]([CH2:30][C:31](=[O:38])[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:20](=[O:39])[C:19]=2[C:18]=1[O:40][CH3:41])=[O:16]
Reactant: COc1c(C(=O)N2CCCCC2CNC(=O)OC(C)(C)C)sc2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1c(C(=O)N2CCCCC2CN)sc2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Yield: 67 %

Procedure:
A solution of the obtained tert-butyl[(1-{[3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno[3,2-c]quinolin-2-yl]carbonyl}piperidin-2-yl)methyl]carbamate (150 mg) and 4N hydrogen chloride ethyl acetate solution (8 mL) in ethyl acetate (15 mL) was stirred at room temperature for 18 hr. The obtained precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure to give the title compound (133 mg, 67%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:21]1[CH2:30][C@H:29]([OH:31])[CH2:28][C@@H:22]1[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[C:36]([O:44][C:45]([F:48])([F:47])[F:46])[CH:35]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:40]([C:37]1[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][C:36]=1[O:44][C:45]([F:46])([F:47])[F:48])(=[O:42])=[O:41])[C:6](=[O:11])[C:5]2([N:21]1[CH2:30][C@H:29]([OH:31])[CH2:28][C@@H:22]1[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20]
Reactant: COc1ccc(C)cc1C1(N2C[C@H](O)C[C@@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C)ccc3OC)(N3C[C@H](O)C[C@@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1

Procedure:
With 700 mg of the compound obtained in Step 133-1 and 505 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, respectively 219 mg (Isomer A: colorless amorphous) and 314 mg (Isomer B: colorless amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Example 2.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][C@@H:6]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24][C:25](=[O:45])[C@H:26]([CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:27][C:28]([O:30][CH3:31])=[O:29])[O:5][CH2:4]1.C(=O)(O)[O-].[Na+].S([N:58]=[N+:59]=[N-])(C(F)(F)F)(=O)=O.CO>C(Cl)Cl.O.S([O-])([O-])(=O)=O.[Cu+2]>[N:1]([CH2:2][C@H:3]1[N:8]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:7][C@@H:6]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24][C:25](=[O:45])[C@H:26]([CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:27][C:28]([O:30][CH3:31])=[O:29])[O:5][CH2:4]1)=[N+:58]=[N-:59]
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CN)CO1)C(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=NS(=O)(=O)C(F)(F)F
Agent: [Cu+2]
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CN=[N+]=[N-])CO1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (2R,5R)-5-(aminomethyl)-2-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}phenyl)ethyl]morpholine-4-carboxylate (1 eq.) in CH2Cl2 (0.4M) was added copper(II) sulfate (0.02 eq.) and sodium bicarbonate (1 eq.) as a solution in water (NaHCO3/CuSO4)) (1M). To that mixture was added triflic azide (3.65 eq.) as a solution in CH2Cl2 (0.4M). The heterogenous mixture was homogenized by the addition of methanol and the reaction was stirred at room temperature for 30 minutes. Upon completion by LCMS, solvents were evaporated and the evaporation residue was used as such for next step.
Reaction SMILES: C(O)CCO.[Si:6]([O:13][CH2:14][CH2:15][CH2:16][OH:17])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]>>[Si:6]([O:13][CH2:14][CH2:15][CH:16]=[O:17])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Solvent: OCCCO
Product: CC(C)(C)[Si](C)(C)OCCC=O

Procedure:
Synthesis by monosilylation of 1,3-propanediol and subsequent Swern oxidation of the 3-[(t-butyldimethylsilyl)oxy]-1-propanol that is produced.
Reaction SMILES: C[Al](C)C.[NH2:5][CH2:6][CH:7]1[CH2:9][CH2:8]1.C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[C:22]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[N:23][O:24][C:25]=2[CH2:26][OH:27])=[N:15][CH:14]=1.C1(C)C=CC=CC=1>O1CCOCC1>[CH:7]1([CH2:6][NH:5][C:12](=[O:11])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[C:22]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)=[N:23][O:24][C:25]=3[CH2:26][OH:27])=[N:15][CH:14]=2)[CH2:9][CH2:8]1
Reactant: NCC1CC1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: O=C(NCC1CC1)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 35.9 %

Procedure:
A trimethylaluminium solution (2 M in toluene, 418 μL, 0.84 mmol) was added to a solution of aminomethylcyclopropane (61.3 mg, 0.84 mmol) in dioxane (3.75 mL). 6-[3-(4-Fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (75.0 mg, 0.21 mmol) in dioxane (3.75 mL) was added after 1 h at 50° C. The reaction mixture was stirred at 85° C. overnight. Again trimethylaluminium solution in toluene (2 M in toluene, 418 μL, 0.84 mmol) was added and stirring was continued for 3 h at 85° C. The solvent was removed by distillation. The residue was purified by chromatography (silica, ethyl acetate:heptane=4:6 to 8:2) to yield the title compound (30 mg, 36%) as a light yellow solid. MS: m/e=398.2 [M+H]+.
Reaction SMILES: CCN(CC)CC.[C:8]([O:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([O:64][CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:22](=[O:63])[CH2:23][CH2:24][C:25](=[O:62])[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:33](=[O:53])[CH2:34][CH2:35][C:36](=[O:52])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[C:72](Cl)(=[O:74])[CH3:73]>C(Cl)Cl>[C:8]([O:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([O:64][CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:22](=[O:63])[CH2:23][CH2:24][C:25](=[O:62])[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:33](=[O:53])[CH2:34][CH2:35][C:36](=[O:52])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][N:43]([O:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:72](=[O:74])[CH3:73])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCNOCc1ccccc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(CCCCCNC(=O)CCC(=O)N(CCCCCNC(=O)CCC(=O)N(CCCCCNC(=O)OC(C)(C)C)OCc1ccccc1)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Yield: 86.6 %

Procedure:
NEt3 (0.16 mL, 1.15 mmol) was added to (11) (0.87 g, 0.98 mmol) in CH2Cl2 (40 mL) and the solution was cooled to 0° C. Acetyl chloride (0.074M in CH2Cl2, 14 mL, 1.04 mmol) was added by syringe over 4 minutes and stirring was continued (0° C. to room temperature) for 24 hours. The aqueous phase was extracted with CH2Cl2 (4×50 mL) and the organic phase was washed with 40 mL portions of cold 0.25M citric acid, 5% NaHCO3 and H2O. Solvent removal and flash column chromatography with 60% acetone/hexane gave 0.79 g (87%) of (12) as an oil: 300 MHz NMR δ 1.23-1.69 (m+s, 27 H), 2.09 (s, 3 H), 2.44-2.53 (m, 4 H), 2.76-2.84 (m, 6 H), 3.03-3.24 (m, 6 H), 3.57-3.68 (m, 6 H), 4.7 (br s, 1 H), 4.81 (s, 2 H), 4.85 and 4.86 (2 s, 4 H), 6.35 (br s, 1 H), 7.38 (s, 15 H). Anal. calcd. for C51H74N6O10 : C, 65.78; H, 8.01; N, 9.03. Found: C, 65.89; H, 8.04; N, 8.95.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[C@@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N+:36]([CH3:39])([O-:38])=[O:37].CC(C)([O-])C.[K+].Cl>O1CCCC1>[C:19]([O:18][C:16]([NH:15][C@@H:10]([CH2:11][C:12](=[O:14])[CH2:39][N+:36]([O-:38])=[O:37])[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:23])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)C[N+](=O)[O-])C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution A of 10 g (30.9 mmol) of 2(S)-tert-butoxycarbonylaminosuccinic acid 1-benzyl ester and 5.27 g (32.5 mmol) of 1,1′-carbonyldiimidazole in 100 ml of tetrahydrofuran is stirred at RT for 5 h. 18.8 g (30.9 mmol) of nitromethane are added dropwise to a solution B of 3.2 g (34.2 mmol) of potassium tert-butoxide in 100 ml of tetrahydrofuran at 0° C. Solution B is stirred while warming to RT, and then solution A is added dropwise at RT. The resulting mixture is stirred at RT for 16 h and adjusted to pH 2 using 20% hydrochloric acid. The solvent is evaporated. The remaining crude product is taken up in ethyl acetate/water. After separation of the phases, the organic phase is extracted twice with water, dried over sodium sulfate and concentrated. 13 g (99% of theory) of product are obtained.
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(O)(=O)C.[C:15]([O:19][CH3:20])(=[O:18])[NH:16][NH2:17]>CO>[CH3:20][O:19][C:15](=[O:18])[NH:16][N:17]=[C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1CCc2ccccc21
Reactant: COC(=O)NN
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)NN=C1CCc2ccccc21
Yield: 71.3 %

Procedure:
To a solution of 39.65 g (0.3 moles) of 1-indanone in 300 ml of methanol 3 ml of acetic acid and 27 g (0.3 moles) of methyl carbazate are added. The reaction mixture is boiled in a flask equipped with a reflux condenser for one hour, then clarified with bone coal, filtered and the filtrate is cooled with icy water. 43.7 g of the desired compound are obtained in the form of white crystals. M.p.: 155°-156° C. The mother liquor is evaporated in vacuo to about one-fourth of its original volume. In this way a another 12.3 g of the desired compound are obtained. Yield: 91.5%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:16](Cl)=[O:17]>C(Cl)CCl>[F:1][C:2]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:3]=1[C:4]([N:6]=[C:16]=[O:17])=[O:5]
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1ccc(C(F)(F)F)cc1F

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 2-fluoro-4-(trifluoromethyl)benzamide (0.200 g, 0.96 mmol), EDC (10 mL) and oxalyl chloride (0.1 mL, 1.15 mmol) to afford 0.200 g of the product.
Reaction SMILES: Cl[C:2]1[N:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][O:16][N:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH3:19])[C:4](=[O:8])[N:5]([CH3:7])[N:6]=1.FC(F)(F)C1C=C(C(=NO)C)C=CC=1.[OH-].[K+].[H-].[Na+].C[C:49](C)([O-:51])C>C1COCC1.CO>[CH3:49][O:51][C:2]1[N:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][O:16][N:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH3:19])[C:4](=[O:8])[N:5]([CH3:7])[N:6]=1
Reactant: CC(=NOCc1ccccc1-n1c(Cl)nn(C)c1=O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)[O-]
Agent: CC(=NO)c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nn(C)c(=O)n1-c1ccccc1CON=C(C)c1cccc(C(F)(F)F)c1

Procedure:
Examples of the combined processes of Steps 2 and 3 include the reaction of 5-chloro-2, 4-dihydro-2-methyl-4-[2-[[[[1-[3(trifluoromethyl)phenyl]-ethylidene]amino]oxy]methyl]phenyl]- 3H-1,2,4-triazol-3-one with 1-[3-(trifluoromethyl)phenyl]ethanone oxime in the presence of a base (e.g., KOH, NaH or K t-butoxide) in a suitable solvent (e.g., THF) and the subsequent reaction of the product of that reaction with methanol in the THF solution to form 2,4-dihydro-5-methoxy-2-methyl-4-[2-[[[[1-[3-(trifluoromethyl)phenyl]-ethylidene]amino]oxy]methyl]phenyl]- 3H-1,2,4-triazol-3-one; the reaction of 5-chloro-2, 4-dihydro-2-methyl-4-[2-[[[[1-[3(trifluoromethyl)phenyl]-ethylidene]amino]oxy]methyl]phenyl]- 3H-1,2,4-triazol-3-one with 1-[3,5-(bistrifluoromethyl)phenyl]ethanone oxime in the presence of a base and the subsequent reaction of the product of that reaction with methanol to form 5-chloro-2, 4-dihydro-2-methyl-4-[2-[[[[1-[3(trifluoromethyl)phenyl]-ethylidene]amino]oxy]methyl]phenyl]-3H-1,2,4-triazol-3-one.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24]([N:26]1[CH2:30][CH2:29][C:28]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)([C:31]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[N:38]([Si](C(C)C)(C(C)C)C(C)C)[CH:37]=[CH:36]3)=[O:32])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[C:19]([O:23][C:24]([N:26]1[CH2:30][CH2:29][C:28]([CH2:52][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)([C:31]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[NH:38][CH:37]=[CH:36]3)=[O:32])[CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(C(=O)C3(Cc4ccccc4)CCN(C(=O)OC(C)(C)C)C3)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(C(=O)c2ccc3[nH]ccc3c2)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92.9 %

Procedure:
A solution of tetrabutylammonium fluoride (1.0 M in THF, 1.2 mL) was slowly added at 0° C. to a solution of 3-benzyl-3-(1-triisopropylsilanyl-1H-indole-5-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (670 mg, 1.19 mmol) in THF (15 mL). The resulting bright yellow mixture was stirred at 0° C. for 20 minutes, then was quenched by addition of water. The resulting mixture was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (30% to 50% of EtOAc in hexane) to give 447 mg (93% yield) of 3-benzyl-3-(1H-indole-5-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a white foam.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)=O>CC(=O)OCC>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1
Reactant: O=C(c1ccccc1)c1ccc2nc(NC(=O)C(F)(F)F)c(-c3cccc(F)c3)n2c1
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(C(=O)c3ccccc3)cn2c1-c1cccc(F)c1

Procedure:
The 2-trifluoroacetamido-3-(3-fluorophenyl)-6-benzoyl-imidazo[1,2-a]pyridine (14.3 g, 33.6 mmol) was converted to product in a manner substantially analogous to Example 56 to yield 8.30 g. (74.7%). EA, MS(FD).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:20]([C:27]1[C:32]([Br:33])=[CH:31][N:30]=[C:29]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=2)[N:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O[CH2:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.N(C(OCC)=O)=NC(OCC)=O.Cl>C(Cl)Cl>[NH:20]([C:27]1[C:32]([Br:33])=[CH:31][N:30]=[C:29]([NH:34][C:35]2[CH:36]=[CH:37][C:38]([O:41][CH2:43][CH2:44][CH2:45][N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:39][CH:40]=2)[N:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCCCN1CCOCC1
Reactant: Oc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Brc1cnc(Nc2ccc(OCCCN3CCOCC3)cc2)nc1Nc1ccccc1
Reaction time: 0.5 h
Yield: 11.6 %

Procedure:
Triphenylphosphine (400 mg, 1.5 mmol) was added to a stirred solution of 4-anilino-5-bromo-2-(4-hydroxyanilino)pyrimidine (Method 4, 178 mg, 0.5 mmol) in DCM (40 ml) and the solution was stirred for 30 minutes. A solution of 4-(3-hydroxypropyl)morpholine (80 mg, 1.5 mmol) in DCM (2 ml) was added and the solution was stirred for 2 minutes. Diethyl azodicarboxylate (0.25 ml, 1.5 mmol) was added dropwise and the mixture was stirred for 20 hours. Volatile material was removed by evaporation and the residue was dissolved into ethyl acetate (100 ml). The solution was washed with water (2×50 ml) and then extracted with 2M hydrochloric acid (2×30 ml). The combined acidic extracts were washed with ethyl acetate (2×50 ml) and then basified by addition of 0.88 ammonia solution. The basified solution was extracted with ethyl acetate (2×50 ml) and the extracts were washed with water (2×50 ml) and saturated sodium chloride (2×50 ml) and dried. Volatile material was removed by evaporation and the residue was loaded on a Varian Mega Bond Elut column. Elution with 0-10% methanol in ethyl acetate and evaporation of the appropriate fractions gave an oil, which was treated with methanolic hydrogen chloride. Volatile material was removed by evaporation and the residue was recrystallized from a mixture of methanol and ether to give the product as a dihydrochloride salt (28 mg). NMR: 2.2 (m, 2H), 3.1 (m, 2H), 3.2 (m, 2H), 3.4 (d, 2H), 3.8-4.1 (m, 6H), 6.8 (d, 2H), 7.2-7.3 (t, 1H), 7.3-7.5 (m, 4H), 7.6 (d, 2H), 8.4 (s, 1H), 9.5 (br s, 1H), 10.1 (br s, 1H), 11.3 (br s, 1H); MS (MH+): 484, 486.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:10])[CH2:8]Br)[N:6]=1.O[CH2:12][CH2:13][NH:14][CH:15]([CH3:29])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=1.C(=O)([O-])O.[K+].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>CC(C)=O>[C:25]([CH2:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH:15]([N:14]2[CH2:13][CH2:12][O:10][CH:7]([C:5]3[N:6]=[C:2]([Cl:1])[S:3][CH:4]=3)[CH2:8]2)[CH3:29])=[CH:18][CH:19]=1)([O:27][CH3:28])=[O:26]
Reactant: O=C(CBr)c1csc(Cl)n1
Reactant: COC(=O)COc1ccc(CC(C)NCCO)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)COc1ccc(CC(C)N2CCOC(c3csc(Cl)n3)C2)cc1

Procedure:
Prepared by analogy to Example 32 by reaction of 5 g (0.0208 mol) of 2-chloro-4-bromoacetyl-thiazole with 5.6 g (0.021 mol) of N-(2-hydroxyethyl)-2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine in 200 ml of acetone and 6.3 g (0.063 mol) of potassium hydrogen carbonate over 20 hours at room temperature. The reduction is carried out in 41 ml of trifluoroacetic acid using 3.5 g (0.029 mol) of triethylsilane for 24 hours. The crude product is purified on a silica gel column using methylene chloride/methanol=20:1 as eluant.