Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:32]([NH:31][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:33])=[CH:3][CH:4]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Solvent: C1CCOC1
Product: O=C1CC(=O)N(c2ccc(NC(=O)Nc3ccccc3)cc2)c2ccc3ccccc3c2N1
Temperature: 65 °C
Yield: 20.6 %

Procedure:
A suspension of 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.10 mmol) obtained in Example 1, (3) in anhydrous tetrahydrofuran (10 mL) was added with phenyl isocyanate (27 μL, 0.25 mmol), the mixture was refluxed by heating at 65° C. for 4 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=50/1) to obtain the title compound (9 mg, yield 21%) as white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([CH3:23])[N:15]=1)[CH2:8][CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:24])[N:7]([CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([CH3:23])[N:15]=1)[CH2:8][CH2:9][CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCN(CCOc1ccc([N+](=O)[O-])c(C)n1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCCN(CCOc1ccc(N)c(C)n1)C(=O)OC(C)(C)C
Yield: 84.5 %

Procedure:
A solution of [2-(6-methyl-5-nitro-pyridin-2-yloxy)-ethyl]-propyl-carbamic acid tert-butyl ester (300 mg, 0.88 mmol) in methanol (10 ml) was hydrogenated using the ThalesNano H-Cube® hydrogenation reactor employing a 10% palladium on charcoal catalyst cartridge. After concentration of the solution under reduced pressure, 230 mg (84.2%) of the title compound were obtained.
Reaction SMILES: O.[C:2]([OH:14])(=[O:13])[CH2:3][C:4]([CH2:9][C:10]([OH:12])=O)(C(O)=O)O.S(=O)(=O)(O)O.S(O)(O)(=O)=O.[CH2:25]([N:27]([CH2:31][CH3:32])[C:28]([NH2:30])=[NH:29])[CH3:26].N>O>[OH:12][C:10]1[CH:9]=[C:4]([CH2:3][C:2]([OH:14])=[O:13])[N:30]=[C:28]([N:27]([CH2:31][CH3:32])[CH2:25][CH3:26])[N:29]=1
Reactant: CCN(CC)C(=N)N
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: CCN(CC)c1nc(O)cc(CC(=O)O)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Powdered citric acid monohydrate (42.0 g) was added in small portions over one hour to concentrated sulphuric acid (180 ml) at 0° C and the mixture stirred until a clear solution was obtained. N,N-Diethylguanidine sulphate (32.8 g) was added over 15 minutes and the solution stirred for one hour at the ambient temperature (ca 22°-24° C) and then at 90° C for a further 2 hours. After dilution of the mixture with deionised water (1050 ml), ammonia solution (s.g. 0.880) was added to adjust the pH to 4, and the mixture cooled to 0° C for one hour. The precipitate was collected by filtration, washed with ice-water (20 ml), acetone (100 ml), and with ether (100 ml) to yield 4-hydroxy-2-diethylaminopyrimidin-6-yl acetic acid as a white powder, having a melting point (with decomposition) of 156°-157° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.[CH3:17][O:18][C:19](=[O:30])[N:20]([CH2:28]Cl)[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1>C1C=CC=CC=1>[CH3:17][O:18][C:19](=[O:30])[N:20]([CH2:28][O:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: COC(=O)N(CCl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COC(=O)N(COc1ccc(Cl)cc1Cl)c1ccc(Cl)cc1

Procedure:
A solution of 16.3 g (0.1 mole) of 2,4-dichlorophenol and 14 ml (0.1 mole) of triethylamine in 100 ml of benzene was added dropwise, over the course of 15 minutes, to a solution of 23.4 g (0.1 mole) of Methyl-N-chloromethyl-N-(4-chlorophenyl)-carbamate in 200 ml of dry benzene. Thereafter the triethylamine hydrochloride was filtered off, the filtrate was washed with 5% strength sodium hydroxide solution and water, and after drying over calcined sodium sulphate the benzene was distilled off under reduced pressure. 52.4 g (92% of theory) of Methyl-N-(2,4-dichlorophenoxymethyl)-N-(4-chlorophenyl)-carbamate, melting at 70° - 80° C after recrystallization from ethanol, were obtained.
Reaction SMILES: OCCN[C:5](=[O:9])[C:6]([NH2:8])=[O:7].[NH2:10][C:11]([CH3:15])([CH3:14])[CH2:12][OH:13]>>[OH:13][CH2:12][C:11]([NH:10][C:5](=[O:9])[C:6]([NH2:8])=[O:7])([CH3:15])[CH3:14]
Reactant: NC(=O)C(=O)NCCO
Reactant: CC(C)(N)CO
Product: CC(C)(CO)NC(=O)C(N)=O
Yield: 96 %

Procedure:
Prepared as in Intermediate 3, using 2-amino-2-methylpropanol. The product did not precipitate out, even on adding diethyl ether. The solution was passed through a SCX cartridge, to remove excess amine, then evaporated to give the title compound as a white powder (1.54 g, 96% ); NMR [(CD3)2SO] 1.25 (6H, s), 3.36 (2H, d), 5.07 (1H, t), 7.74 (1H, s), 7.78 (1H, br s), and 8.04 (1H, br s).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH2:19](O)[CH3:20]>>[CH3:6][C:7]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=1[C:9]([O:11][CH2:19][CH3:20])=[O:10]
Reactant: CCO
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1C

Procedure:
Concentrated sulfuric acid (12 ml) was added to a solution of 2-methyl-5-nitrobenzoic acid (10.87 g) in ethanol (60 ml). The mixture was heated under reflux overnight. The reaction solution was concentrated under the reduced pressure. Water was then added to the residue. The mixture was extracted with diethyl ether. The extract was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to give ethyl 2-methyl-5-nitrobenzoate (11.86 g).
Reaction SMILES: C[Al](C)C.[NH:5]1[CH2:10][CH2:9][S:8][CH2:7][CH2:6]1.C[O:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:23]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)=[N:24][O:25][C:26]=2[CH3:27])=[N:16][CH:15]=1.O>O1CCOCC1>[F:34][C:30]1[CH:29]=[C:28]([C:23]2[C:22]([CH2:21][O:20][C:17]3[N:16]=[CH:15][C:14]([C:13]([N:5]4[CH2:10][CH2:9][S:8][CH2:7][CH2:6]4)=[O:12])=[CH:19][CH:18]=3)=[C:26]([CH3:27])[O:25][N:24]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Reactant: C1CSCCN1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc(C(=O)N2CCSCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 600 μL, 1.2 mmol) was added dropwise (exothermic) to a solution of thiomorpholine (124 mg, 120 μL, 1.2 mmol) in dioxane (7.5 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (103 mg, 0.3 mmol) in dioxane (4 mL) was added. The resulting mixture was then heated at 85-95° C. for 4 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:3) afforded the title compound (124 mg, 100%) which was obtained as a light yellow gum. MS: m/e=414.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:63]1[CH2:68][CH:67]=[CH:66][CH2:65][CH2:64]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:63]1[CH2:64][CH:65]=[CH:66][CH2:67][CH2:68]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: C1=CCNCC1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CC=CCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 1,2,3,6-tetrahydropyridine in DMSO at ambient temperature.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][N:9]2[C:17]([CH2:18]O)=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][C:14]=3[NH2:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Br)(Br)[Br:22]>C(Cl)Cl>[CH:1]1([CH2:7][CH2:8][N:9]2[C:17]([CH2:18][Br:22])=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][C:14]=3[NH2:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ncnc2c1nc(CO)n2CCC1CCCCC1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Nc1ncnc2c1nc(CBr)n2CCC1CCCCC1

Procedure:
A solution of N9-cyclohexylethyl-8-hydroxymethyladenine (1 mmol) in methylene chloride was treated with PBr3 (1 mmol) at 25° C. for 1 h. Extraction and chromatography give N9-cyclohexylethyl-8-bromomethyl-adenine as a white solid.
Reaction SMILES: Cl[C:2]1SC2C(O)=C(C(OC)=O)N(C)S(=O)(=O)C=2C=1.NC1C=CC=CN=1.[Cl:26][C:27]1[S:31][C:30]([C:32]([OH:34])=[O:33])=[C:29]([S:35](=[O:39])(=[O:38])[NH:36][CH3:37])[CH:28]=1.C.ClC1SC2C(O)=C(C(=O)NC3C=CC=CN=3)N(C)S(=O)(=O)C=2C=1>OCC(CO)O.C1(C)C(C)=CC=CC=1>[Cl:26][C:27]1[S:31][C:30]([C:32]([O:34][CH3:2])=[O:33])=[C:29]([S:35](=[O:38])(=[O:39])[NH:36][CH3:37])[CH:28]=1
Reactant: CNS(=O)(=O)c1cc(Cl)sc1C(=O)O
Reactant: COC(=O)C1=C(O)c2sc(Cl)cc2S(=O)(=O)N1C
Agent: CN1C(C(=O)Nc2ccccn2)=C(O)c2sc(Cl)cc2S1(=O)=O
Agent: Nc1ccccn1
Solvent: Cc1ccccc1C
Solvent: OCC(O)CO
Product: CNS(=O)(=O)c1cc(Cl)sc1C(=O)OC
Reaction time: 12 h

Procedure:
1200 ml. of absolute xylene are placed in a 2 liter volume flask and 11 g. of 6-chloro-4-hydroxy-2-methyl-3-methoxycarbonyl-2H-thieno[2,3-e]-1,2-thiazine-1,1-dioxide are added while stirring. 4.42 g. of 2-aminopyridine are next added and the solution is then boiled under reflux until all the starting product has been shown by thin layer chromatography to have reacted (about 4 hours). A gentle stream of nitrogen is passed through the mixture during boiling under reflux, in order to entrain the methanol that is formed. After the end of the reaction, the solution is cooled to about 120°, activated charcoal is added, and the solution is boiled for an additional short time. A hot water funnel is filled with glycerol and preheated to 120°, and the hot reaction solution at 120° is then filtered through this funnel. When the temperature of the solution has fallen to 70°, the solution is then scratched, whereupon small orange crystals begin to separate out. When cold, the solution is kept for 12 hours in an icebox (-5°) and the precipitate that has separated out is filtered under suction and washed with xylene. The product is dried in vacuo (1 mm, 120°, 2 hours). The orange to yellow crystals thus obtained are 6-chloro-4-hydroxy-2-methyl-3-(2-pyridylcarbamoyl)-2H-thieno[2,3-e]-1,2-thiazine-1,1-dioxide with a melting point of 225°-230° (with decomposition).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[OH:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17].[H-].[Na+].[Cl-].[NH4+]>CN(C)C=O.O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([O:9][CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH:7]=1
Reactant: O=C1CCCN1CCO
Reactant: Clc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCCN1CCOc1cc(Cl)ncn1
Reaction time: 0.5 h

Procedure:
To a solution of 4,6-dichloropyrimidine (600 mg) and 1-(2-hydroxyethyl)-2-pyrrolidinone (0.728 mL) in N,N-dimethylformamide (2 mL) was added sodium hydride (60% oil, 209 mg) under ice-cooling, and the mixture was stirred for 30 min. The reaction mixture was poured into saturated aqueous ammonium chloride solution (10 mL), water (5 mL) was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with, water (10 mL, threetimes) and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained pale-yellow oil was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (634 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([C:9]2[O:13][CH:12]=[N:11][C:10]=2[CH3:14])(O)[CH3:7])=[CH:2]1.Cl.C(OCC)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[O:1]1[CH:5]=[CH:4][C:3]([C:6]([C:9]2[O:13][CH:12]=[N:11][C:10]=2[CH3:14])=[CH2:7])=[CH:2]1
Reactant: Cc1ncoc1C(C)(O)c1ccoc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: C=C(c1ccoc1)c1ocnc1C
Reaction time: 0.17 h

Procedure:
1-(3-Furyl)-1-(4-methyl-5-oxazolyl)ethanol (900 mg) in dry chloroform was treated with 1M anhydrous hydrogen chloride in diethylether (1.1 equivalents). After 10 minutes at room temperature, aqueous sodium hydrogen carbonate was added and the mixture was extracted with dichloromethane. The material thus obtained was purified by flash chromatography to give the title compound as an almost colourless liquid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[CH3:24][O:25][C:26](=[O:66])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([CH2:62][CH3:63])([C:43]3[CH:48]=[CH:47][C:46]([C:49]#[C:50][C:51]4([O:56][Si](C)(C)C)[CH2:55][CH2:54][CH2:53][CH2:52]4)=[C:45]([CH3:61])[CH:44]=3)[CH2:41][CH3:42])=[CH:36][C:35]=2[CH3:64])=[CH:30][C:29]=1[F:65].[Cl-].[NH4+]>>[CH3:24][O:25][C:26](=[O:66])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([CH2:62][CH3:63])([C:43]3[CH:48]=[CH:47][C:46]([C:49]#[C:50][C:51]4([OH:56])[CH2:55][CH2:54][CH2:53][CH2:52]4)=[C:45]([CH3:61])[CH:44]=3)[CH2:41][CH3:42])=[CH:36][C:35]=2[CH3:64])=[CH:30][C:29]=1[F:65]
Reactant: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(C#CC2(O)CCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Reaction time: 0.67 h
Yield: 88.9 %

Procedure:
A 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.105 mL, 0.105 mmol) was added to (4′-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclopentylethynyl)-phenyl]-propyl}-3-fluoro-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 93-(1); 52.6 mg, 0.0878 mmol), and the mixture was stirred for 40 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with diethyl ether. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20% ethyl acetate/hexane) to give the title compound (41.1 mg, 88%).
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])[CH2:17][CH3:18]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:17]([CH3:18])[C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])=[CH:9][CH:10]=1
Reactant: COc1ccc(Br)cc1
Reactant: CCC(=O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)C(=O)c2ccccc2)cc1
Temperature: 80 °C
Yield: 78.7 %

Procedure:
A dry Schlenk tube was charged with Pd(OAc)2 (2.2 mg, 0.01 mmol) and sodium tert-butoxide (125 mg, 1.3 mmol). The tube was then evacuated and filled with argon. Toluene (1 mL), 4-bromoanisole (187 mg, 0.125 mL, 1.0 mmol) and propiophenone (161 mg, 0.160 mL, 1.2 mmol) were sequentially added with a syringe, and the tube was sealed and heated in an oil bath at 80° C. for 14 h. The mixture was cooled, and partitioned between ether and water. The aqueous layer was extracted twice with ether, and the combined organics were dried over Na2SO4, filtered and concentrated. Chromatography on silica gel (12:1 hexane:ethyl acetate was the eluent) gave 0.189 g (79%) of α-(4-methoxyphenyl)propiophenone, a white solid. 1H NMR (CDCl3, 300 MHz) a 7.96 (m, 2H); 7.48 (m, 1H); 7.39 (m, 2H); 7.21 (d, 2H, J=8.7 Hz); 6.84 (d; 2H, 8.7 Hz); 4.66 (q, 1H, J=6.9 Hz); 3.76 (s, 3H); 1.52 (d, 3H, J=6.9).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[C:8]([N:13]([CH3:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:9][CH:10]=[CH:11][CH:12]=1)=O.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([CH3:20])[C:8]2[N:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=1
Reactant: CN(c1ccccc1)c1ncccc1NC(=O)c1ccccc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CN1c2ccccc2C(c2ccccc2Cl)=Nc2cccnc21

Procedure:
Following the procedure of example 58, 2-chloro-N-[2-(methylphenylamino)-3-pyridinyl]benzamide was cyclized to the title compound with phosphorus oxychloride and isolated, recrystallizing from isopropyl alcohol as yellow solid, m.p. 131.5°-133° C.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.C[O:25][C:26](=[O:39])[C@@H:27]([NH2:38])[C@@H:28]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)[CH3:29]>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:38][C@@H:27]([C@@H:28]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=3)[CH3:29])[C:26]([OH:25])=[O:39])=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: COC(=O)[C@@H](N)[C@H](C)c1ccc(Cl)c(Cl)c1
Product: C[C@H](c1ccc(Cl)c(Cl)c1)[C@H](NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12)C(=O)O

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoic acid was coupled to (2S,3R)-2-amino-3-(3,4-dichloro-phenyl)-butyric acid methyl ester as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC: RT=10.22 min. MS (ESI−): mass calcd. for C23H17Cl3N4O5S2, 597.97; m/z found, 597/599 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.26 (s, 1H), 8.36 (d, J=7.0, 1H), 8.21 (d, J=8.8, 1H), 7.73-7.70 (m, 2H), 7.37 (d, J=8.3, 1H), 7.27 (m, 1H), 7.23 (d, J=6.4, 1H), 7.04 (dd, J=8.2, 2.0, 1H), 6.96 (dd, J=8.4, 2.0, 1H), 6.44 (d, J=8.6, 1H), 4.97-4.94 (m, 1H), 3.38-3.36 (m, 1H), 1.46 (d, J=7.2, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@H:35]([C:37]([OH:39])=O)[CH3:36])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.[NH2:89][C@@H:90]([CH2:103][C:104]1[CH:109]=[CH:108][CH:107]=[CH:106][CH:105]=1)/[CH:91]=[CH:92]/[C:93]1[CH:98]=[CH:97][C:96]([S:99]([OH:102])(=[O:101])=[O:100])=[CH:95][CH:94]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@@H:35]([CH3:36])[C:37](=[O:39])[NH:89][C@H:90](/[CH:91]=[CH:92]/[C:93]1[CH:94]=[CH:95][C:96]([S:99]([OH:102])(=[O:100])=[O:101])=[CH:97][CH:98]=1)[CH2:103][C:104]1[CH:105]=[CH:106][CH:107]=[CH:108][CH:109]=1)=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: N[C@H](/C=C/c1ccc(S(=O)(=O)O)cc1)Cc1ccccc1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](/C=C/c1ccc(S(=O)(=O)O)cc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 90 mg (0.13 mmol) of N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-2-carboxy-1-methoxypropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide in 4 ml of DMF were added 60 mg (0.16 mmol) of HATU and 69 μl of (0.39 mmol) HüNig's base. The reaction mixture was stirred at RT for 30 min and then admixed with 60 mg (0.15 mmol) 60.3 mg (0.13 mmol) of 4-[(1E,3S)-3-amino-4-phenylbut-1-en-1-yl]benzenesulphonic acid trifluoroacetate. After stirring overnight, the reaction mixture was purified by prep. HPLC. This gave 127 mg of a 44:56 mixture of the title compound and of the already deprotected amine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:9]=[CH:10][CH:11]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C1COCC1>[CH3:23][S:24]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12]([NH2:15])(=[O:13])=[O:14])[CH:7]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: NS(=O)(=O)c1cccc(CCCCO)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCc1cccc(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-(4-hydroxybutyl)benzenesulfonamide (458 mg) in dry THF (10 ml) was treated with triethylamine (0.307 ml) and the resultant solution cooled to 0° C. Methanesulfonyl chloride (0.17 ml) was added dropwise. The mixture was allowed to warm to room temperature and stirred for a further 15 minutes. The reaction mixture was partitioned between 1M HClaq and EtOAc. The aqueous phase was washed with EtOAc. The combined organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound LCMS RT=2.67 min.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:21])[C:16]([CH:19]=O)=[CH:17][N:18]=3)[S:13][C:6]=12.[CH3:29][O:30][CH2:31][CH2:32][NH2:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:21])[C:16]([CH2:19][NH:33][CH2:32][CH2:31][O:30][CH3:29])=[CH:17][N:18]=3)[S:13][C:6]=12
Reactant: Cn1c(C=O)cnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Reactant: COCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COCCNCc1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)n1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.6 %

Procedure:
To a suspension of 43 (1.3 g, 3.26 mmol) in dry DCM (50 mL) at RT was added 2-methoxyethanamine (1.226 g, 16.32 mmol), acetic acid (0.98 g, 16.32 mmol) and sodium triacetoxyborohydride (3.46 g, 16.32 mmol), and the reaction mixture was stirred at RT for 24 hours. It was then diluted with additional DCM and washed with saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated to dryness to afford 44 (1.5 g, 100% yield) as an yellow oil which was used crude in the next step with no additional purification. MS (m/z): 458.2 (M+H).