Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[S:6][C:5]([CH3:7])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:3]=1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18].N1C=CN=C1>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:17]([Si:20]([O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:4]2[CH:3]=[C:2]([I:1])[S:6][C:5]=2[CH3:7])=[CH:10][CH:11]=1)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1sc(I)cc1Cc1ccc(O)cc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1sc(I)cc1Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.2 %

Procedure:
To a solution of phenol 23 (0.54 g, 1.64 mmol) in DMF (15 mL) were added TBDMSCl (1M in CH2Cl2, 3.5 mL, 3.28 mmol), imidazole (0.35 g, 4.92 mmol) and DMAP (50 mg, 0.33 mmol) at room temperature. The mixture was stirred at ambient temperature for 15 hours. The mixture was extracted with EtOAc/H2O (50 mL/150 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (Biotage) to provide the title compound 24 (0.65 g, 89%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[C:24](=[O:25])[C:23]3[S:22][C:21]4[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=4[C:15]=3[CH:14]=[N:13]2)=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][N:43]([CH:46]4[CH2:49][O:48][CH2:47]4)[CH2:42][C@@H:41]3[CH3:50])=[CH:36][N:35]=2)[C:30](=[O:51])[N:29]([CH3:52])[CH:28]=1)(=O)C.[OH-].[Li+]>>[F:26][C:9]1[CH:8]=[C:7]([C:27]2[CH:32]=[C:31]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([N:40]4[CH2:45][CH2:44][N:43]([CH:46]5[CH2:47][O:48][CH2:49]5)[CH2:42][C@@H:41]4[CH3:50])=[CH:36][N:35]=3)[C:30](=[O:51])[N:29]([CH3:52])[CH:28]=2)[C:6]([CH2:5][OH:4])=[C:11]([N:12]2[C:24](=[O:25])[C:23]3[S:22][C:21]4[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=4[C:15]=3[CH:14]=[N:13]2)[CH:10]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)cc(F)cc1-n1ncc2c3c(sc2c1=O)CCCC3
Agent: [Li+]
Agent: [OH-]
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CCCC6)c3CO)cn(C)c2=O)nc1
Yield: 59 %

Procedure:
Following the procedures as described for 101, hydrolysis of 102a (210 mg, 0.29 mmol) with lithium hydroxide afforded 102 as a white solid (117 mg, 85%). LCMS: [M+H]+ 684. 1H NMR (500 MHz, CDCl3) δ 8.61 (d, J=2.5, 1H), 8.26 (s 1H), 7.99 (d, J=2.5, 1H), 7.83 (s, 1H), 7.46 (d, J=2.0, 1H), 7.29-7.32 (m, 2H), 7.11 (dd, J=2.0, 8.0, 1H), 6.82 (d, J=9.0, 1H), 4.62-4.73 (m, 4H), 4.31 (d, J=6.5, 2H), 4.02 (t, J=6.5, 1H), 3.71 (s, 3H), 3.52-3.55 (m, 1H), 3.45-3.49 (m, 1H), 3.09 (t, J=4.5, 2H), 2.99 (t, J=4.5, 2H), 2.87 (t, J=4.5, 2H), 2.56 (dd, J=3.0, 11.0, 1H), 2.46-2.49 (m, 2H), 2.19-2.25 (m, 1H), 1.96-2.01 (m, 4H), 1.00 (d, J=6.0, 3H)
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[C:7]([O:14][CH3:15])[CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH2:16]([C:18]1[CH:19]=[C:20]([CH:25]=[C:26]([CH3:29])[C:27]=1[OH:28])[C:21]([NH:23]O)=[NH:22])[CH3:17]>>[CH2:16]([C:18]1[CH:19]=[C:20]([C:21]2[N:23]=[C:11]([C:9]3[CH:8]=[C:7]([O:14][CH3:15])[CH:6]=[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[N:10]=3)[O:13][N:22]=2)[CH:25]=[C:26]([CH3:29])[C:27]=1[OH:28])[CH3:17]
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Reactant: COc1cc(CC(C)C)nc(C(=O)O)c1
Product: CCc1cc(-c2noc(-c3cc(OC)cc(CC(C)C)n3)n2)cc(C)c1O

Procedure:
The title compound is prepared in analogy to Example 2 starting from 6-isobutyl-4-methoxy-pyridine-2-carboxylic acid and 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine; LC-MS: tR=1.11 min, [M+H]+=368.12; 1H NMR (CDCl3): δ 0.99 (d, J=6.8 Hz, 6H), 1.32 (t, J=7.8 Hz, 3H), 2.24 (hept, J=6.8 Hz), 2.35 (s, 3H), 2.73 (q, J=7.8 Hz, 2H), 2.78 (d, J=7.3 Hz, 2H), 3.98 (s, 3H), 5.02 (s, 1H), 6.85 (d, J=1.3 Hz, 1H), 7.70 (d, J=1.3 Hz, 1H), 7.89 (s, 2H).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:13]([NH:15][C@H:16]([C:24]([O:26][CH3:27])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>>[NH2:1][C@@H:2]([C:13]([NH:15][C@H:16]([C:24]([O:26][CH3:27])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[F:35][C:36]([C:37]([OH:39])=[O:38])([F:41])[F:40]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Yield: 61 %

Procedure:
Condensation of BocDTrpOPFP (7.06 g.) and HPheOMe hydrochloride salt (3.24 g.) by the activated ester method gave BocDTrp-PheOMe in 81% yield. De-t-butoxycarbonylation of BocDTrp-PheOMe (5.0 g.) using trifluoroacetic acid gave HDTrp-PheOMe trifluoroacetate salt in 61% yield. Condensation of BocProOPFP (2.23 g.) and HDTrp-PheOMe trifluoroacetate salt (2.75 g.) by the activated ester method gave BocPro-DTrp-PheOMe in 74% yield. Hydrazinolysis of BocPro-DTrp-PheOMe (2.00 g.) gave BocPro-DTrp-PheNHNH2 yield.
Reaction SMILES: C([N:8]([CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:25]([F:35])[CH:24]=2)[CH2:18]1)CC1C=CC=CC=1)C1C=CC=CC=1.N#N.[H][H]>[Pd].C(OCC)(=O)C>[NH2:8][CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[C:25]([F:35])[CH:24]=2)[CH2:18]1
Reactant: O=C1O[C@@H](CN(Cc2ccccc2)Cc2ccccc2)CN1c1ccc(N2CCOCC2)c(F)c1
Reactant: [H][H]
Agent: [Pd]
Agent: N#N
Solvent: CCOC(C)=O
Product: NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 50 °C
Yield: 89.7 %

Procedure:
(S)-5-((dibenzylamino)methyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one (0.95 g, 2 mmol) and 0.5 g of 10 wt % Pd—C were added to 20 mL ethyl acetate and the air was replaced with N2. Hydrogen was passed into the mixture and the mixture was heated to 50° C. and reacted for 20 hours. Filtered and the solvent was evaporated to provide 0.53 g of white solid in 90% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][CH:19]=[C:6]2[C:7]([N:9]([C:12]3[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=3)[C:10](=[O:11])[C:5]=12)=[O:8])([O-])=O.[N-:22]=[N+:23]=[N-].[Na+]>CS(C)=O>[N:1]([C:4]1[CH:21]=[CH:20][CH:19]=[C:6]2[C:7]([N:9]([C:12]3[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=3)[C:10](=[O:11])[C:5]=12)=[O:8])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=Nc1cccc2c1C(=O)N(c1ccc(N)cc1)C2=O
Yield: 99.8 %

Procedure:
13.5 g (0.047 mol) of 4-(3-nitrophthalimidyl)aniline and 3.4 g (0.051 mol) of sodium azide in 120 ml of dimethylsulphoxide are heated for 18 hours at 80° C. The reaction mixture is then concentrated in vacuo at 80° C. and diluted with 100 ml of water, the mixture is filtered with suction and the filter residue is washed with 20 ml of water and dried for 24 hours in a drying cabinet at 80° C./100 mm Hg. 13.1 g (100% of theory) of 4-(3-azidophthalimidyl)-aniline are obtained; melting point 176° C. (with decomposition). IR spectrum (KBr): 1780 and 1725 cm-1 (CO--N--CO); 2130 cm-1 (N3).
Reaction SMILES: COCCOC[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=[CH:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH:9]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[CH:15]=[CH:14][C:10]1[CH:9]=[C:8]([OH:7])[CH:13]=[CH:12][CH:11]=1
Reactant: COCCOCOc1cccc(C=Cc2ccc3ccccc3n2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Oc1cccc(C=Cc2ccc3ccccc3n2)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of 1-(2-methoxyethoxy)-methoxy-3-(2-quinolin-2-yl-vinyl)-benzene (120 mg, 0.35 mmol, example 16) is added p-toluene sulphonic acid monohydrate. (74 mg, 0.39 mmol). The resulting solution is heated to 60° C. and stirred at this temperature for 4 h. The reaction mixture is then cooled, concentrated and the residue taken up in dichloromethane. This solution is washed with sat. NaHCO3 solution, dried over MgSO4 then concentrated to give the title compound as a solid. MS (ESI) 248 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([CH:15]([CH3:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([CH:15]([CH3:22])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: CC(c1ccccc1)c1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(C(C)c2ccccc2)ncn1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
In 2 ml of tetrahydrofuran was suspended 0.06 g of sodium hydride (60% in oil), to which 0.6 ml of a tetrahydrofuran solution containing 0.08 g of 2-butyn-1-ol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, to which 0.6 ml of a tetrahydrofuran solution containing 0.2 g of 4-chloro-6-(α-methylbenzyl)pyrimidine was slowly added dropwise at room temperature, followed by stirring for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.16 g of 4-(2-butynyloxy)-6-(α-methylbenzyl)pyrimidine (the present compound (94)).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16]2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].I[C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(O)(C)C>[OH:31][C:27]1[CH:26]=[C:25]([NH:1][C:2]2[CH:14]=[C:13]([N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[CH:12]=[CH:11][C:3]=2[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH:30]=[CH:29][CH:28]=1
Reactant: Oc1cccc(I)c1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CCc3ccccc32)cc1N
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)c1ccc(N2CCc3ccccc32)cc1Nc1cccc(O)c1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
To 2-methyl-2-propanol 3.0 mL solution of tert-butyl 2-amino-4-(indolin-1-yl)benzoate 0.12 g were added 3-iodophenol 0.22 g, cesium carbonate 0.26 g, tris(dibenzylideneacetone)dipalladium(0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.5 mg at room temperature, and it was stirred at 70° C. for 12 hours. Tris(dibenzylideneacetone)dipalladium(0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.5 mg were added to it, and it was stirred at 70° C. for 7 hours. Cesium carbonate 0.26 g, tris(dibenzylideneacetone)dipalladium(0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.5 mg were added to it, and it was stirred at 70° C. for 12 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2,008, eluent; hexane:ethyl acetate=4:1] to give tert-butyl 2-((3-hydroxyphenyl)amino)-4-(indolin-1-yl)benzoate.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:30]N1C(C)(C)C(=O)N(Br)C1=O>C(Cl)(Cl)(Cl)Cl>[Br:30][CH2:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cnc2ccccc2n1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cnc2ccccc2n1

Procedure:
To a stirring solution of 2-methylquinoxaline (20.0 g, 155 mmol) and benzoyl peroxide (3 g, 12 mmol) in carbon tetrachloride (800 mL) was added 1,3-dibromo-5,5-dimethyl hydantoin (22 g, 77 mmol). The resulting mixture was irradiated with a spotlight (200 watt) for 1.5 hours. The mixture was cooled, filtered, and concentrated to afford crude product which was purified by HPLC (4:1 hexane/ethyl acetate) to yield 14.0 g (40%) of monobromomethyl product as a grey solid: 1H NMR (CDCl3): δ9.00 (s, 1H, ArH), 8.10 (m, 2H, ArH), 7.80 (m, 2H, ArH), 4.72 (s, 2H, BrCH2 --Ar); and 15.0 g (35%) of dibromomethyl product as a white solid: 1H NMR (CDCl3): δ9.39 (s, 1H, ArH), 8.15 (m, 2H, ArH), 7.90 (m, 2H, ArH), 6.76 (s, 1H, Br2CH--Ar).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[CH:16]=[CH:17]/[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-])=O>CO.C(OCC)(=O)C.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)CCc1ccc(-c2ccccc2)c(N)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
tert-Butyl trans-3-(3-nitro-4-phenylphenyl)acrylate (6.52 g, 20.0 mmol) was dissolved in methanol (100 mL) and ethyl acetate (100 mL), 10% palladium-carbon (500 mg) was added thereto, and the mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours. The reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure to obtain tert-butyl 3-(3-amino-4-phenylphenyl)propionate (5.94 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:23]=[O:24])=[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[BH4-].[Na+].CCCCCC>C(O)C.C(OCC)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([CH2:23][OH:24])=[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1cccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1cccs1
Yield: 90.6 %

Procedure:
To a solution of diethyl 2-methyl-4-(2-thienyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (940.68 mg) in 99% ethanol (30 ml) was gradually added sodium borohydride (113.5 mg) under stirring and this was further stirred at room temperature for 2 hours. After removal of ethanol, the residue was extracted with ethyl acetate and the extract was washed twice with water and then dried. The solvent was removed from the extract to give a pale yellow oil. The oil was pulverized with n-hexane. The powder was dissolved in ethyl acetate. After collecting by filtration of the insoluble product, to the filtrate was added n-hexane and the mixture was allowed to stand in refrigerator. The appearing crystals were collected by filtration to give pale yellow granules (857.2 mg) of diethyl 2-methyl-4-(2-thienyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate, m.p. 125° to 126° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])=[O:4].[CH3:38][O:39][CH2:40][C:41](O)=[O:42]>>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C@H:9]([CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:41](=[O:42])[CH2:40][O:39][CH3:38])[CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)(=[O:19])=[O:18])=[CH:25][CH:24]=1
Reactant: COCC(=O)O
Reactant: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](N)Cc1cccc2ccccc12)S(=O)(=O)c1ccc(N)cc1
Product: COCC(=O)N[C@@H](Cc1cccc2ccccc12)C(=O)NCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,4S)-2-amino-N-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentyl}-3-naphthalen-1-yl-propionamide (product of example 8) as described in general procedure E using methoxyacetic acid. The final product was obtained in 30% yield.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][C:2]1=[O:12].P(Cl)(Cl)(Cl)(Cl)Cl.II.[Br:21]Br>C(Cl)(Cl)Cl>[Br:21][CH:3]1[CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:1][C:2]1=[O:12]
Reactant: O=C1CCCc2ccccc2N1
Reactant: BrBr
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: II
Solvent: ClC(Cl)Cl
Product: O=C1Nc2ccccc2CCC1Br

Procedure:
To a solution of 2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one (2.5 g) in chloroform (30 ml), phosphorus pentachloride (3.2 g) was added in portions, while maintaining the temperature at 0°-5°. When the addition was complete, iodine (30 mg) was added followed by bromine (2.5 g), which was added dropwise over 5 minutes. The mixture was then refluxed for 4 hours. The chloroform solution was evaporated and the residue was partitioned between ice-water (30 ml) and dichloromethane (75 ml). The organic phase was dried over magnesium sulfate and evaporated under reduced pressure. The crude residue was purified by chromatography over silica gel, eluting with ether and hexane (7:3). Concentration of the appropriate fractions yielded 3-bromo-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one, m.p. 146°-148°.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][S:11]2(=[O:17])=[O:16])[CH:3]=1.[ClH:18]>C(O)C.[Pd]>[ClH:18].[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][S:11]2(=[O:16])=[O:17])[CH:3]=1
Reactant: N#Cc1ccc(F)cc1N1CCCCS1(=O)=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1ccc(F)cc1N1CCCCS1(=O)=O
Reaction time: 4 h
Yield: 100 %

Procedure:
Intermediate 75, 4-fluoro-2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)benzonitrile (1.37 g, 5.4 mmol) was dissolved in ethanol (120 mL). To this was added 1N HCl (20 mL) and a catalytic amount of 10% Pd—C. The mixture was shaken under hydrogen at 55 psi for 4 h then filtered through Celite and concentrated to give the title compound as white solid (1.58 g, 100% yield). 1H-NMR (300 MHz, CD3OD) δ ppm: 7.61 (1H, dd, J=8.4, 6.2 Hz), 7.38 (1H, dd, J=9.3, 2.7 Hz), 7.28 (1H, td, J=8.2, 2.7 Hz), 7.26 (2H, dd, J=21.4, 13.7 Hz), 3.93–3.84 (1H, m), 3.50–3.41 (3H, m), 2.40–2.31 (2H, m), 2.04–1.96 (2H, m). LCMS [M+H]+ calcd for C11H16N2O6FS: 259.087. found: 259.24.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=3)=[C:12]([F:13])[C:7]=2[N:6]([CH3:21])[C:5]1=[O:22].Br[C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.[Cu]I>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=3)[O:20][C:26]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=3)=[C:12]([F:13])[C:7]=2[N:6]([CH3:21])[C:5]1=[O:22]
Reactant: N#Cc1ccc(Br)cc1
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccc(O)c3)c(F)c21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccc(Oc4ccc(C#N)cc4)c3)c(F)c21
Reaction time: 2 h

Procedure:
A solution of 1-(2,2-dimethylpropyl)-4-fluoro-5-(3-hydroxyphenyl)-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (7-15, 55 mg, 0.17 mmol) in NMP (1 ml) was sequentially charged with 4-Bromobenzonitrile (61.0 mg, 0.34 mmol, 2.0 eq), Cesium carbonate (109 mg, 0.34 mmol, 2.0 eq) and Copper(I) iodide (31.9 mg, 0.17 mmol, 1.0 eq). The resulting mixture was irradiated in a microwave at 195 deg C. for 2 h. LC/MS analysis showed only partial conversion, therefore additional amounts of 4-Bromobenzonitrile (61.0 mg, 0.34 mmol, 2.0 eq) and Cu(I)I (31.9 mg, 0.17 mmol, 1.0 eq) were added and the reaction was irradiated again at 195 deg C. for 1 h. The completed reaction was filtered and the filtrate purified via reverse-phase HPLC (Acetonitrile/Water gradient with 0.1% TFA present) to afford the title compound, 4-{3-[1-(2,2-dimethylpropyl)-4-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]phenoxy}benzonitrile (9-1), as a tan solid-oil. 1H NMR (400 MHz, CDCl3) δ 7.62 (d, 2H, J=8.9 Hz), 7.50-7.46 (m, 1H), 7.39 (m, 1H), 7.25 (s, 1H), 7.09-7.04 (m, 4H), 6.87 (d, 1H, J=8.2 Hz), 3.67 (s, 2H), 3.64 (s, 3H), 1.05 (s, 9H). LRMS m/z: Calc'd for C26H24FN3O2(M+H) 430.2, found 430.5.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[C:8](OC(=O)C)(=[O:10])[CH3:9]>>[C:8]([N:5]1[C:4](=[O:6])[CH:3]=[CH:2][C:1]1=[O:7])(=[O:10])[CH3:9]
Reactant: O=C1C=CC(=O)N1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1C(=O)C=CC1=O
Yield: 65.8 %

Procedure:
A solution of maleimide (68 g; 700 mmol) in acetic anhydride (500 ml) is placed in a 1000 ml three-necked flask and the reaction mixture is then brought to reflux for 3 hours. After returning to 20° C., the reaction mixture is evaporated under reduced pressure, resulting in an oil, which is crystallized from ethyl acetate (100 ml). After filtering-off the solid and washing with ethyl acetate (25 ml) and diisopropyl ether (100 ml), and drying under reduced pressure at constant weight, N-acetylmaleimide (64.1 g; 65.8%) is isolated, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[CH:3]=1.N1C=CC=CC=1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][S:26]([NH:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[CH:3]=1)(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)CCCCCl
Reactant: COC(=O)c1cc(N)c2nc[nH]c2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(NS(=O)(=O)CCCCCl)c2nc[nH]c2c1
Reaction time: 1 h
Yield: 50.2 %

Procedure:
To a solution of methyl 4-amino-1H-benzimidazole-6-carboxylate (D251) (1.1 g, 5.76 mmol, 1 equiv) in CH2Cl2 (80 ml) at room temperature were added pyridine (1.02 ml, 12.67 mmol, 2.2 equiv), 4-chloro-1-butanesulfonyl chloride (D20) (2.31 g, 12.1 mmol, 2.1 equiv) and DMAP (704 mg, 5.76 mmol, 1 equiv) and the resulting mixture was stirred for 1 h then concentrated in vacuo. The residue was diluted with AcOEt and the organic phase was washed with a 2N aqueous HCl solution and brine, then dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (AcOEt/iso-hexane: 2/3) gave methyl 4-{[(4-chlorobutyl)sulfonyl]amino}-1H-benzimidazole-6-carboxylate (D252) (1 g, 50%) as a colorless oil. [M+H]+=346.1, RT=2.97 min.