Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:26])=[C:7]([N:9]2[C:13](=[O:14])[NH:12][C:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]#[C:22][CH:23]4[CH2:25][CH2:24]4)=[CH:17][CH:16]=3)=[N:10]2)[CH:8]=1.C[O:28][CH2:29][C:30]([CH3:35])([CH3:34])[C:31](O)=[O:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:26][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:29](=[O:28])[C:30]([CH3:35])([CH3:34])[CH2:31][OH:32])=[CH:8][C:7]=1[N:9]1[C:13](=[O:14])[NH:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[C:22][CH:23]3[CH2:25][CH2:24]3)=[CH:17][CH:16]=2)=[N:10]1
Reactant: NCc1ccc(Cl)c(-n2nc(-c3ccc(C#CC4CC4)cc3)[nH]c2=O)c1
Reactant: COCC(C)(C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(CO)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(C#CC4CC4)cc3)[nH]c2=O)c1
Yield: 9.4 %

Procedure:
The title compound was prepared according to the procedure described in Example-107 by using 1-(5-(aminomethyl)-2-chlorophenyl)-3-(4-(cyclopropylethynyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (0.080 g, 0.228 mmol), DMF (5 mL), 3-methoxy-2,2-dimethylpropanoic acid (0.040 g, 0.342 mmol), BOP (0.151 g, 0.342 mmol), TEA (2.0 mL) to afford 0.010 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.75 (m, 2H), 0.83 (m, 2H), 1.10 (s, 6H), 1.51 (m, 1H), 3.34 (m 2H), 4.31 (br s, 2H), 4.85 (m, 1H), 7.37-7.50 (m, 3H), 7.58 (d, J=7.8 Hz, 1H), 7.77-7.83 (m, 3H), 8.11 (br s, 1H), 12.56 (s, 1H); MS (m/z): 465.07 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:14]([OH:16])=O)=[CH:11][NH:12][CH:13]=1.C([N:19](CC)CC)C.S(Cl)(Cl)=O.CN(C)C=O.N>O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:14]([NH2:19])=[O:16])=[CH:11][NH:12][CH:13]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1c[nH]cc1-c1cccc(Cl)c1Cl
Agent: N
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: NC(=O)c1c[nH]cc1-c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
A mixture of 4-(2,3-dichlorophenyl)pyrrole-3-carboxylic acid (2.43 g, 9.5 mmol) and triethylamine (7 mL, 50 mmol) in tetrahydrofuran is stirred for 15 minutes at room temperature and concentrated in vacuo to obtain a residue. A mixture of the residue, thionyl chloride (2.77 mL, 38 mmol) and N,N-dimethylformamide (0.73 mL, 9.5 mmol) is stirred overnight at room temperature and concentrated in vacuo to obtain a yellow oil. The oil is added to a concentrated ammonia solution and stirred for 1 hour. This mixture is filtered to give a solid. The solid is washed with water, dried and chromatographed using silica gel and a 4:1 hexanes/ethyl acetate mixture to obtain the title product as a white solid (1.6 g, mp 185°-190° C.).
Reaction SMILES: [N+:1]([C:4]([N+:8]([O-:10])=[O:9])(O)[CH2:5]C)([O-:3])=[O:2].[C:11]([OH:20])(=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl[CH:22](Cl)C>>[C:11]([O:20][CH2:22][C:4]([N+:8]([O-:10])=[O:9])([N+:1]([O-:3])=[O:2])[CH3:5])(=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC(=O)O
Reactant: CCC(O)([N+](=O)[O-])[N+](=O)[O-]
Reactant: CC(Cl)Cl
Product: CCCCCCCC(=O)OCC(C)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 70 °C
Yield: 90 %

Procedure:
Dinitropropanol (25.5 g, 0.17 mol), octanoic acid (27.4 g, 0.19 mol) and 50 g of polyphosphoric acid were added to 50 mL of dichloroethane and the resulting mixture was slowly stirred using a stirrer. The solution thus obtained was slowly heated to 70° C. and then reacted for 15 hr (overnight). After the reaction, the temperature of the reactor was lowered to room temperature, and the stirrer was powered off. When the temperature of the reactor was room temperature, the dichloroethane layer was decanted, followed by extraction with a 1 N sodium hydroxide aqueous solution and then distillation under reduced pressure, affording 2,2-dinitropropyl octanoate (42.3 g, yield: 90%).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH2:9][S:10][CH2:11][CH2:12][NH2:13].C(N(CC)CC)C.[F:21][C:22]([F:41])([F:40])[CH2:23][N:24]=[C:25]([NH2:39])[NH:26][C:27]1[S:28][CH:29]=[C:30]([CH2:32][CH2:33][CH2:34][CH2:35][N:36]=[C:37]=[S:38])[N:31]=1.[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]\[C:45]([OH:47])=[O:46]>O1CCCC1.CC(C)=O>[F:41][C:22]([F:21])([F:40])[CH2:23][N:24]=[C:25]([NH2:39])[NH:26][C:27]1[S:28][CH:29]=[C:30]([CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([NH:13][CH2:12][CH2:11][S:10][CH2:9][C:8]2[NH:7][CH:6]=[N:5][C:4]=2[CH3:3])=[S:38])[N:31]=1.[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]\[C:45]([OH:47])=[O:46]
Reactant: NC(=NCC(F)(F)F)Nc1nc(CCCCN=C=S)cs1
Reactant: Cc1nc[nH]c1CSCCN
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: Cc1nc[nH]c1CSCCNC(=S)NCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reaction time: 8 h

Procedure:
A mixture of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrochloride (0.5 g.), triethylamine (1 ml.) and 2-[2-(2,2,2-trifluoroethyl)guanidino]-(4-isothiocyanatobutyl)thiazole (0.5 g.) in tetrahydrofuran (15 ml.) was allowed to stand at room temperature overnight. The solution was then filtered, and the filtrate evaporated to dryness. The residue was purified by preparative thin layer chromatography using ethyl acetate/methanol/ammonia 6:1:1 v/v/v as developing solvent. The appropriate band was isolated and further purified by preparative thin layer chromatography using methanol/chloroform/ammonia 15:85:1 v/v/v as developing solvent. The appropriate band after extraction and evaporation yielded a brown gum. This was treated in acetone with excess maleic acid to give 1-[4-(2-[2-(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)butyl]-3-[2-([4-methylimidazol-5-yl]methylthio)ethyl]thiourea containing 2.25 equivalents of maleic acid. The n.m.r. spectrum in d6 dimethyl sulphoxide containing tetramethylsilane as internal standard (δ=0) included the following resonances (δ): 1.5 (multiplet, 4H); 2.25 (singlet, 3H); 2.5 (multiplet, 4H); 3.3 (multiplet, 4H); 3.8 (singlet, 2H); 4.1 (quartet, 2H); 6.45 (singlet, 1H); 8.8 (singlet, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25]>>[C:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:12]([CH2:11]/[CH:10]=[CH:9]/[C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)[S:13]([CH3:16])(=[O:15])=[O:14])#[N:25]
Reactant: N#CCCCCCCBr
Reactant: CS(=O)(=O)NC/C=C/c1cc(Cl)cc(Cl)c1
Product: CS(=O)(=O)N(C/C=C/c1cc(Cl)cc(Cl)c1)CCCCCCC#N
Yield: 79.7 %

Procedure:
In an analogous manner to the procedure described in Step A of Example 1, trans-N-[3-(3,5-dichloro-phenyl)-allyl]-methanesulfonamide (500 mg, 2.45 mmol) was alkylated with 7-bromoheptanenitrile (781 mg, 2.94 mmol) at room temperature over 24 h to provide the title compound of Step A (760 mg). 1H NMR (CDCl3 400 MHz) δ 7.26 (m, 3H), 6.49 (d, 1H), 6.22 (m, 1H), 3.98 (m, 2H), 3.22 (t, 2H), 2.88 (s, 3H), 2.36 (t, 2H), 1.68-1.35 (m, 8H).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[O:8]1CCO[CH2:10][CH2:9]1.[Br:14]CCO.CC(C)=O>CCOCC>[Br-:14].[OH:8][CH2:9][CH2:10][N+:6]1[C:5]([CH3:7])=[CH:4][S:3][C:2]=1[CH3:1]
Reactant: Cc1csc(C)n1
Reactant: OCCBr
Reactant: C1COCCO1
Solvent: CC(C)=O
Solvent: CCOCC
Product: Cc1csc(C)[n+]1CCO
Product: [Br-]
Reaction time: 0.5 h

Procedure:
To the mixture of 2.4-dimethylthiazole (26.0 g) and dioxane (30 ml) was added 2-bromoethanol (40 g), and the resulting mixture was heated under reflux for 5 hours. To the mixture left standing at room temperature for about 0.5 hour was added acetone (150 ml) with stirring to give pale yellowish white solids. To the mixture was further added ether (150 ml), and the resulting powdery crystals were collected by filtration, washed with acetone and dried under reduced pressure.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([OH:37])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1.[O:41]1[CH2:45][CH2:44][CH:43]([CH2:46]O)[CH2:42]1.C(P(CCCC)CCCC)CCC>C(Cl)Cl.CCOCC>[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH2:46][CH:43]4[CH2:44][CH2:45][O:41][CH2:42]4)=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1
Reactant: OCC1CCOC1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCC1CCOC1
Reaction time: 18 h
Yield: 30.7 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (560 mg, 2.2 mmol) was added in portions to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (240 mg, 0.75 mmol), (prepared as described for the starting material in Example 2), tetrahydro-3-furanmethanol (90 mg, 0.88 mmol) and tributylphosphine (440 mg, 2.2 mmol) in methylene chloride (12 ml) and the mixture stirred for 18 hours. The mixture was diluted with ether, and the resulting precipitate was removed by filtration. The solvent was removed from the filtrate by evaporation, and the residue was dissolved in acetone and ethereal hydrogen chloride (0.75 ml of a 1M solution, 0.75 mmol) was added. The mixture was diluted with ether and the resulting precipitate was collected by filtration. The solid was purified by column chromatography eluting with methylene chloride/acetonitrile/methanol (a gradient from 50150/1 to 50/5012). The purified product was triturated with ether, collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(tetrahydrofuran-3-ylmethoxy)quinazoline (93 mg, 31%).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH:9]=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][SiH:18]([CH3:24])[O:19][Si:20]([CH3:23])([CH3:22])[CH3:21].C[SiH2]C1C=CC=CC=1>CCCCCC>[C:1]1([CH:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:9][CH2:10][Si:18]([CH3:24])([CH3:17])[O:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCC(c1ccccc1)c1ccccc1
Reactant: C[SiH](C)O[Si](C)(C)C
Agent: C[SiH2]c1ccccc1
Solvent: CCCCCC
Product: C[Si](C)(C)O[Si](C)(C)CCCC(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
4,4-Diphenyl-1-butene (compound 1, 0.40 mmol) and pentamethyl disiloxane (0.6 mmol) were dissolved in hexane (2.0 ml), added with poly (methylphenylsilane)-supported platinum (200 mg, 5.5 mol %) prepared in Example 10A and stirred at 20° C. for 2 hr. The filtrate was washed with hexane after separation from catalyst, concentrated, and purified by silica gel column chromatography using hexane as an eluting solvent. (4,4-Diphenylbutyl) pentamethyl disiloxane was obtained as oil without color (140 mg (98%)) and 1,1-diphenyl butane was obtained (2 mg (yield 2%)).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:26][O:27][C@H:28]([CH3:32])[C:29](O)=[O:30].CN(C)C=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:26][O:27][C@H:28]([CH3:32])[C:29]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([NH:18][C:15]2[N:14]=[CH:13][C:12]3=[CH:11][CH:10]=[C:9]([C:6]4[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:17]3[N:16]=2)[CH:20]=1)=[O:30]
Reactant: CO[C@H](C)C(=O)O
Reactant: COc1ccc(-c2ccc3cnc(Nc4cccc(N)c4)nn23)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(-c2ccc3cnc(Nc4cccc(NC(=O)[C@@H](C)OC)c4)nn23)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.1 %

Procedure:
N-[7-(6-Methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-benzene-1,3-diamine (50.0 mg, 0.150 mmol), (R)-(+)-2-Methoxypropionic acid (18.8 mg, 0.180 mmol) N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (34.6 mg, 0.180 mmol) and N,N-Dimethylformamide (0.999 mL, 12.9 mmol) were combined in a vial and stirred at rt for 1 hour. LCMS showed complete conversion to product. Diluted reaction mixture with sat'd NaHCO3 and filtered off resulting ppt. Took ppt up in CH2Cl2 and purified by ISCO silica gel chromatography (0-100%) EtOAc in hexanes to afford title compound (12 mg, 15%) LCMS=419.0 (M+H), HPLC rt=2.935 min, purity=99%. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.74 (d, J=2.1 Hz, 1H), 8.72 (s, 1H), 8.48 (dd, J=2.6 Hz, 8.9H, 1H), 8.31 (s, 1H), 7.89 (s, 1H), 7.38-7.36 (m, 1H), 7.32-7.29 (m, 2H), 6.95-6.92 (m, 2H), 6.89 (d, J=8.6 Hz, 1H), 6.85 (d, J=4.5 Hz, 1H), 4.01 (s, 3H), 3.90-3.85 (m, 1H), 3.45 (s, 3H), 1.48 (d, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([O:38]C(C)=O)[C:5]([C@@:7]1([CH3:37])[C@H:12]([C@@H:13]2[O:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[C@:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][C@@H:10]2[CH2:9][CH2:8]1)=[O:6].O.NN.C(OCC)(=O)C>C(O)C>[CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([OH:38])[C:5]([C@@:7]1([CH3:37])[C@H:12]([C@@H:13]2[O:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[C@:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][C@@H:10]2[CH2:9][CH2:8]1)=[O:6]
Reactant: CC(=O)O[C@H]1C(=O)[C@]2(C)CC[C@H]3OC[C@@]3(OC(C)=O)[C@H]2[C@H](OC(=O)c2ccccc2)[C@]2(O)C[C@H](O)C(C)=C1C2(C)C
Agent: NN
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@]12CO[C@@H]1CC[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](O)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Temperature: 25 °C
Reaction time: 7 h
Yield: 52.6 %

Procedure:
6.85 g of 7-deoxybaccatin III was dissolved in 250 ml of 95% ethanol, and 25 ml of hydrazine monohydrate was added thereto, followed by stirring at room temperature for 7 hours. Ethyl acetate was added to the reaction solution, the resulting mixture was washed successively with water and a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (a developing solvent; hexane:ethyl acetate=3:2 (v/v)) to yield 3.34 g of the titled compound as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:5]([Cl:19])=[CH:4][N:3]=1.[CH3:20][O:21][CH2:22][CH2:23][N:24]1[CH2:30][CH2:29][C:28]2[CH:31]=[C:32]([NH2:35])[CH:33]=[CH:34][C:27]=2[CH2:26][CH2:25]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[N:7][C:2]([NH:35][C:32]2[CH:33]=[CH:34][C:27]3[CH2:26][CH2:25][N:24]([CH2:23][CH2:22][O:21][CH3:20])[CH2:30][CH2:29][C:28]=3[CH:31]=2)=[N:3][CH:4]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CS(=O)(=O)N[C@@H]1CCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCC[C@H]4NS(C)(=O)=O)n3)cc2CC1
Temperature: 120 °C
Yield: 75.4 %

Procedure:
N-[trans-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclopentyl]-methanesulfonamide (60 mg, 0.185 mmol), 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (40 mg, 0.185 mmol) and camphorsulfonic acid (64 mg, 0.278 mmol) were combined in 2 mL isopropanol and heated at 120° C. in microwave for a total of 90 min. The reaction was concentrated to be taken up in dichloromethane and washed with saturated sodium bicarbonate solution (2×30 mL). The organic layer was dried over MgSO4 and filtered. The filtrate was chromatographed on a 4 g amine capped ISCO flash column using a gradient of 0-100% ethyl acetate in hexanes. The product was collected as a foam after concentrating to afford 71 mg (76%) of a pale yellow solid. Compound 1: mp 74° C.; MS (ES+ calculated—508; found—509 M+H). 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.06 (d, J=9 Hz, 1H), 6.96 (s, 1H), 6.38 (br s, 1H), 5.39 (d, J=6 Hz, 1H), 5.32 (s, 1H), 4.16 (m, 1H), 3.55 (t, J=6 Hz, 2H), 3.38 (s, 3H), 2.93 (m, 4H), 2.85 (s, 3H), 2.76 (m, 4H), 2.30 (m, 2H), 1.86 (m, 2H), 1.23 (t, 2H) ppm.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([CH3:8])[NH:3]1.[Cl:9][C:10]1[C:14](Cl)=[N:13][S:12][N:11]=1.O>CN(C=O)C>[Cl:9][C:10]1[C:14]([N:6]2[CH2:5][CH:4]([CH3:8])[NH:3][CH:2]([CH3:1])[CH2:7]2)=[N:13][S:12][N:11]=1
Reactant: CC1CNCC(C)N1
Reactant: Clc1nsnc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC1CN(c2nsnc2Cl)CC(C)N1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 97 %

Procedure:
2,6-Dimethyl-piperazine (8.1 g, 71 mmol) was heated to 100° C. in DMF (8.0 ml). 3,4-Dichloro-1,2,5-thiadiazole (3.3 ml, 35 mmol) was added and the mixture stirred at 100° C. for 3-4 h. The reaction mixture was poured into H2O and extracted with EtOAc (4×). The combined EtOAc extractions were washed with sat'd NaHCO3 (1×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo to give 7.9 g (97%) of 1-(4-chloro-[1,2,5]thiadiazol-3-yl)-3,5-dimethyl-piperazine which was used without further purification. 1H NMR (CDCl3) 3.90-3.86 (m, 2H), 3.05 (m, 2H), 2.52 (m, 2H), 1.12 (d, 6H) ppm. LC-MS (MH+)=233.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:31]=[C:32]([C:43]([OH:45])=O)[CH:33]=[C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=2)[CH:35]=1)=[O:5])C.[CH3:46][NH:47][CH3:48]>>[C:4]([CH2:6][CH2:7][C:8]1[C:9]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=3)[CH:33]=[C:32]([C:43](=[O:45])[N:47]([CH3:48])[CH3:46])[CH:31]=2)=[CH:10][CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])([OH:3])=[O:5]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3cccc(F)c3)c2)c1CCC(=O)OCC
Reactant: CNC
Product: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2cccc(F)c2)c1

Procedure:
The title compound was prepared according to the general procedure described in Steps 7 and 8 of Method C starting from 5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-3′-fluoro-biphenyl-3-carboxylic acid and dimethylamine (6% yield after two steps).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([CH3:8])=[CH:6][CH:7]=1.[F:10][C:11]([F:19])([F:18])[C:12]([F:17])([F:16])C(O)=O.[Na].CN1CCCC1=O>[Cu]I.CCCCCC>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]([F:17])([F:16])[C:11]([F:19])([F:18])[F:10])=[CH:3][C:4]=1[CH3:9]
Reactant: O=C(O)C(F)(F)C(F)(F)F
Reactant: Cc1ccc(I)cc1C
Agent: [Cu]I
Agent: [Na]
Solvent: CN1CCCC1=O
Solvent: CCCCCC
Product: Cc1ccc(C(F)(F)C(F)(F)F)cc1C
Temperature: 170 °C

Procedure:
Into a nitrogen purged, flame dried round bottom flask was added 4-iodo-o-xylene (15.0 g, 64.7 mmol), sodium pentafluoropropionic acid (16.8 g, 90.5 mmol), copper (I) iodide (12.3 g, 64.6 mmol) and 100 mL of anhydrous N-methylpyrrolidinone. The reaction mixture was heated at 170° C. for 16 hours, then cooled to room temperature, and run through a thick silica gel plug with hexane. The collected yellow liquids were then evaporated to dryness on a rotary evaporator, and the oil distilled at 60° C. (10−1 Torr) to collect the desired product (9.14 g, 63%) as a colorless liquid. Analysis of the product provided the following data: 1H NMR (200 MHz, CDCl3) δ=2.347 (s, 6H), 7.247 (d, J=7.8 Hz, 1H), 7.357 (s, 1H), 7.401 (s, 1H). 13C NMR (50 MHz, CDCl3) δ=19.810, 19.840, 124.013 (t, J=6.1 Hz), 127.472 (t, J=6.1 Hz), 130.158, 137.563, 141.205. GC-MS: m/z: 224 (C10H9F5).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.CC1(C)COB([C:23]2[CH:24]=[C:25]([C:29]3[N:30]=[N:31][N:32]([CH3:34])[N:33]=3)[CH:26]=[CH:27][CH:28]=2)OC1>>[CH3:34][N:32]1[N:31]=[N:30][C:29]([C:25]2[CH:26]=[C:27]([C:2]3[CH:11]=[CH:10][N:9]=[C:8]4[C:3]=3[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]4)[CH:28]=[CH:23][CH:24]=2)=[N:33]1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Reactant: Cn1nnc(-c2cccc(B3OCC(C)(C)CO3)c2)n1
Product: Cn1nnc(-c2cccc(-c3ccnc4nc(C(F)(F)F)ccc34)c2)n1
Yield: 6.4 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 5-[3-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)phenyl]-2-methyl-2H-tetrazole (76 mg, 0.28 mmol) as described in Example 7 part g), affording 5-[3-(2-methyl-2H-tetrazol-5-yl)phenyl]-2-trifluoromethyl[1,8]naphthyridine (5 mg, 7%). δH (360 MHz, CDCl3) 4.43 (3H, s), 7.59-7.65 (2H, m), 7.73 (1H, t, J 7.7), 7.83 (1H, d, J 8.4), 8.29 (1H, s), 8.34 (1H, d, J 7.4), 8.56 (1H, d, J 8.1), 9.30 (1H, d, J 3.9). m/z (ES+) 357 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[N:14]([CH:21]([CH2:35][CH2:36][CH3:37])[CH2:22][C:23]([NH:25][S:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:28])=[O:27])=[O:24])[C:13]3=[O:38])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.IC.[C:41](=O)([O-])[O-].[Cs+].[Cs+].[NH4+].[Cl-]>O.CN(C=O)C>[CH3:41][N:25]([C:23](=[O:24])[CH2:22][CH:21]([N:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:12]([CH2:11][C:9]2[C:10]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=3[S:7][CH:8]=2)[C:13]1=[O:38])[CH2:35][CH2:36][CH3:37])[S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: CCCC(CC(=O)NS(=O)(=O)c1ccccc1)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CCCC(CC(=O)N(C)S(=O)(=O)c1ccccc1)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Temperature: 65 °C
Yield: 70 %

Procedure:
N-{3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoyl}-benzenesulfonamide (33 mg, 0.061 mmol) and Iodomethane (0.015 mL, 0.24 mmol) are added into DMF (1.0 mL) at room temperature. Then cesium carbonate (80 mg, 0.24 mmol) is added and the mixture is warmed up to 65° C. for 10 min. Then it is cooled down to room temperature for 16 hrs. Saturated NH4Cl solution (3.0 mL) and water (10 mL) are added and the mixture is extracted with EtOAc (3×20 mL). The organic layers are combined, dried (MgSO4) and concentrated to give crude product. Purification by flash column chromatography using EtOAc in hexanes (from 0% to 30%) affords 24 mg (71%) of N-Methyl-N-{3-[3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoyl}-benzenesulfonamide. LCMS (ESMS): m/z 562.19 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:53])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4].[C:54]([O:58][C:59]([NH:61][CH2:62][C:63]([NH:65][CH2:66][C:67](O)=[O:68])=[O:64])=[O:60])([CH3:57])([CH3:56])[CH3:55]>ClCCl>[C:54]([O:58][C:59]([NH:61][CH2:62][C:63]([NH:65][CH2:66][C:67]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:53])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4])=[O:68])=[O:64])=[O:60])([CH3:57])([CH3:56])[CH3:55]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)CNC(=O)CNC(=O)OC(C)(C)C
Yield: 81 %

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-octadecyl-oleamide and N-tert-butyloxycarbonyl-glycyl-glycine. Yield 81%. [α]D =+15.0° (c=0.94, dichloromethane).