Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]1[N:27]([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[N:40]([CH3:44])[CH:39]=[CH:38]3)[C:28]([NH:31][C:32](=[O:34])[CH3:33])=[N:29][N:30]=1)C1C=CC=CC=1.O1CCCC1>[Pd].[OH-].[Pd+2].[OH-].CO>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]1[N:27]([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[N:40]([CH3:44])[CH:39]=[CH:38]3)[C:28]([NH:31][C:32](=[O:34])[CH3:33])=[N:29][N:30]=1
Reactant: CC(=O)Nc1nnc(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)n1-c1ccc2c(ccn2C)c1
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1nnc(-c2cc(C(C)C)c(O)cc2O)n1-c1ccc2c(ccn2C)c1
Reaction time: 16 h

Procedure:
A flask was charged with N-(5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)acetamide, tetrahydrofuran (10 mL), methanol (10 mL), 10% palladium on carbon (50 mg.) (in some cases palladium hydroxide was used). The reaction was stirred under an atmosphere of hydrogen for 16 hours, filtered through celite, and evaporated to give N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)acetamide. 1H-NMR (CDCl3): 8.60 (br, 1H); 7.60 (d, 1H); 7.49 (d, 1H); 7.29 (br, 1H); 7.23 (d, 1H); 7.14 (dd, 1H); 6.55 (d, 1H); 6.40 (s, 1H); 6.38 (s, 1H); 3.94 (s, 3H); 2.82 (q, 1H); 2.20 (s, 3H); 0.47 (d, 6H). MS: expected ion=406.2; observed ion=406.3.
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:12][CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1>>[Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH:19][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([C:13]#[N:12])=[CH:15][CH:16]=1)=[O:5]
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: N#Cc1ccc(CN)cc1
Product: N#Cc1ccc(CNC(=O)C(Br)c2ccccc2)cc1

Procedure:
α-Bromophenylacetic acid was reacted with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-2-bromo-N-(4-cyano-benzyl)-2-phenyl-acetamide. White solid. MS 329.1 ([M+H]+)
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3]([CH2:17][F:18])([CH2:15][F:16])[O:4][C:5]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:6]=12.[NH3:19]>C(O)C>[NH2:19][CH:7]1[C:6]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:5]=2[O:4][C:3]([CH2:17][F:18])([CH2:15][F:16])[CH:2]1[OH:1]
Reactant: O=[N+]([O-])c1ccc2c(c1)C1OC1C(CF)(CF)O2
Reactant: N
Solvent: CCO
Product: NC1c2cc([N+](=O)[O-])ccc2OC(CF)(CF)C1O
Temperature: 25 °C
Reaction time: 42 h

Procedure:
A mixture of 0.53 g of 3,4-epoxy-2,2-bisfluoromethyl-3,4-dihydro-6-nitro-2H-1-benzopyran, 15 ml of a concentrated aqueous ammonia solution and 15 ml of ethanol was stirred at room temperature for 42 hours. The solvent was distilled off and methylene chloride was added thereto. The mixture was extracted with 1N hydrochloric acid and 2N sodium hydroxide was added to an aqueous layer to form an alkaline solution. The solution was extracted with methylene chloride and the organic layer was washed with water and dried. The solvent was distilled off and the resultant residue was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain 0.32 g of 4-amino-2,2-bisfluoromethyl-3,4-dihydro-6-nitro-2H-1-benzopyran-3-ol represented by the following formula having a melting point of 174-177° C. (decomp.).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:33])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)C.Cl>CO>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([CH2:26][CH2:25][N:17]([CH2:16][CH2:15][CH2:14][O:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([OH:33])=[O:5])[CH2:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH:28]=1
Reactant: CCOC(=O)c1ccccc1OCCCN(CCc1cccnc1)Cc1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccccc1OCCCN(CCc1cccnc1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 131.9 %

Procedure:
A 1N-sodium hydroxide aqueous solution (1.8 ml) was added to a methanol solution (3 ml) of 2-{3-[N-(2-pyridin-3-ylethyl)-N-(pyridin-4-ylmethyl)amino]propoxy}benzoic acid ethyl ester (372 mg). The mixture was stirred at room temperature overnight. 6N-Hydrochloric acid (0.3 ml) was added to the reaction mixture and condensed under reduced pressure. Metanol was added to the residue, and the generated insoluble matter was separated by filtration. The filtrate was condensed under reduced pressure to give the title compound (458 mg) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:32][CH:29]3[CH2:30][CH2:31][NH:26][CH2:27][CH2:28]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NC1CCNCC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC3CCNCC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and piperidin-4-amine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 8.05 (t, J=8 Hz, 2 H), 7.88 (d, J=8 Hz, 1 H), 7.73-7.69 (m, 2 H), 7.59-7.57 (m, 2 H), 6.04 (s, 1 H), 5.33 (s, 2 H), 4.52 (s, 2 H), 4.18-4.11 (m, 1 H), 3.74 (s, 2 H), 3.61-3.57 (m, 2 H), 3.33-3.26 (m, 2 H), 2.46 (s, 3 H), 2.24-2.19 (m, 2 H), 2.01-1.91 (m, 2 H).
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[OH:18])[N:14]=[CH:13][CH:12]=[C:11]2[O:19][C:20]1[C:21]([CH3:30])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2.Br[CH:32]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:14]=[CH:13][CH:12]=[C:11]2[O:19][C:20]1[C:21]([CH3:30])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1OC)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 181.6 %

Procedure:
N,N-Dimethylformamide (3 ml) was added to 6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (50 mg), diethyl 2-bromo-malonate (75 mg), and potassium carbonate (62 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (134 mg, yield 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](I)[C:3]=1[OH:10].C([Mg]Cl)(C)C.[Cl-].[Li+].[F:18][C:19]([F:26])([F:25])[C:20](OCC)=[O:21]>O1CCCC1>[Cl:1][C:2]1[C:3]([OH:10])=[C:4]([C:20](=[O:21])[C:19]([F:26])([F:25])[F:18])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: Oc1c(Cl)cc(Cl)cc1I
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1cc(Cl)cc(Cl)c1O)C(F)(F)F
Temperature: -35 °C
Reaction time: 0.75 h
Yield: 67.1 %

Procedure:
2,4-Dichloro-6-iodophenol (2.0 grams (g), 6.9 millimoles (mmol)) was dissolved in dry tetrahydrofuran (THF; 20 milliliters (mL)), cooled to −30 to −40° C., treated in portions with isopropyl magnesium chloride-lithium chloride complex (1.3 M in THF; 7.3 mmol) and stirred for 45 minutes (min) as the temperature was allowed to rise to 0° C. The mixture was cooled to −30° C., treated with 8 mL (10 mmol) of the Grignard reagent and stirred for 30 min at −30° C. Ethyl trifluoroacetate (2.4 mL, 2.8 g, 20 mmol) was added, and the mixture was stirred for 15 min at −30° C., warmed to 25° C. and stirred for 2 hours (h). The reaction was quenched by addition of saturated (satd) ammonium chloride (NH4C1; 10 mL), diluted with ethyl acetate (EtOAc; 50 mL) and washed with 1 M hydrochloric acid (HCl; 20 mL), satd sodium chloride (NaCl; 10 mL), dried over sodium sulfate (Na2SO4) and evaporated. The residue was purified by silica gel chromatography with 0-20% EtOAc/hexane to give the purified ketone (1.2 g): mp 50-52° C.; 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J=2.4 Hz, 1H), 7.34 (d, J=2.4 Hz, 1H), 5.92 (s, 1H); EIMS m/z 258.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:11][CH:12]=[CH2:13])[C:9]=1[OH:10])[CH2:5][OH:6].Br[CH:15]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([CH2:11][CH:12]=[CH2:13])[C:9]=1[O:10][CH:15]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: C=CCc1cc(CO)cc(Cl)c1O
Reactant: COC(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCc1cc(CO)cc(Cl)c1OC(C(=O)OC)c1ccccc1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a magnetically stirred solution of 0.545 g (2.74 mmol) of the product of Step B in 10 mL acetone was added 0.628 g (2.74 mmol) of methyl α-bromophenylacetate, 0.757 g (5.48 mmol) of potassium carbonate and the reaction mixture was heated at reflux for 2.5 hours. The reaction mixture was cooled to room temperature, filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 15% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded 0.789 g (83%) of the title compound.
Reaction SMILES: Cl.[OH:2][CH2:3][C:4](=[NH:8])OCC.[C:9]([OH:14])(=[O:13])[C:10]([OH:12])=[O:11].C(O)(=O)/C=C/C(O)=O.[NH2:23][CH2:24][C@@H:25]([O:32][C:33]1[CH:40]=[C:39]([Cl:41])[C:38]([F:42])=[CH:37][C:34]=1[C:35]#[N:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:9]([OH:14])(=[O:13])[C:10]([OH:12])=[O:11].[Cl:41][C:39]1[C:38]([F:42])=[CH:37][C:34]([C:35]#[N:36])=[C:33]([CH:40]=1)[O:32][CH:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:24][NH:23][C:4](=[NH:8])[CH2:3][OH:2].[Cl:41][C:39]1[C:38]([F:42])=[CH:37][C:34]([C:35]#[N:36])=[C:33]([CH:40]=1)[O:32][CH:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:24][NH:23][C:4](=[NH:8])[CH2:3][OH:2]
Reactant: CCOC(=N)CO
Reactant: N#Cc1cc(F)c(Cl)cc1O[C@H](CN)c1ccccc1
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C(O)C(=O)O
Product: N#Cc1cc(F)c(Cl)cc1OC(CNC(=N)CO)c1ccccc1

Procedure:
The title compound was prepared by the method of Example 5 using ethyl 2-hydroxyethanimidate hydrochloride in metianol and the ethanedioic acid salt of the product from Example 1 step (c). M.p. 196° C.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:24]([S:26](Cl)(=[O:28])=[O:27])[CH3:25].C(O)(C(F)(F)F)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([NH:23][S:26]([CH2:24][CH3:25])(=[O:28])=[O:27])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)c1nc2cc(N)ccc2n1CC1CCC(F)(F)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)Nc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-amine (440 mg, 1.37 mmol) and DMAP (165 mg, 1.37 mmol) were dissolved in 50 mL of DCM. Ethanesulfonyl chloride (0.170 mL, 1.78 mmol) was added dropwise and the solution was stirred at rt for 2.5 h. The solution was washed with saturated aqueous NaHCO3 solution, saturated aqueous NaCl solution and dried over anhydrous Na2SO4. The product was purified by silica gel flash chromatography using EtOAc as eluent. The fractions were concentrated and the residue was dissolved in 25 mL of MeOH. TFA (0.155 mL, 2.06 mmol) was added dropwise and the solution was stirred at rt for 30 min. The solvent was evaporated and the product was precipitated in ether affording the title compound as its corresponding TFA salt. Yield: 565 mg (78%). 1H NMR (400 MHz, METHANOL-D4) δ 1.29 (t, J=7.42 Hz, 3 H), 1.48-1.60 (m, 2 H), 1.64 (s, 9 H), 1.66-1.72 (m, 2 H), 1.73-1.82 (m, 2 H), 1.99-2.09 (m, 2 H), 2.18 (m, 1 H), 3.11 (m, 2 H), 4.50 (d, J=7.62 Hz, 2 H), 7.38 (dd, J=9.08, 2.05 Hz, 1 H), 7.72 (d, J=2.15 Hz, 1 H), 7.85 (d, J=8.98 Hz, 1 H); MS (ESI) (M+H)+ 414.0.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[F:14][C:15]1([F:24])[O:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[O:16]1.CN([CH:28]=[O:29])C.Cl>C1(C)C=CC=CC=1>[CH:21]1[CH:20]=[C:18]2[O:19][C:15]([F:14])([F:24])[O:16][C:17]2=[C:23]([CH:28]=[O:29])[CH:22]=1
Reactant: FC1(F)Oc2ccccc2O1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: O=Cc1cccc2c1OC(F)(F)O2
Reaction time: 0.5 h

Procedure:
94.0 g (272 mmol) of n-butyllithium (18.5% in toluene) are added dropwise under a nitrogen atmosphere, at from -15° to -10° C., over a period of 1.5 hours, to 29.5 g (254 mmol) of N,N,N',N'-tetramethylethylenediamine and 40.0 g (253 mmol) of 2,2-difluoro-1,3-benzodioxole in 35 ml of toluene, an orange suspension being formed. 19.7 g (270 mmol) of DMF are then metered in at from -15° to -10° C. over a period of 1/2 hour. The pale yellow suspension is poured at +10° C. onto 346 g (1.105 mol) of 11.6% aqueous hydrochloric acid and the whole is stirred for 1/2 hour to complete the reaction. The aqueous phase is separated off and the organic phase is concentrated by evaporation in a vacuum rotary evaporator at 50° C./200 mbar under nitrogen to yield the desired product.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:13](Cl)(=O)C(Cl)=O.CO>C(Cl)Cl.N1C=CC=CC=1>[Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:13])=[O:6]
Reactant: COc1c(Br)cccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: COC(=O)c1cccc(Br)c1OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.6 %

Procedure:
3-Bromo-2-methoxybenzoic acid (2 g, 8.65 mmol, 1.0 eq) was dissolved in dry DCM and stirred for 10 minutes, cooled to 0° C. and slowly treated with oxalyl chloride (3.3 g, 25.9 mmol, 3 eq). Methanol in pyridine was added dropwise and the reaction mixture was stirred at ambient temperature. The solvents were evaporated under reduced pressure and the reaction mass was diluted with water. The aqueous mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous Na2SO4 and concentrated under vacuum to afford the desired product (1.9 g, 90%). 1H NMR (400 MHz, CDCl3) δ 3.93 (s, 6H), 7.02-6.06 (t, 1H), 7.72-7.76 (m, 2H). MS (ESI): 247.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([C:18]3[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=3)=[C:13]([CH:17]=2)[C:14](O)=[O:15])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:29][NH2:30].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([C:18]3[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=3)=[C:13]([CH:17]=2)[C:14]([NH:30][CH2:29][C:28]2[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:26]([O:25][CH3:24])[CH:27]=2)=[O:15])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Cl)cc(-c2cnc(-c3cnn(C)c3)c(C(=O)O)c2)c1
Reactant: COc1ccc(CN)cc1OC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)c2cc(-c3cc(C)cc(Cl)c3)cnc2-c2cnn(C)c2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(3-chloro-5-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)nicotinic acid (2-2, 0.050 g, 0.153 mmol) and 3,4-dimethoxybenzylamine (0.099 g, 0.595 mmol) in dimethylformamide (1 mL) was added EDC (0.132 g, 0.686 mmol), HOBt (0.105 g, 0.686 mmol) followed by N-methylmorpholine (0.250 mL, 2.28 mmol) and the system was stirred at 25° C. overnight. The reaction mixture was partitioned between ethyl acetate and water, washed with saturated sodium carbonate and dried over magnesium sulfate. The reaction mixture was filtered and purified via normal phase chromatography (0→5% MeOH in DCM) to afford the title compound (2-3) as a bone-colored powder. 1H NMR (500 MHz, CDCl3) δ 8.81 (d, J=2.5 Hz, 1H), 7.99 (s, 1H), 7.92 (d, J=2.5 Hz, 1H), 7.78 (s, 1H), 7.38 (s, 1H), 7.28 (m, 2H), 7.23 (s, 1H), 6.84 (s, 2H), 6.06 (m, 1H), 4.55 (d, J=6 Hz, 2H), 3.88(s, 3H), 3.87(s, 3H), 3.86(s, 3H), 2.42 (s, 3H). HRMS [M+H] C26H25ClN4O3 calc'd 477.1688, found 477.1682.
Reaction SMILES: [N:1]1([C:7]([NH:9][C@@H:10]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:11](O)=[O:12])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:35]([C@H:40]([CH2:45][OH:46])[CH2:41][CH2:42][CH2:43][NH2:44])[CH2:36][CH:37]([CH3:39])[CH3:38])(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:35]([CH2:36][CH:37]([CH3:39])[CH3:38])[C@H:40]([CH2:45][OH:46])[CH2:41][CH2:42][CH2:43][NH:44][C:11]([C@@H:10]([NH:9][C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:8])[CH2:14][C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:22]=[CH:23][CH:24]=2)=[O:12])(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=C(O)[C@H](Cc1cccc2ccccc12)NC(=O)N1CCOCC1
Reactant: CC(C)CN([C@H](CO)CCCN)S(=O)(=O)c1ccc(N)cc1
Product: CC(C)CN([C@H](CO)CCCNC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)N1CCOCC1)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from general procedure A using (2S)-2-[(morpholine-4-carbonyl)-amino]-3-naphthalen-1-yl-propionic acid and amine intermediate VII. The final product was obtained in 11% yield.
Reaction SMILES: C1([CH2:7][O:8][C@H]2[C@H](OCC3C=CC=CC=3)[C@@H](COCC3C=CC=CC=3)OC2O)C=CC=CC=1.[C:32]1([CH2:38][O:39][C@H:40]2[C@H:46]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C@@H:45]([CH2:55][O:56][CH2:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[O:44][C@@H:41]2[CH:42]=[O:43])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C=O.C(=O)([O-])[O-].[K+].[K+].S(=O)(=O)(O)O>CO>[OH:43][CH2:42][C:41]1([O:44][C@H:45]([CH2:55][O:56][CH2:57][C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[C@@H:46]([O:47][CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C@@H:40]1[O:39][CH2:38][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:7][OH:8]
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: O=C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: C=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CO
Product: OCC1(CO)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 85 °C

Procedure:
A 1 177 g portion of 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)-D-mannose (prepared in accordance with Example 20) was dissolved in 8.5 ml of methanol and then treated with 5.11 ml of 37% formalin and 480 mg of potassium carbonate. This mixture was heated under argon at 85° C. for 4 hours, then cooled, neutralized with 10% sulfuric acid and evaporated. The residue was taken up in chloroform, washed with brine and evaporated. The residual oil was flash chromatographed, eluting with hexane:ethyl acetate (3:2). The combined fractions gave 860 mg of the desired product, [α]D26 =+37°±2 (c. 0.555, chloroform).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1.O>C1COCC1>[CH:19]1([C:22]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]2)=[O:23])[CH2:21][CH2:20]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(Cl)C1CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a solution of ethyl piperidine-4-carboxylate (5 g) and triethylamine (5.3 mL) in THF (100 mL) was added cyclopropylcarbonyl chloride (3.99 g) at 0° C., and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and brine and dried, and the solvent was evaporated under reduced pressure to give ethyl 1-(cyclopropylcarbonyl)piperidine-4-carboxylate (6.32 g, 81%) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][N:7]1[CH2:11][C@H:10]2[C@@H:12]([NH:15][C:16](=[O:23])[C@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH2:18])[CH2:13][CH2:14][C@H:9]2[CH2:8]1.C(N(CC)CC)C.[CH:36]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37]1>ClCCl>[CH:36]1([S:39]([NH:18][C@H:17]([C:16]([NH:15][C@@H:12]2[C@H:10]3[C@H:9]([CH2:8][N:7]([CH2:6][C:5]4[CH:24]=[CH:25][CH:26]=[C:3]([C:2]([F:27])([F:1])[F:28])[CH:4]=4)[CH2:11]3)[CH2:14][CH2:13]2)=[O:23])[CH2:19][CH:20]([CH3:21])[CH3:22])(=[O:41])=[O:40])[CH2:38][CH2:37]1
Reactant: CC(C)C[C@H](N)C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: O=S(=O)(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NS(=O)(=O)C1CC1)C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N1-{(3aS,4S,6aR)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide from Step A (80 mg, 0.184 mmol) in dichloromethane (0.5 mL) was added triethylamine (0.064 mL, 0.461 mmol) followed by cyclopropanesulfonyl chloride (38.9 mg, 0.277 mmol) in a solution of 300 μL dichloromethane and the reaction mixture was stirred at room temperature overnight. The reaction was reduced in volume and loaded onto a silica gel cartridge (Analogix®, Burlington, Wis., RS-12). The title compound was eluted with a gradient of 20% to 100% ethyl acetate/hexanes over 20 minutes to give N2-(cyclopropylsulfonyl)-N1-{(3aS,4S,6aR)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide: 1H NMR (500 MHz, pyridine-d5) δ ppm 9.34 (d, J=9.0, 1H), 8.84 (d, J=6.8, 1H), 7.73 (s, 1H), 7.64 (d, J=7.5, 1H), 7.59 (d, J=12.3, 1H), 7.43 (dd, J=6.6, 14.3, 1H), 4.53-4.42 (m, 2H), 3.76 (d, J=13.2, 1H), 3.41 (d, J=13.2, 1H), 2.99 (qd, J=4.2, 8.0, 1H), 2.90 (dd, J=3.6, 9.5, 1H), 2.82-2.74 (m, 1H), 2.57-2.48 (m, 1H), 2.40 (dd, J=8.5, 19.8, 2H), 2.30 (dd, J=3.4, 9.2, 1H), 2.02 (td, J=6.5, 13.7, 1H), 1.94-1.85 (m, 2H), 1.85-1.78 (m, 1H), 1.71 (td, J=6.2, 11.6, 1H), 1.67-1.58 (m, 1H), 1.40-1.28 (m, 2H), 1.22 (dt, J=4.7, 10.8, 1H), 0.93 (ddd, J=6.6, 12.3, 14.0, 2H), 0.87 (d, J=6.5, 3H), 0.84 (d, J=6.7, 3H); MS (ESI+) m/z 502 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[CH:4]1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>CN(C)C=O>[CH2:13]([N:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[CH:4]1)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCBr
Reactant: c1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCn1ccc2cccnc21
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
To a suspension of sodium hydride in anhydrous N,N-dimethylformamide (40.0 mL) was added 1H-pyrrolo[2,3-b]pyridine (5.00 g, 42.4 mmol) at 0° C. The reaction mixture was stirred for 0.5 h, followed by the addition of 1-bromopentane (9.25 g, 61.2 mmol). The reaction mixture was stirred at ambient temperature for 3.5 h, quenched with water (20.0 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers was washed with water (3×50.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness to give the title compound (8.00 g, 100%) as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ 8.29 (dd, 1H), 7.86 (d, 1H), 7.19 (d, 1H), 7.02-6.98 (m, 1H), 6.41 (d, 1H), 4.25 (t, 2H), 1.89-1.79 (m, 2H), 1.35-1.25 (m, 4H), 0.85 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 147.4, 142.6, 128.6, 127.9, 120.6, 115.5, 99.2, 44.6, 30.1, 29.0, 22.4, 13.9.