Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C@H:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C@H:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: O=C(Cl)c1ccc(I)cc1
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(I)cc1)C(=O)OCC
Yield: 56 %

Procedure:
Diethyl N-(4-iodobenzoyl)-L-glutamate is prepared from 4-iodobenzoyl chloride and diethyl L-glutamate in 56% yield by the same method. m.p. 105°-106° C.; NMR (CDCl3, 300 MHz) delta 1.26 (t, 3H, J=7.2 Hz), 1.33 (t, 3H, J=7.2 Hz), 2.11-2.60 (m, 4H), 4.14 (q, 2H, J=7.2 Hz), 4.78 (m, 1H), 7.15 (d, 1H, J=7.2 Hz), 7.58 (d, 2H, J=8.4 Hz), 7.83 (d, 2H, J=8.4 Hz).
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]#[CH:20])[C:11](Cl)=[O:12].[CH:21]1([C@@H:27]([NH2:29])[CH3:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C>C(OCC)(=O)C>[CH:21]1([C@@H:27]([NH:29][C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]#[CH:20])=[C:8]([O:7][CH3:6])[CH:9]=2)[CH3:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C[C@H](N)C1CCCCC1
Reactant: C#CCOc1ccc(C(=O)Cl)cc1OC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#CCOc1ccc(C(=O)N[C@@H](C)C2CCCCC2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.3 %

Procedure:
To a mixture of 10 ml of THF and 0.30 g of 3-methoxy-4-(2-propynyloxy)benzoyl chloride were added 0.21 g of (1S)-1-(cyclohexyl)ethylamine and 0.20 g of triethylamine in order at room temperature. The mixture obtained was stirred at room temperature for 4 hours. Then, ethyl acetate was added to the reaction mixture and the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was washed with methyl tert-butyl ether and hexane to obtain 0.33 g of N-((1S)-1-cyclohexylethyl)-4-(2-propynyloxy)-3-methoxybenzamide (hereinafter, described as the compound 21 of the present invention) represented by the formula:
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:10][C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]([N+:22]([O-:24])=[O:23])=[C:13](F)[C:12]=1[F:26]>>[F:26][C:12]1[C:11]([F:10])=[CH:16][C:15]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:14]([N+:22]([O-:24])=[O:23])[C:13]=1[NH:4][C:3]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=1[F:1]
Reactant: COCCOc1cc(F)c(F)c(F)c1[N+](=O)[O-]
Reactant: Nc1ccc(I)cc1F
Product: COCCOc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Yield: 32 %

Procedure:
2-Fluoro-4-iodoaniline (1.6 g, 6.8 mmol) and 1,2,3-trifluoro-5-(2-methoxyethoxy)-4-nitrobenzene (1.7 g, 6.8 mmol) were reacted using the condition described in Example 1 (Step A) to form the title compound (1.02 g, 32%); m/z=467 [M-1].
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([N:18]([CH3:20])[CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]([C:29]3[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[OH:22])[CH:8]=2)[N:3]=1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36].CC[O-].[Na+].C[O-].[Na+]>CCO.CO>[CH3:19][N:18]([CH3:20])[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]([C:29]3[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=3)([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[OH:22])[CH:8]=2)[N:3]=[C:2]([O:36][CH2:35][CH3:37])[C:11]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]
Reactant: CN(C)c1c(-c2ccccc2)c(Cl)nc2ccc(C(O)(c3ccncc3)c3cncn3C)cc12
Agent: CC[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCOc1nc2ccc(C(O)(c3ccncc3)c3cncn3C)cc2c(N(C)C)c1-c1ccccc1

Procedure:
The title compound was prepared using (2-chloro-4-(dimethylamino)-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-4-yl)methanol (Example 47) and NaOEt in EtOH in place of (3-chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(pyridin-3-yl)methanol and NaOMe in MeOH, respectively, according to the procedure described in Example 79. 1H NMR (400 MHz, MeOH-d4) δ 9.07 (s, 1H), 8.82 (d, J=5.62 Hz, 2H), 8.09 (s, 1H), 7.99 (d, J=5.38 Hz, 2H), 7.87 (d, J=8.56 Hz, 1H), 7.63 (dd, J=1.96, 8.56 Hz, 1H), 7.41-7.48 (m, 2H), 7.39 (d, J=7.09 Hz, 1H), 7.24 (d, J=7.82 Hz, 2H), 7.17 (s, 1H), 4.42 (q, J=7.01 Hz, 2H), 3.72 (s, 3H), 2.57 (s, 6H), 1.24 (t, J=6.97, 3H); MS m/e 480.3 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:21]1[S:25][C:24]([C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=2)=[N:23][CH:22]=1)CCC>>[CH3:15][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:6]2[N:7]=[C:2]([C:21]3[S:25][C:24]([C:26]4[CH:27]=[CH:28][C:29]([C:30]#[N:31])=[CH:32][CH:33]=4)=[N:23][CH:22]=3)[CH:3]=[CH:4][CH:5]=2)[CH:14]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(-c2ccc(C#N)cc2)s1
Reactant: Cc1ccnc(Nc2cccc(Br)n2)c1
Product: Cc1ccnc(Nc2cccc(-c3cnc(-c4ccc(C#N)cc4)s3)n2)c1

Procedure:
By following essentially the same procedure in preparative example 020 and starting with 6-bromo-N-(4-methylpyridin-2-yl)pyridin-2-amine (100 mg 0.38 mmol) and 4-(5-(tributylstannyl)thiazol-2-yl)benzonitrile (328 mg, 0.69 mmol), the 4-(5-(6-(4-methylpyridin-2-ylamino)pyridin-2-yl)thiazol-2-yl)benzonitrile was obtained and purified by dry flash chromatography over SiO2 eluting with EtOAc/Cyclohexane 50/50-MeOH (5%) and by trituration with Et2O (51 mg, 37%). 1H NMR (300 MHz, DMSO-d6) δ 9.77 (br s, 1H), 8.65 (s, 1H), 8.20-8.10 (m, 3H), 8.00 (d, J=8.4 Hz, 2H), 7.93 (br s, 1H), 7.75 (t, J=7.9 Hz, 1H), 7.55 (d, J=7.4 Hz, 1H), 7.50 (d, J=8.3 Hz, 1H), 6.80 (d, J=5.1 Hz, 1H), 2.39 (s, 3H). (APCI+) m/z 370 (M+H)+.
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([CH:10]3[O:15][CH2:14][C:13](=O)[N:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11]3)[CH:7]=[CH:6][C:5]=12.S(C)C.CO>O1CCCC1>[N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([CH:10]3[O:15][CH2:14][CH2:13][N:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11]3)[CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)N1CC(c2ccc3nnnn3c2)OCC1=O
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: CC(C)(C)N1CCOC(c2ccc3nnnn3c2)C1
Yield: 100.3 %

Procedure:
To a solution of 2-(tetrazolo[1,5-a]pyrid-6-yl)-4-(1,1-dimethylethyl)-5-oxo-morpholine (2.09 g) in 100 ml of dry tetrahydrofuran (THF), a 2.0M solution of BH3.Me2S in tetrahydrofuran (10 ml) was added dropwise under nitrogen. The reaction mixture was then heated at reflux for 5 hours. The mixture was cooled and treated with 25 ml of methanol. The mixture was then heated at reflux for 3 hours. The solution was concentrated under reduced pressure and the residue (2.45 g) purified by column chromatography (95:5 methylene chloride:ethanol) on silica gel to give 1.99 g of product. Mass spectrum (FAB) 262 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([Cl:19])[CH:13]=2)[CH:3]=1.[NH2:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24]>>[ClH:1].[Cl:19][C:14]1[CH:13]=[C:12]([C:4]2[CH:3]=[C:2]([NH:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=[CH:16][C:15]=1[CH3:18]
Reactant: Cc1ccc(-c2cc(Cl)c3ccccc3n2)cc1Cl
Reactant: NCC(O)CO
Product: Cc1ccc(-c2cc(NCC(O)CO)c3ccccc3n2)cc1Cl
Product: Cl

Procedure:
The title compound, m.p. 230-231° C. and MS: m/e=343.1 (M+H+), was prepared from 4-chloro-2-(3-chloro-4-methyl-phenyl)-quinoline and (RS)-3-amino-1,2-propandiol.
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.N1C=CC=CC=1.C(N(CC)CC)C.[CH2:20]([O:22][C:23]([C:25]1[CH:26]=[N:27][NH:28][C:29]=1[C:30]([F:33])([F:32])[F:31])=[O:24])[CH3:21]>C1COCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:20]([O:22][C:23]([C:25]1[C:29]([C:30]([F:32])([F:33])[F:31])=[N:28][N:27]([CH:1]2[CH2:3][CH2:2]2)[CH:26]=1)=[O:24])[CH3:21]
Reactant: CCOC(=O)c1cn[nH]c1C(F)(F)F
Reactant: OB(O)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)c1cn(C2CC2)nc1C(F)(F)F
Temperature: 60 °C
Reaction time: 36 h
Yield: 29 %

Procedure:
Cyclopropyl boronic acid (11 g, 127 mmol), Copper acetate (17.4 g, 95.7 mmol), Pyridine (17.7 g, 223 mmol) and triethylamine (22.4 mL, 160 mmol) were added successively to a solution of 5-Trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (Preparation 143, 6.63 g, 31.9 mmol) in THF (70 mL) and the resulting mixture was allowed to stir at 60° C. for 36 hours. The reaction mixture was filtered over a celite bed and filtrate was concentrated in vacuo and diluted with EtOAc (200 mL). The organic layer was washed with 1N HCl (1×25 mL), brine (1×25 mL) and dried (Na2SO4) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (Hexane:EtOAc 85:15) to afford the title compound as brown solid in 29% yield, 2.3 g.
Reaction SMILES: ClC(OCC)=O.[C:7]([O:11][C:12](=[O:29])[C@@H:13]([NH:19][C:20]([O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])[CH2:14][CH2:15][C:16](O)=[O:17])([CH3:10])([CH3:9])[CH3:8].CN1CCOCC1.[BH4-].[Na+]>C1COCC1.O>[OH:17][CH2:16][CH2:15][CH2:14][C@@H:13]([C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:29])[NH:19][C:20]([O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])=[O:21]
Reactant: CC(C)(C)OC(=O)[C@H](CCC(=O)O)NC(=O)OCC[Si](C)(C)C
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)[C@H](CCCO)NC(=O)OCC[Si](C)(C)C
Temperature: 0 °C
Yield: 97.1 %

Procedure:
Ethyl chloroformate (0.441 ml, 4.59 mmol) was added slowly to a stirred solution of (4S)-5-tert-butoxy-5-oxo-4-({[2-(trimethylsilyl)ethoxy]carbonyl}amino) pentanoic acid (1.33 g, 3.83 mmol) and N-methylmorpholine (0.547 ml, 4.98 mmol) in THF (10 ml) at −20° C. A thick white solid precipitated from the solution and hindered stirring. THF (ca. 4 ml) was added to mobilise the suspension. The resulting mixture was stirred at −20° C. for 30 min, then allowed to warm slowly to 0° C. over the course of 2 h. The mixture was therefore stirred at 0° C. for a further 1 h. The slurry was filtered and the filtrate added portion wise over 30 min to a stirred solution of sodium borohydride (0.434 g, 11.48 mmol) in THF (4 ml) and water (1 ml) at 0° C. The mixture was quenched with NH4Cl solution, diluted with Et2O (50 ml) and the phases separated. The aqueous phase was extracted with Et2O (25 ml) and the combined organic phases were washed with NaHCO3 solution (25 ml) and brine (25 ml), dried (MgSO4) and evaporated to give tert-Butyl 5-hydroxy-N-{[2-(trimethylsilyl)ethoxy]carbonyl}-L-norvalinate (1.24 g) as a clear colourless oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([N:18]1[CH2:23][C:22](=[O:24])[N:21]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20][C:19]1=[O:32])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Br[CH:34]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1.CN(C)C=O>[CH2:25]([N:21]1[CH2:20][C:19](=[O:32])[N:18]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:23]([CH:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:22]1=[O:24])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: O=C1CN(Cc2ccccc2)C(=O)CN1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1C(C(c2ccccc2)c2ccccc2)N(Cc2ccccc2)C(=O)CN1Cc1ccccc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.0M in tetrahydrofuran) (77 ml) was added portionwise to a stirred solution of 1,4-dibenzyl-2,5-piperazinedione (20.6 g) in a mixture of tetrahydrofuran (400 ml) and N,N-dimethylformamide (200 ml) at 0° C. The whole was stirred at 5° C. for 1 hour and thereto a solution of bromodiphenylmethane (19 g) in tetrahydrofuran (100 ml) was added at −78° C. and the mixture was stirred for 2 hours at the same temperature. After being stirred at 5° C. for 2 hours, the mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with a mixed solvent of ethyl acetate and isopropyl alcohol, and the resulting solid was collected by filtration to give 1,4-dibenzyl-3-benzhydryl-2,5-piperazinedione (10.55 g) as a colorless powder.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:12][CH:11]=1.C(O)(C)(C)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:9][C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[CH:12][CH:11]=1
Reactant: Cc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 40 %

Procedure:
N-Bromosuccinimide (NBS) (35.8 g, 0.20 mol) was added in several portions to a solution of 1,1-dimethylethyl 4-methylbenzoate (prepared by the reaction of the respective acid chloride with t-butanol.) (38.0 g, 0.20 mol) and benzoyl peroxide (0.36 g. 1.5 mmol) in carbon tetrachloride (1200 mL) at vigorous reflux. Another portion of benzoyl peroxide (0.36 g. 1.5 mmol) was added just before the final addition of NBS. After the foaming subsided, the reaction mixture was cooled to room temperature, washed with water (2×60 mL) and dried over magnesium sulfate. Filtration and concentration provided an oil that was purified by HPLC on silica gel eluting with a mixture of hexanes and ethyl acetate to give 1,1-dimethylethyl 4-bromomethylbenzoate (21.4 g) in 40% yield.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:26]=[C:25]([C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37]C(C3C=CSC=3)=O)[CH:32]=2)=[O:28])[CH:24]=[C:23]([Cl:45])[C:5]=1[C:6]([NH:8][C@H:9]([C:19]([O:21]C)=[O:20])[CH2:10][NH:11][C:12]([C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)=[O:13])=[O:7].ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=C(Cl)C=1C(N[C@H](C(OC)=O)CNC(C1C=CSC=1)=O)=O>CO>[Cl:3][C:4]1[CH:26]=[C:25]([C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=2)=[O:28])[CH:24]=[C:23]([Cl:45])[C:5]=1[C:6]([NH:8][C@H:9]([C:19]([OH:21])=[O:20])[CH2:10][NH:11][C:12]([C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)=[O:13])=[O:7]
Reactant: COC(=O)[C@H](CNC(=O)c1ccsc1)NC(=O)c1c(Cl)cc(C(=O)NCc2cccc(OC(=O)c3ccsc3)c2)cc1Cl
Agent: COC(=O)[C@H](CNC(=O)c1ccsc1)NC(=O)c1c(Cl)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NCc1cccc(O)c1)c1cc(Cl)c(C(=O)N[C@@H](CNC(=O)c2ccsc2)C(=O)O)c(Cl)c1
Reaction time: 8 h
Yield: 130.4 %

Procedure:
An aqueous solution of sodium hydroxide (1 M; 0.305 Ml, 0.305 mmol) was added to a solution of N-[2,6-dichloro-4-[[[[3-[(thiophene-3-carbonyl)oxy]phenyl]methyl]amino]carbonyl]benzoyl]-3-[(thiophene-3-carbonyl)amino]-L-alanine, methyl ester (101 mg, 0.153 mmol) in methanol (2 Ml). The solution was allowed to stir overnight and then concentrated. An aqueous solution of sodium hydroxide (1 M; 0.210 Ml, 0.210 mmol) was added to a solution of N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]-benzoyl]-3-[(thiophene-3-carbonyl)amino]-L-alanine, methyl ester (58 mg, 0.105 mmol) in methanol (2 Ml). The solution was allowed to stir overnight and then concentrated. The residues from the two reactions were purified by HPLC and lyophilized to give N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]-benzoyl]-3-[(thiophene-3-carbonyl)amino]-L-alanine (107 mg, 78%) as a white solid.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[CH3:5][N:6]([CH3:19])[C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[CH:10]=O.C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH3:5][N:6]([CH3:19])[C:7]1[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[C:9]([CH:10]=[CH:4][N+:1]([O-:3])=[O:2])[CH:8]=1
Reactant: C[N+](=O)[O-]
Reactant: CN(C)c1cc(C=O)cc(C(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CN(C)c1cc(C=C[N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 110 °C
Yield: 36.8 %

Procedure:
Nitromethane (0.473 g) is added to a solution of 3-dimethylamino-5-trifluoromethyl-benzaldehyde (0.885 g) and ammonium acetate (0.339 g) in acetic acid (3.4 mL) and the solution is heated at 110° C. for 6 hours. The reaction mixture is cooled to 0° C. and a solid forms which is filtered and washed with 1:1 water-acetic acid. This solid is recrystallized from ethanol to provide the desired product as a red solid (0.39 g).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][O:7][C@H:8]1[O:13][C@H:12]([CH3:14])[CH2:11][N:10](CC=C)[C@@H:9]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(#N)C.O>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C(Cl)Cl.C(#N)C>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=1)[CH2:6][O:7][C@H:8]1[O:13][C@H:12]([CH3:14])[CH2:11][NH:10][C@@H:9]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C=CCN1C[C@@H](C)O[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccccc1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: C[C@@H]1CN[C@H](c2ccccc2)[C@@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)O1
Yield: 27.8 %

Procedure:
A similar reaction was carried out using 55 mg (0.12 mmol) of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-4-(2-propenyl)-6-(R)-methyl morpholine (from Example 23, Step A) and 111 mg (0.12 mmol) of tris(triphenylphosphine)rhodium chloride in 12 mL of 4:1 v/v acetonitrile/water. Flash chromatography on 4 g of silica gel using 50:1 v/v methylene chloride/acetonitrile as the eluant afforded 14 mg (28%) of 2-(S)-(3,5-bis(trifluoromethyl)-benzyloxy)-3-(R)-phenyl-6-(R)-methyl morpholine as an oil.
Reaction SMILES: [OH-:1].[K+].[CH3:3][C:4]1[N:8]([CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[C:7]2[CH:20]=[C:21]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:22]=[C:23]([C:24]#[N:25])[C:6]=2[N:5]=1.OO>O.C1COCC1>[CH3:3][C:4]1[N:8]([CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[C:7]2[CH:20]=[C:21]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:22]=[C:23]([C:24]([NH2:25])=[O:1])[C:6]=2[N:5]=1
Reactant: Cc1nc2c(C#N)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Reactant: [OH-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2c(C(N)=O)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 35 °C
Yield: 72 %

Procedure:
A solution of KOH (45 mg, 0.8 mmol) in water (10 mL) was added dropwise to solution of 2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole-4-carbonitrile (prepared using the same procedure as Example 24, 150 mg, 0.4 mmol) and 30% H2O2 (3 ml) in THF (15 mL) at rt. The mixture was heated to 35° C. for 1 h. When TLC showed no starting material remaining, water (50 mL) was added, then it was filtered. The filter cake was purified by silica gel chromatography eluted with petroleum ether:EtOAc=1:2 to give the product (115 mg, 72%), as a white solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 2.47 (s, 3H), 3.05 (t, 4H, J=4.8 Hz), 3.69 (t, 4H, J=4.8 Hz), 6.05 (s, 2H), 6.34 (d, 1H, J=7.2 Hz), 7.25 (d, 1H, J=2.4 Hz), 7.34 (t, 1H, J=7.8 Hz), 7.53 (d, 1H, J=2.4 Hz), 7.63-7.70 (m, 2H,), 7.77 (d, 1H, J=3.0 Hz), 7.86 (d, 1H, J=8.1 Hz), 8.01 (d, 1H, J=7.2 Hz), 8.24 (d, 1H, J=8.1 Hz), 9.24 (d, 1H, J=3.0 Hz); LC-MS: m/e=401 [M+1]+
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[CH3:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26]>O1CCOCC1.CC#N>[F:8][C:7]1[C:2]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[CH3:22])=[C:3]([S:9]([NH:21][C:18]2[CH:19]=[N:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)(=[O:11])=[O:10])[CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(N)cn1
Reactant: O=S(=O)(Cl)c1cccc(F)c1F
Reactant: Cc1ccccc1CN
Solvent: CC#N
Solvent: C1COCCO1
Product: COc1ccc(NS(=O)(=O)c2cccc(F)c2NCc2ccccc2C)cn1
Yield: 10.3 %

Procedure:
The title compound (139 mg, 0.35 mmol) was prepared in two steps from 2,3-difluorobenzenesulfonyl chloride (1.0 g, 4.7 mmol) and 6-methoxypyridin-3-amine (642 mg, 5.2 mmol) in 1,4-dioxane at 100° C.; followed by 2-methylbenzyl amine (425 uL, 3.4 mmol) in MeCN (3 mL) at 180° C. in a Biotage Initiator microwave reactor using the methods of (IntB1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:19])[N:5]=[C:6]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)(=[O:11])=[O:10])[N:7]=1.[CH2:20]([N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[CH2:31]Cl)[CH3:21].C(N(CC)CC)C.[I-].[Na+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:19])[N:5]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH2:31][C:23]3[N:22]([CH2:20][CH3:21])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[N:7]=1
Reactant: Cc1cc(C)nc(NS(=O)(=O)c2ccc(N)cc2)n1
Reactant: CCn1c(CCl)nc2ccccc21
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCn1c(CNc2ccc(S(=O)(=O)Nc3nc(C)cc(C)n3)cc2)nc2ccccc21

Procedure:
32.4 mg (0,12 mmol) sulfamethazine and 36 mg (0.18 mmol) 1-ethyl-2-chloromethylbenzimidazole were dissolved in 4 ml methanol. 64 μl (0.44 mmol) triethylamine and catalytic amount of sodium iodide were added to the reaction mixture. Solution was stirred and refluxed overnight. The reaction mixture was then evaporated to dryness, and purified on silica using gradient elution (chloroform to 5% methanol in chloroform) to provide white crystals of the title compound, 10 mg (20%). 1H NMR (DMSO-d6, 500 MHz): 7.68 (2H, m), 7.60 (1H, m), 7.52 (1H, m), 7.22 (1H, m), 7.17 (1H, m), 7.00 (1H, br, s), 6.78 (3H, m), 6.60 (1H, br, s), 4.60 (2H, m), 4.30 (2H, q, 7.2 Hz), 2.18 (6H, s), 1.28 (3H, t, 7.2 Hz); MS (ESI+): m/z 437 (M+H)+.
Reaction SMILES: [C:1]([O:6]C)(=O)[C:2]#[C:3][CH3:4].[CH2:8]([Mg]Br)[CH3:9].[Cl-].[NH4+].[CH3:14][CH2:15]OCC>>[CH2:14]([C:1]([OH:6])([CH2:8][CH3:9])[C:2]#[C:3][CH3:4])[CH3:15]
Reactant: CC[Mg]Br
Reactant: CCOCC
Reactant: CC#CC(=O)OC
Agent: [Cl-]
Agent: [NH4+]
Product: CC#CC(O)(CC)CC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of methyl 2-butynoate (1.5 g) in ether (50 ml) was cooled to 0°, treated with ethyl magnesium bromide (21 ml of a 3M solution in ether) and stirred at room temperature for 4 hours. The mixture was then cooled to 0° and treated with saturated ammonium chloride solution, whereafter the product was extracted into ether and the title compound (1.2 g) was isolated by chromatography. IR (CCl4) νmax 2200 (C≡C), 3450 cm-1 (OH); NMR (CCl4) δ 1.83 (s, H3C--C≡), 2.3 (s), 1.36-1.6 (m, CH2CH3), 0.93 (t, CH3CH2).