Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH:34]=[N:33][NH:32][C:31]3=[O:35])=[CH:26][CH:25]=2)[CH:23]=[CH:22][N:21]=[CH:20]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:32]1[C:31](=[O:35])[N:30]([C:27]2[CH:28]=[CH:29][C:24]([N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)=[CH:25][CH:26]=2)[CH:34]=[N:33]1)[CH3:12]
Reactant: O=c1[nH]ncn1-c1ccc(-n2ccnc2)cc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Product: C[C@@H](n1ncn(-c2ccc(-n3ccnc3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane was reacted with 4-[4-(1H-1-imidazolyl)phenyl]-3(2H,4H)-1,2,4-triazolone in the same manner as in Working Example 11 to give 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(1H-1-imidazolyl)phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 22).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:15])[C:7]([C:12](O)=[O:13])=[CH:8][O:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:15])[C:7]([C:12]([Cl:18])=[O:13])=[CH:8][O:9]2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1coc2cc(O)ccc2c1=O
Product: O=C(Cl)c1coc2cc(O)ccc2c1=O

Procedure:
In accordance with the procedure described in Example 5-a), 7-hydroxychromone-3-carboxylic acid (206 mg, 1 mmol) was treated with thionyl chloride (0.3 ml, 4.1 mmol) to obtain 7-hydroxychromone-3-carbonyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:4][C:3]2[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:2]=2[Br:1])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=Cc1cc(F)ccc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(F)ccc2Br)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-bromo-5-fluoro-benzaldehyde (3.00 g, 14.8 mmol), piperazine-1-carboxylic acid tert-butyl ester (2.75 g, 14.8 mmol) and sodium triacetoxyborohydride (4.38 g, 20.7 mmol) was prepared in DCE (80 mL) and stirred at RT for 3 hours. The reaction mixture was diluted with DCM (100 mL), and then washed with a mixture of saturated aqueous solution of Na2CO3 (100 mL) and water (50 mL). The aqueous layer was extracted with DCM (100 mL). The organic layers were combined, dried (Na2SO4) and concentrated under vacuum. After purification by filtration through a silica pad (EtOAc), the title compound was obtained as a white powder (5.12 g, 93%). 1H NMR (300 MHz, CDCl3) δ 7.48 (dd, J=8.8, 5.3 Hz, 1H), 7.26 (dd, J=9.6, 3.1 Hz, 1H), 6.85 (ddd, J=8.8, 7.8, 3.1 Hz, 1H), 3.56 (s, 2H), 3.49-3.42 (m, 4H), 2.50-2.42 (m, 4H), 1.46 (s, 9H). HPLC (max plot) 94.1%; Rt 2.73 min. UPLC/MS: (MS+) 373.1 and 375.1 ([M+H]+).
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:36])[C@@H:15]([N:22]2[CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][C:28]=3[C:31]([F:34])([F:33])[F:32])[C:23]2=[O:35])[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:9]1)(C)(C)C.O.[OH-].[Li+]>O1CCCC1.O>[CH:17]1([CH2:16][C@H:15]([N:22]2[CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][C:28]=3[C:31]([F:33])([F:34])[F:32])[C:23]2=[O:35])[C:14]([NH:13][C:10]2[CH:11]=[CH:12][N:8]([CH2:7][C:6]([OH:37])=[O:5])[N:9]=2)=[O:36])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)N2Cc3c(cccc3C(F)(F)F)C2=O)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)N2Cc3c(cccc3C(F)(F)F)C2=O)n1
Reaction time: 2 h
Yield: 97.7 %

Procedure:
A mixture of {3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-acetic acid tert-butyl ester (133 mg, 0.26 mmol, prepared as in Example 3) and lithium hydroxide monohydrate (22 mg, 0.52 mmol) in tetrahydrofuran:water (1:1, 10 mL) at room temperature was stirred for 2 h. The reaction mixture was then concentrated in vacuo and partitioned between a 1 N aqueous hydrochloric acid solution and ethyl acetate. The organic layer was then dried over magnesium sulfate, filtered to remove the drying agent, and the filtrate concentrated in vacuo to afford {3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-acetic acid (118 mg, 98%) as a white foam: HR-ES(+) m/e calcd for C22H23N4O4F3 [M+H]+ 465.1744, observed 465.1744; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.93 (s, 1H), 8.01 (dd, J=7.67, 13.00 Hz, 2H), 7.69-7.80 (m, 1H), 7.59 (d, J=2.13 Hz, 1H), 6.45 (d, J=2.13 Hz, 1H), 4.95-5.12 (m, 2H), 4.81 (s, 2H), 4.72 (d, J=17.90 Hz, 1H), 1.09-2.11 (m, 11H).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([CH3:27])[CH:21]=1>CN(C=O)C>[C:1]1([S:7][CH2:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([CH3:27])[CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cc(C)c(CCl)c(-c2ccc(F)c(C)c2)c1
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CSc2ccccc2)c(-c2ccc(F)c(C)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
Thiophenol (1.4 ml, 13.6 mmoles) was added dropwise to a stirred suspension of sodium hydride (0.653 g, 13.6 mmoles) in dry DMF under an atmosphere of nitrogen. The mixture was then heated at 50° C. for 30 minutes until all of the sodium hydride was consumed and hydrogen evolution ceased. To this solution was added a solution of 2-chloromethyl-4'-fluoro-3,3',5-trimethyl-1,1'-biphenyl (3.27 g crude, approximately 11.3 mmoles) in 8 ml of dry DMF and the mixture was heated at 50° with stirring for 30 minutes. The reaction was cooled to room temperature and partitioned between ether (200 ml) and dilute sodium hydroxide solution (50 ml). The ether solution was extracted with dilute sodium hydroxide solution (50 ml) again, then extracted with dilute sodium chloride solution (2×100 ml). The ether solution was then dried (MgSO4), filtered, and the solvent was evaporated to leave 3.75 g of product. This material was purified by flash chromatography on silica gel with a 60×150 mm column eluting with methylene chloride/hexane, 1/4 (v:v) to give 3.1 g of the title compound, m.p. 72°-74° C.
Reaction SMILES: [CH3:1][CH:2]([C:4]([CH3:9])([OH:8])[CH:5]([CH3:7])[CH3:6])[CH3:3].[H-].[Na+].[CH3:12][N:13]([CH3:17])[C:14](Cl)=[O:15]>C1(C)C=CC=CC=1.CC(OC)(C)C>[CH:2]([C:4]([O:8][C:14](=[O:15])[N:13]([CH3:17])[CH3:12])([CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:1]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)C(C)(O)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)C(C)(OC(=O)N(C)C)C(C)C
Temperature: 100 °C
Reaction time: 19 h
Yield: 61 %

Procedure:
A solution of 2,3,4-Trimethyl-pentan-3-ol (13.0 g, 100 mmol, 1 equiv.) in toluene (50 ml) was added to a suspension of NaH (55% in mineral oil, 4.80 g, 110 mmol, 1.1 equiv.) in toluene (50 ml). The mixture was heated to 100° C. for 1 h, then cooled to 0° C. A solution of dimethyl carbamoyl chloride (12.9 g, 120 mmol, 1.2 equiv.) in toluene (30 ml) was added over 45 min. The resulting suspension was stirred at room temperature for 19 h, then diluted with MTBE and worked up as describe in Example 1. Distillation of the crude at 0.05 mbar/52-61° C. yielded 61% of product.
Reaction SMILES: [CH2:1](OC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)C1C=CC=CC=1>O>[C:22]1([N:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: c1ccc(COc2ccccc2)cc1
Solvent: ClCc1ccccc1
Solvent: O
Product: c1ccc(CN(c2ccccc2)c2ccccc2)cc1

Procedure:
N-phenylbanzaldimine (1.81 g, 0.010 mol) and benzylphenyl ether (1.84 g, 0.010 mol) were heated at 75° C. in Na/DMF solution (2.0 g; 50 mL) for 30 minutes. The solution was then poured in 200 mL of water, the precipitate was filtered washed with water and dried. Recrystallization from methanol, 70 mL, gave white needles (73% isolated) mp 88°-90° C. (lit mp 86°-7°C8, 88°-9°C9). No depression in melting point occurred when this material was admixed with an authentic sample prepared from diphenylamine and benzyl chloride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][C:12]([F:18])=[CH:11][C:10]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[Cl-].[NH4+]>CCO.[Zn]>[CH2:1]([O:8][C:9]1[C:10]([F:19])=[CH:11][C:12]([F:18])=[CH:13][C:14]=1[NH2:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: Nc1cc(F)cc(F)c1OCc1ccccc1
Temperature: 60 °C

Procedure:
To a solution of 2-benzyloxy-1,5-difluoro-3-nitrobenzene (2.60 g, 9.80 mmol) in EtOH (20 mL)/water (10 mL) is added zinc (3.4 g, 49 mmol) and ammonium chloride (1.0 g, 19.6 mmol) and the mixture is heated at 60° C. for 2 h. The mixture is extracted with EtOAc and the solvent is removed under reduced pressure. The residue is dissolved in methylene chloride and the solution washed with water. The organic phase is dried over sodium sulfate. The solvent is removed under reduced pressure to give the title compound which is used directly to the next step without purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[O:11])=[CH:5][CH:4]=1)#[CH:2].Br[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([CH:35]=1)[C:23]([N:25]=[S@@:26]([CH3:34])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].CCN(CC)CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCOC(C)=O>[CH3:34][S@:26](=[O:33])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[N:25][C:23](=[O:24])[C:22]1[CH:35]=[C:18]([C:2]#[C:1][C:3]2[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[O:11])=[CH:7][CH:8]=2)[CH:19]=[N:20][CH:21]=1
Reactant: C#Cc1ccc(NC(=O)c2cccs2)cc1
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccc(NC(=O)c3cccs3)cc2)c1)c1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
In a 4 mL vial, thiophene-2-carboxylic acid (4-ethynyl-phenyl)-amide (0.100 g, 0.443 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (100 mg, 0.295 mmol) were added and dissolved into EtOAc (2 mL). The mixture was then degassed for ˜20 min after which NEt3 (0.141 mL, 1.035 mmol) was added followed by Pd(PPh3)2Cl2 (20.7 mg, 0.0295 mmol) and CuI (2.8 mg, 0.148 mmol). The reaction mixture was allowed to stir at 50° C. for 3 hours after which the reaction mixture was extracted twice with EtOAc (˜5 mL) and of water (˜5 mL). The organic extracts were combined and dried over anhydrous Na2SO4(s) and then concentrated in vacuo. The crude residue was then purified by chromatography (silica gel, gradient elution, 25% EtOAc/hexanes to 100% EtOAc/hexanes). The product containing fractions were concentrated to give the title compound as a tan solid (87 mg, 0.18 mmol, 61%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1Br)(=[O:3])[CH3:2].[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:30]1[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccccc1Br
Reactant: OB(O)c1ccncc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccccc1-c1ccncc1
Yield: 65 %

Procedure:
By carrying out the operation analogously to example 1, starting from 2-bromophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 4-pyridineboronic acid, the expected product is obtained in the form of a white powder with a yield of 65%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[C:8]2[C:9]3[N:10]([N:13]=[CH:14][C:15]=3[C:16](OCC)=O)[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5]1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].C(N(CC)CC)C.[C:62](OC(=O)C)(=[O:64])[CH3:63]>O1CCCC1.O>[CH3:16][C:15]1[CH:14]=[N:13][N:10]2[CH:11]=[CH:12][C:7]3[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][NH:1][C:62](=[O:64])[CH3:63])[C:8]=3[C:9]=12
Reactant: CCOC(=O)c1cnn2ccc3c(c12)C(CCN)CC3
Reactant: CC(=O)OC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)NCCC1CCc2ccn3ncc(C)c3c21
Reaction time: 3 h
Yield: 17.2 %

Procedure:
To a solution of ethyl 9-(2-aminoethyl)-8,9-dihydro-7H-cyclopenta[c]pyrazolo[1,5-a]pyridine-1-carboxylate (45.0 mg, 0.165 mmol) in tetrahydrofuran (1.7 mL) was added 1.5M diisobutylaluminum hydride toluene solution (1.3 mL, 1.95 mmol) at room temperature, and the mixture was stirred for 3 hr. Sodium sulfate decahydrate (1.3 g) was added, and the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. To a mixture of the residue and triethylamine (34.5 μL, 0.248 mmol) in tetrahydrofuran (1.7 mL) was added acetic anhydride (23.4 μL, 0.248 mmol) under ice-cooling, and the mixture was stirred at room temperature for 15 min. Water (50 μL) was added, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) and recrystallization (ethyl acetate/diisopropyl ether) to give the title compound (7.3 mg, yield 17%).
Reaction SMILES: [C:1]([C@@H:4]1[CH2:7][C@H:6]([C:8]([OH:10])=[O:9])[C:5]1([CH3:12])[CH3:11])(=[O:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1>CN(C=O)C.CCOC(C)=O>[C:1]([C@@H:4]1[CH2:7][C@H:6]([C:8]([O:10][CH2:25][C:22]2[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=2)=[O:9])[C:5]1([CH3:12])[CH3:11])(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(=O)[C@@H]1C[C@H](C(=O)O)C1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)[C@@H]1C[C@H](C(=O)OCc2ccccc2)C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
A stirred solution of (1S,3R)-3-acetyl-2,2-dimethylcyclobutanecarboxylic acid (6.0 g, 35.29 mmol) in DMF (20 ml) at 0° C., Cs2CO3 (13.8 g, 42.34 mmol) followed by BnBr (5.06 ml, 42.34 mmol) were added slowly portion wise. The reaction was stirred at room temperature for about 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc (100 ml) and washed with water (50 ml), brine (50 ml) and dried with Na2SO4. The solvent was evaporated and purified by silica gel column (60-120, elution 4% EtOAc in hexane) to afford title compound as a pale yellow syrup. Wt: 5.6 g; Yield: 61.5%; 1H NMR (300 MHZ, CDCl3): δ 7.42-7.31 (m, 5H), 5.13 (s, 2H), 2.93-2.81 (m, 2H), 2.68 (q, 1H, J=10.5 Hz,), 2.05 (s, 3H), 1.97-1.88 (m, 1H), 1.43 (s, 3H), 0.87 (s, 3H); Mass: [M+1]+ 261 (20%), [M+Na]+ 283 (87%); IR (KBr, cm−1): 2889, 1732, 1708, 1498, 1456, 1329, 1279, 1183, 1027, 954, 752, 698.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][NH2:5].[CH2:8]([N:15]([CH:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28])[CH:16]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:17][C:18](O)=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:8]([N:15]([CH:27]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH3:28])[CH:16]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:17][C:18]([NH:5][CH2:4][CH2:3][C:2]([CH3:7])([CH3:6])[CH3:1])=[O:19])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(c1ccccc1)N(Cc1ccccc1)C(CC(=O)O)C1CCCCC1
Reactant: CC(C)(C)CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(c1ccccc1)N(Cc1ccccc1)C(CC(=O)NCCC(C)(C)C)C1CCCCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 3,3-dimethyl butylamine (0.6 mL, 4.2 mmol), 3-[benzyl-(1-phenyl-ethyl)-amino]-3-cyclohexyl-propionic acid (1.83 g, 3.8 mmol), HBTU (2.2 g, 5.7 mmol), DIPEA (1.5 mL, 8.6 mmol) and DMF (25 mL) was stirred at room temperature for 14 hours. To the reaction mixture was then added sodium bicarbonate(s) (100 mL) and the desired product was extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with water, dried over MgSO4 and concentrated to yield a solid. The solid was purified by column chromatography (10% EtOAc/heptane) to yield a residue.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.O.[C:14](OCC)(=O)C>CO.Cl>[CH3:1][O:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:14])=[O:9])=[CH:6][CH:5]=1
Reactant: CCOC(C)=O
Reactant: COCc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: COCc1ccc(C(=O)OC)cc1
Reaction time: 2.5 h

Procedure:
Methyl 4-(methoxymethyl)benzenecarboxylate (MMBC) was prepared from 4-(methoxymethyl)benzoic acid (Sigma-Aldrich) by esterification in methanol using HCl as catalyst. The reaction was conducted under reflux conditions for 2.5 hours. Following the reaction, water and ethyl acetate was added and the MMBC product was separated using liquid extraction into the ethyl acetate phase. The ethyl acetate was then removed by rotary evaporation to obtain the isolated MMBC product. The 1H NMR spectrum of the product was collected in CDCl3, and the peak positions and integrated areas matched that of the reported 1H NMR spectrum for this molecule.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:22])[C:14]=1[N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[Cl:23][C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27]>>[Cl:23][C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH:22][C:13]1[C:14]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[C:2]([Cl:1])[CH:3]=[C:4]2[C:12]=1[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1)=[O:27]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CN1CCN(c2c(Cl)cc3c([nH]c4cnccc43)c2N)CC1
Product: CN1CCN(c2c(Cl)cc3c([nH]c4cnccc43)c2NC(=O)c2cccnc2Cl)CC1
Yield: 25 %

Procedure:
The desired compound was prepared according to Method A from 6-chloro-7-(4-methyl-piperazin-1-yl)-8-amino-9H-β-carboline and 2-chloro-nicotinic acid in 25% yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([CH2:9]O)=[CH:4][N:3]=1.S(Cl)([Cl:13])=O>ClCCl>[Cl:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([CH2:9][Cl:13])=[CH:4][N:3]=1
Reactant: OCc1cnc(Cl)c(Br)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1cnc(Cl)c(Br)c1
Reaction time: 5 h
Yield: 62.7 %

Procedure:
To a solution of 2-chloro-3-bromo-5-hydroxymethylpyridine (1.0 g, 4.5 mmol) in dichloromethane (20 mL) at 25° C. was added thionyl chloride (361 μL, 4.9 mmol) dropwise. The solution was stirred for 5 h, after which the reaction was quenched with saturated aqueous NaHCO3 and the layers separated. The aqueous phase further extracted with EtOAc (3×) and the combined organic phases dried over MgSO4 and concentrated to furnish 2-chloro-3-bromo-5-chloromethylpyridine as a yellow solid (0.68 g, 63%). GC-MS: Exact mass calcd for C6H5BrCl2N [M+H]+, 241. Found 241.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[F:13].[C:14]([O:18][C:19]([N:21]1[CH2:28][CH:27]2[O:29][CH:23]([CH2:24][NH:25][CH2:26]2)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:14]([O:18][C:19]([N:21]1[CH2:22][CH:23]2[O:29][CH:27]([CH2:26][NH:25][CH2:24]2)[CH:28]1[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[F:13])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Reactant: N#Cc1ccc(OCCBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CNCC(O2)C1CCOc1ccc(C#N)cc1F
Temperature: 60 °C
Reaction time: 120 h
Yield: 65.8 %

Procedure:
A suspension of 4-(2-bromoethoxy)-3-fluorobenzonitrile (21.6 g, 0.0885 mol; see step (v) above), 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (21.1 g, 0.07965 mol; see WO 01/28992) and dry K2CO3 (48.9 g, 0.354 mol) in 200 mL of dry acetonitrile was stirred at 60° C. for five days under a nitrogen atmosphere. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel, using 27% ethyl acetate in petroleum ether as eluent, to yield 20.5 g of the sub-title compound as a solid.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:19][O:20][CH3:21])[C:7]([CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:8][C:4]=2[CH:3]=1.BrC1C=CC2N=C(CN(C)C(=O)O[C:37]([CH3:40])(C)[CH3:38])N(COC)C=2C=1.C1(B(O)O)CC1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1.O>[CH:40]1([C:2]2[CH:23]=[CH:22][C:5]3[N:6]([CH2:19][O:20][CH3:21])[C:7]([CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:8][C:4]=3[CH:3]=2)[CH2:37][CH2:38]1
Reactant: COCn1c(CN(C)C(=O)OC(C)(C)C)nc2ccc(Br)cc21
Reactant: COCn1c(CN(C)C(=O)OC(C)(C)C)nc2cc(Br)ccc21
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COCn1c(CN(C)C(=O)OC(C)(C)C)nc2cc(C3CC3)ccc21
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a mixture of a mixture (1.25 g) of tert-butyl {[5-bromo-1-(methoxymethyl)-1H-benzimidazol-2-yl]methyl}methylcarbamate and tert-butyl {[6-bromo-1-(methoxymethyl)-1H-benzimidazol-2-yl]methyl}methylcarbamate and toluene/water (20/1, 26.3 mL) were added cyclopropylboronic acid (840 mg), palladium (II) acetate (146 mg), tricyclohexylphosphine (365 mg), and potassium phosphate (4.14 g), followed by heating and stirring at 100° C. overnight. The reaction mixture was diluted with EtOAc, and washed with water, 1 M hydrochloric acid solution, and brine in this order. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: Hex/EtOAc=80/20-55/45) to obtain a mixture (505 mg) of tert-butyl {[5-cyclopropyl-1-(methoxymethyl)-1H-benzimidazol-2-yl]methyl}methylcarbamate and tert-butyl {[6-cyclopropyl-1-(methoxymethyl)-1H-benzimidazol-2-yl]methyl}methylcarbamate.