Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:6]=[C:5]2[CH2:21][CH2:22][N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:41][CH2:42][CH3:43].CCOC(C)=O>CN(C=O)C>[CH2:41]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:11]([CH:12]([CH3:14])[CH3:13])([CH:18]([CH3:19])[CH3:20])[CH:15]([CH3:16])[CH3:17])[CH:6]=[C:5]2[CH2:21][CH2:22][N:23]1[C:24](=[O:33])[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31]1=[O:32])[CH2:42][CH3:43]
Reactant: CCCI
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(CCN2C(=O)c3ccccc3C2=O)c2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOc1ccc2c(c1)c(CCN1C(=O)c3ccccc3C1=O)cn2[Si](C(C)C)(C(C)C)C(C)C

Procedure:
Combine 2-(2-(5-hydroxy-1-triisopropylsilanyl-1H-indol-3-yl)ethyl)isoindole-1,3-dione (0.7 g, 1.5 mmol), cesium carbonate (1 g, 3 mmol) and 1-iodopropane (0.4 g, 2.3 mmol) in DMF (25 mL) and stir at ambient temperature overnight Pour the reaction mixture into 50% EtOAc in hexanes and wash three times with brine. Dry the organic layer over MgSO4 and concentrate under vacuum to give an oil. Chromatograph the oil on silica gel eluting with 5% EtOAc in hexanes to give the title compound: ISMS 505 (M+1); 1H NMR (CDCl3) 7.80-7.78 (m, 2H), 7.67-7.65 (m, 2H), 7.30-7.27 (d, 1H), 7.12-7.11 (d, 1H), 7.02 (s, 1H), 6.77-6.74 (m, 1H), 4.01-3.96 (m, 4H), 3.12-3.08 (m; 2H), 1.86-1.81 (m, 2H), 1.64-1.57 (m, 3H), 1.08-1.04 (m, 21H).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])[CH2:11]2)=[N:7][CH:6]=1)[NH2:4].[C:26](OC(=O)C)(=O)[CH3:27].Cl>N1C=CC=CC=1.O>[CH3:26][C:27]1[O:1][N:2]=[C:3]([C:5]2[S:9][C:8]([N:10]3[CH2:14][CH2:13][CH:12]([O:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:22]([F:25])([F:24])[F:23])[CH2:11]3)=[N:7][CH:6]=2)[N:4]=1
Reactant: NC(=NO)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)C2)s1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1nc(-c2cnc(N3CCC(Oc4ccccc4C(F)(F)F)C3)s2)no1
Temperature: 100 °C

Procedure:
To N′-hydroxy-2-{3-[2-(trifluoromethyl)phenoxy]pyrrolidin-1-yl}-1,3-thiazole-5-carboximidamide (190 mg, 0.51 mmol) in pyridine (1.5 mL) at rt was added acetic anhydride (48 μL, 0.51 mmol) and heated at 100° C. for 4 h. After cooling, the reaction mixture was diluted with water, acidified with 1 N HCl (20 mL) and extracted with EtOAc. The EtOAc layer was washed with diluted brine, dried (Na2SO4) and concentrated. Combi-Flash chromatography (10 g, 50-100% EtOAc in hexanes in 20 min, 20 mL/min, 15 mL/fraction) gave a white solid which was triturated with Et2O to give the title compound as a white powder. 1H NMR (400 MHz, acetone-d6): δ 7.81 (s, 1 H), 7.71-7.65 (m, 2 H), 7.41 (d, 1 H), 7.17 (t, 1 H), 5.52 (s, 1 H), 3.98 (m, 1 H), 3.84-3.67 (m, 3 H), 2.61 (s, 3 H), 2.60-2.43 (m, 2 H). MS (+ESI) m/z 397 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:31][C@H:30](COC(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C@@H:9]([O:10]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C@@H]2F)[C:5]2[CH:54]=[C:55]([Cl:59])[C:56]([Cl:58])=[CH:57][C:4]=2[N:3]=1.[C:60]([OH:66])([C:62](F)(F)[F:63])=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:6]([C@@H:7]2[O:31][C@H:30]([CH2:9][OH:10])[C@H:62]([F:63])[C@H:60]2[OH:66])[C:5]2[CH:54]=[C:55]([Cl:59])[C:56]([Cl:58])=[CH:57][C:4]=2[N:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: F[C@H]1[C@H](OC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O[C@H]1n1c(Cl)nc2cc(Cl)c(Cl)cc21
Solvent: ClC(Cl)Cl
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@H]1F

Procedure:
While the desired 3',5'-di-O-trityl derivative, compound 2, was only obtained in 10% yield from compound 1, the isomeric 2',5'-ditrityl derivative, compound 3, was obtained in a 30% yield. The fluorination of compound 3 using DAST and pyridine in CH2Cl2 gave 2,5,6-trichloro-1-(2,5-di-O-trityl-3-deoxy-3-fluoro-β-D-xylofuranosyl)benzimidazole (compound 5) in a 71% yield. The fluorination of compound 2 using the same conditions gave 2,5,6-trichloro-1-(3,5-di-O-trityl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)benzimidazole (compound 4) in a 63% yield. Both compounds 4 and 5 were deprotected using 10% CF3COOH in CHCl3 to give good yields of the deprotected nucleosides 2,5,6-trichloro-1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)benzimidazole (compound 6) and 2,5,6-trichloro-1-(3-deoxy-3-fluoro-β-D-xylofuranosyl)benzimidazole (compound 7), respectively.
Reaction SMILES: [OH:1][B:2]([OH:11])[C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.O[C:13]([C:16](O)([CH3:18])[CH3:17])([CH3:15])[CH3:14].O>C1(C)C=CC=CC=1>[CH3:14][C:13]1([CH3:15])[C:16]([CH3:18])([CH3:17])[O:1][B:2]([C:3]2[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=2)[O:11]1
Reactant: O=C(O)c1ccc(B(O)O)s1
Reactant: CC(C)(O)C(C)(C)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)OB(c2ccc(C(=O)O)s2)OC1(C)C
Temperature: 115 °C
Yield: 75 %

Procedure:
To a solution of 5-(dihydroxyboryl)-2-thiophenecarboxylic acid (4.0 g) in toluene (50 ml) was added pinacol (2.75 g). The reaction mixture was heated at 110-120° C. and the water set free during the reaction was continuously removed by a Dean-Stark apparatus. After 4 hours heating, the reaction mixture was cooled down to room temperature thus providing 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophene-carboxylic acid as a white solid which was filtered off (4.43 g, yield: 75%) and used as such for further reaction. The pure compound was characterized by its 1H NMR spectrum (300 MHz, CD3OD) as follows: peaks at 1.42 (12H, s), 7.63 (1H, d) and 7.89 (1H, d) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][CH2:32][C:33](=[O:43])[CH2:34][C:35](=[O:42])[CH2:36][C:37]([O:39]CC)=O)[C:10]([CH:28]([CH3:30])[CH3:29])=[C:11]([C:19](=[O:27])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.FC1C=CC([C:51]2[N:52](CC[C@@H](O)CC(O)CC(OC)=O)[C:53](C(C)C)=C(C(=O)NC3C=CC=CC=3)C=2C2C=CC=CC=2)=CC=1>>[CH3:51][N:52]([CH3:53])[C:37](=[O:39])[CH2:36][CH:35]([OH:42])[CH2:34][C@H:33]([OH:43])[CH2:32][CH2:31][N:9]1[C:10]([CH:28]([CH3:30])[CH3:29])=[C:11]([C:19](=[O:27])[NH:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1
Reactant: CCOC(=O)CC(=O)CC(=O)CCn1c(-c2ccc(F)cc2)c(-c2ccccc2)c(C(=O)Nc2ccccc2)c1C(C)C
Reactant: COC(=O)CC(O)C[C@H](O)CCn1c(-c2ccc(F)cc2)c(-c2ccccc2)c(C(=O)Nc2ccccc2)c1C(C)C
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)CC(O)CC(=O)N(C)C

Procedure:
In a process analogous to Step 6 METHOD A, using alternative Ru(II)-chiral diphosphine complexes in place of RuCl2(DMF)n[(R)—Cl-MeO—BIPHEP)] as the hydrogenation catalyst, one can obtain the identical products with varying enantiomeric excess at C-5. For example, in the reduction of 7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dioxo-heptanoic acid, ethyl ester to (5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid, methyl ester proceeded as follows:
Reaction SMILES: O1CCCC1.Br[C:7]1[CH:16]=[N:15][C:10]2[O:11][CH2:12][CH2:13][NH:14][C:9]=2[CH:8]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O>[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:7]1[CH:16]=[N:15][C:10]2[O:11][CH2:12][CH2:13][NH:14][C:9]=2[CH:8]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Brc1cnc2c(c1)NCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)c1ccccc1-c1cnc2c(c1)NCCO2
Reaction time: 2 h
Yield: 64.6 %

Procedure:
To 3 ml of tetrahydrofuran/0.5 ml of distilled water, 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (80.0 mg, 0.37 mmol), 2-trifluoromethyl-phenyl boronic acid (78 mg, 0.41 mmol), potassium carbonate (103 mg, 0.74 mmol) and tetrakis triphenylphosphine palladium (21 mg, 0.02 mmol) were added and then stirred at 800 for 2 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on amine silica eluting with a solvent of dichloromethane:methanol=50:1. The fractions containing the product were collected and evaporated to obtain 7-(2-trifluoromethyl-phenyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine as white solid (67 mg, 64%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[OH:35])[CH:28]=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:35][C:33]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:34]=3[N:25]=[CH:26][CH:27]=[CH:28]4)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: Oc1cccc2cccnc12
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC(NC(=O)c1coc(Oc2cccc3cccnc23)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 58.3 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with quinolin-8-ol (38 mg, 0.26 mmol) to give the title compound (37 mg, 58%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: C([O:3][P:4]([CH2:9][S:10][CH2:11][CH2:12][O:13][N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][CH:17]=[N:18][C:19]=2[NH2:23])([O:6]CC)=[O:5])C.Br[Si](C)(C)C>ClCCl>[P:4]([CH2:9][S:10][CH2:11][CH2:12][O:13][N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][CH:17]=[N:18][C:19]=2[NH2:23])([OH:6])([OH:5])=[O:3]
Reactant: CCOP(=O)(CSCCOn1cnc2c(N)ncnc21)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: Nc1ncnc2c1ncn2OCCSCP(=O)(O)O
Reaction time: 3 h
Yield: 72.8 %

Procedure:
A solution of 9-[2-(diethoxyphosphorylmethylthio)-ethoxy]adenine (0.1 g, 0.27 mmol) in dry dichloromethane at room temperature was treated with bromotrimethylsilane (0.46 g, 30 mmol) and allowed to stand for 3 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in methanol and allowed to stand for 5 minutes. The solvent was removed in vacuo and the residue was crystallised from water to give the title compound (0.06 g, 71%) as colourless crystals, m.p. 211°-13° C.; υmax (KBr) 3060, 2960, 1695, 1600, 1555, 1470, 1450, 1400, 1350 and 1300 cm-1 ; 6H [(CD3)2SO] 2.7 (2H, d J 13Hz. PCH2S), 3.1 (2H, t J 6.5Hz, CH2O), 4.6 (2H, t J 6.5Hz CH2S), 7.4 (2H, br.s, exchangeable with D2O, NH2), 8.15 (1 H, s, 2-H), 8.4 (1H, s, 8-H). (Found: C, 31.58; H, 3.92; N, 23.26%. C8H12N5O4PS requires C, 31.47; H, 3.96; N, 22.95%).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[NH:8][CH:9]=[C:10]([CH3:12])[N:11]=1.NC(N)=O.[N+:17]([O-])([OH:19])=[O:18]>>[CH3:6][C:7]1[NH:8][C:9]([N+:17]([O-:19])=[O:18])=[C:10]([CH3:12])[N:11]=1
Reactant: Cc1c[nH]c(C)n1
Reactant: O=[N+]([O-])O
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Product: Cc1nc(C)c([N+](=O)[O-])[nH]1
Temperature: 200 °C
Reaction time: 0.17 h
Yield: 67.5 %

Procedure:
Sulfuric acid (30 ml, 0.56 mole) was added dropwise to 2,4-dimethylimidazole (10 g, 0.104 mole), and urea (6.24 g, 0.104 mole), in a 1 l. flask cooled in ice. This was followed by the addition of fuming nitric acid (30 ml, 0.72 mole). When all had been added, the flask was heated at 200° C. for 1-2 minutes, whereupon a vigorous reaction ensued, necessitating the removal of the heat. When the reaction subsided, heating is continued for 10 minutes. The flask was then allowed to cool, and the reaction mixture was added to 300 ml of H2O. The solution was adjusted to pH 5 with aqueous sodium hydroxide (about 40 g of sodium hydroxide was required). The resulting precipitate was filtered off and dried in vacuum to give 9.9 g of 2,4-dimethyl-5-nitroimidazole.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.[C:26](Cl)([CH3:28])=[O:27].C([O-])(O)=O.[Na+]>C1COCC1>[C:26]([NH:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[O:5][N:4]=1)(=[O:27])[CH3:28]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)NCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
A solution of tert-butyl(3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (219 mg, 0.62 mmol) in THF (10 ml) was treated with AcCl (53 μl, 0.75 mmol) and stirred at room temperature for 1 hour. More AcCl (200 μl) was added and stirred for a further hour. Sat. NaHCO3 solution was added and the layers separated. The organic extract was washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure to afford the title compound as a colourless oil (247 mg, 100%).
Reaction SMILES: [NH2:1][C@@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30](Cl)=[O:31])[CH:26]=[CH:27][CH:28]=1>>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@@H:2]([NH:1][C:30](=[O:31])[CH2:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=2)[C:3]1=[O:20]
Reactant: CN1C(=O)[C@H](N)N=C(c2ccccc2)c2ccccc21
Reactant: COc1cccc(CC(=O)Cl)c1
Product: COc1cccc(CC(=O)N[C@@H]2N=C(c3ccccc3)c3ccccc3N(C)C2=O)c1

Procedure:
The procedure of Example 134 was carried out using equivalent amounts of 3-(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 3-methoxyphenylacetyl chloride. The product was purified by chromatography on silica gel (hexane-ethyl acetate elution). The combined product fractions were evaporated to dryness in vacuo and crystallized to give the title compound which was dried at 65° C.: m.p. 198°-199° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[CH2:16]([NH2:19])[CH2:17][CH3:18].C(N(CC)CC)C>>[CH2:16]([NH:19][S:12]([C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1])(=[O:14])=[O:13])[CH2:17][CH3:18]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Reactant: CCCN
Solvent: CCN(CC)CC
Product: CCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Yield: 712.8 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.3 g, 4.48 mmol), propylamine (264 mg, 4.48 mmol) and triethylamine(0.94mL, 6.72 mmol) were reacted to form the desired product (10 g, 71%). 1H NMR (MeOD-d4): δ7.92 (d, 1H), 7.78 (d, 1H), 3.00 (t, 2H), 1.50 (m, 2H), 0.88 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[C@H:5]([OH:9])[C:6]([OH:8])=O.Cl.[NH2:15][C@H:16]([C:18]([NH:20][N:21]1[C:27](=[O:28])[CH:26]([CH3:29])[C:25]2[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:24]=2[C:23]2[CH:35]=[CH:36][CH:37]=[CH:38][C:22]1=2)=[O:19])[CH3:17]>CO.C(Cl)(Cl)Cl>[F:13][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([F:1])[CH:12]=1)[C@H:5]([OH:9])[C:6]([NH:15][C@H:16]([C:18]([NH:20][N:21]1[C:27](=[O:28])[CH:26]([CH3:29])[C:25]2[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:24]=2[C:23]2[CH:35]=[CH:36][CH:37]=[CH:38][C:22]1=2)=[O:19])[CH3:17])=[O:8]
Reactant: O=C(O)[C@@H](O)c1cc(F)cc(F)c1
Reactant: CC1C(=O)N(NC(=O)[C@H](C)N)c2ccccc2-c2cc(F)ccc21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC1C(=O)N(NC(=O)[C@H](C)NC(=O)[C@@H](O)c2cc(F)cc(F)c2)c2ccccc2-c2cc(F)ccc21

Procedure:
Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-alaninyl)-amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-Q), the title compound was prepared. The reaction was monitored by tlc (Rf=0.4, 10% MeOH/CHCl3) and product was purified by chromatography (silica, 2.5% MeOH/CHCl3).
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17]=2[CH:33]=1)(C)(C)C>FC(F)(F)C(O)=O.O>[C:27]1([N:18]2[C:17]3[CH:33]=[C:13]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][C:6]([OH:34])=[O:5])[CH:14]=[CH:15][C:16]=3[N:20]=[C:19]2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)CCOCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)CCOCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Reaction time: 15 h

Procedure:
50 mg of 3-[2-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]ethoxy]propanoic acid-tert-butyl ester was dissolved in 0.5 ml of trifluoroacetic acid and stirred for 15 hours. Then, it was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was chromatographed on silica gel.
Reaction SMILES: [Li][CH3:2].[CH2:3]([O:5][C:6](=[O:27])[C:7](=[CH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4].[NH4+].[OH-]>C1COCC1.[Cu]I>[CH2:3]([O:5][C:6](=[O:27])[CH:7]([CH:13]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:16][CH2:15]1)[CH3:2])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(=CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCC
Reactant: [Li]C
Agent: [Cu]I
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C(C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
MeLi (5.34 mL, 8.54 mmol, 1.6 M in diethyl ether) was added dropwise to a slurry of CuI (0.74 g, 3.88 mmol) in THF (5 mL) at −78° C. under argon and the mixture was stirred for 30 min. A solution of 2-(1-tert-butoxycarbonyl-piperidin4-ylmethylene)-malonic acid diethyl ester (0.69 g, 1.94 mmol) in THF (5 mL) was added dropwise and the reacton mixture was stirred for 120 min at −78° C. and was then allowed to warm to room temperature during 60 min. Concentrated aqueous NH4OH was added and the mixture was then extracted with EtOAc, washed with concentrated aqueous NH4OH and brine, dried and concentrated under reduced pressure. The crude was purified by flash chromatography (heptane/EtOAc, 3:1→1:6) to give 2-[1-(1-tert-butoxycarbonyl-piperidin-4-yl)-ethyl]-malonic acid diethyl ester (0.39 g, 54%).
Reaction SMILES: [C:1]([C:3]1[C:8](F)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1>CN(C=O)C.O>[N:16]1([C:8]2[C:3]([C:1]#[N:2])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: c1nc[nH]n1
Reactant: N#Cc1ncccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ncccc1-n1cncn1
Temperature: 65 °C
Reaction time: 4 h

Procedure:
To a solution of 2-cyano-3-fluoro-pyridine (2.99 g, 24.49 mmol) in DMF (30 ml) is added cesium carbonate (2.03 g, 29.39 mmol) and 1,2,4-triazole (2.03 g, 29.39 mmol) and the reaction mixture is stirred at 65° C. for 4 h. After cooling to room temperature, the mixture is diluted with water and extracted with EtOAc 3 times. The aqueous layer is saturated with LiCl and further extracted with EtOAc. The combined organic layer is dried on sodium sulfate, concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, 2% MeOH containing 10% NH4OH in CH2Cl2 to 6%) to give 3-[1,2,4]Triazol-1-yl-pyridine-2-carbonitrile. 1H NMR (CDCl3, 400 MHz) δ8.95 (s, 1H); 8.8 (d, J=4 Hz, 1H); 8.24 (s, 1H); 8.22 (d, J=8.5 Hz, 1H); 7.75 (dd, J=4, 8.5 Hz, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.O>CS(C)=O>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:15][CH:14]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Clc1ccc(Cn2ccc3ccccc32)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 5.86 g (0.05 mol) of indole in 25 ml of DMSO is added to a mixture of 1.32 g of sodium hydride (0.055 mol, mineral oil suspension) in 50 ml of dimethyl sulfoxide. The resultant mixture is heated at 60° C. for 1.3 hours; after that, it is allowed to cool down and 17.7 g (0.11 mol) of 4-chlorobenzyl chloride are added dropwise. The solution is heated to 60° C. and allowed to stand overnight; it is then poured into 200 ml of water while stirring. This mixture is extracted several times with a total of 75 ml of CH2Cl2, after which the organic phase is dried with anhydrous sodium sulfate and filtered and the filtrate is evaporated in vacuo.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@H:9]1[CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:13][C@@H:11]1[CH2:12][NH:8][C@H:9]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:10]1
Reactant: COC(=O)CCCCOC[C@@H]1C[C@H](F)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCCCOC[C@@H]1C[C@H](F)CN1
Reaction time: 3.5 h

Procedure:
Methyl 5-((2S,4S)-1-(tert-butoxycarbonyl)-4-fluoro-2-pyrrolidinylmethoxy)pentanoate (1.09 g, 3.27 mmol) was dissolved in methylene chloride (50 ml). At room temperature, trifluoroacetic acid (10 ml) was added to the resulting solution. The mixture was stirred at the same temperature for 3.5 hours. The residue obtained by distilling off the solvent under reduced pressure was diluted with methylene chloride (50 ml). The solution was basified with 1N NaOH, followed by extraction with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, whereby the title compound (590 mg, 77%) was obtained as a yellow oil (this compound was provided for the subsequent reaction without further purification).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20].[CH:22]([N:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)([CH3:24])[CH3:23]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[S:15][C:14]([C:16]([NH:31][CH:28]2[CH2:29][CH2:30][N:25]([CH:22]([CH3:24])[CH3:23])[CH2:26][CH2:27]2)=[O:18])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2nc3ccccc3s2)s1
Reactant: CC(C)N1CCC(N)CC1
Product: CC(C)N1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3nc4ccccc4s3)s2)CC1

Procedure:
Prepared according to the procedure described for example 44 from 5-(1,3-benzothiazol-2-ylsulfanyl)-4-nitro-thiophene-2-carboxylic acid as in step A of example 256 (34 mg, 0.1 mmol) and 1-isopropylpiperidin-4-amine (17.0 mg, 0.12 mmol). The title compound was obtained as a solid (6.5 mg, 15% yield). MS m/z: 463.09, 465.09 [M+H]+.