Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=2[C:15]#[N:16])[CH:7]=1.[OH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.[C:32](=O)([O-])[O-].[Cs+].[Cs+].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH2:20]([O:19][C:17]([C:4]1[CH:3]=[C:2]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH2:22][OH:21])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=2[C:15]#[N:16])[CH:5]=1)=[O:18])[CH3:32]
Reactant: OCc1ccccc1B(O)O
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Br)cc(-c2ccc(C)cc2C#N)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(C)cc2C#N)cc(-c2ccccc2CO)c1

Procedure:
Into a 5 mL microwave vial were charged methyl 5-bromo-2′-cyano-4′-methylbiphenyl-3-carboxylate (95 mg, 0.29 mmol), 2-(hydroxymethyl)phenylboronic acid (87 mg, 0.57 mmol), cesium carbonate (466 mg, 1.43 mmol), tetra-n-butylammonium iodide (106 mg, 0.29 mmol), POPd (14 mg, 0.029 mmol), water (0.2 mL) and N,N-dimethylformamide (1 mL). The reaction mixture was subjected to microwave irradiation for 10 mins at 150° C. After cooling, the reaction mixture was extracted with ethylacetate. The organic layer was washed with brine, dried, and concentrated under reduced pressure to give the residue which was purified by HPLC to yield the title compound.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([C:7]([F:10])([F:9])[F:8])([CH3:6])[CH2:4][OH:5].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl.O>[F:1][C:2]([F:11])([F:12])[C:3]([CH3:6])([C:7]([F:9])([F:8])[F:10])[CH2:4][O:5][S:21]([CH3:20])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(CO)(C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(COS(C)(=O)=O)(C(F)(F)F)C(F)(F)F
Yield: 101.7 %

Procedure:
To 2,2-bis(trifluoromethyl)propanol (4.34 g, 22.1 mmol) in DCM (100 mL) at 0° C. add with stirring triethylamine (6.2 mL, 44 mmol) followed by methanesulfonyl chloride (2.6 mL, 33 mmol). After 15 min at 0° C. dilute with water and extract three times with EtOAc. Dry over anhydrous Na2SO4 and concentrate in vacuo to give the crude desired intermediate as a yellow oil (6.16 g, 100%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[O:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][NH:17][CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C.CN1CCCC1=O>[Cl-].[Na+].O>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([N:17]2[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:14][CH2:15][CH2:16]2)[CH:11]=1
Reactant: Clc1cc(Cl)c2ccccc2n1
Reactant: c1ccc2c(c1)CNCCO2
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(N2CCOc3ccccc3C2)nc2ccccc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 382.9 %

Procedure:
The mixture of 2,4-dichloroquinoline (198 mg, 0.1 mmol), 2,3,4,5-tetrahydro-1,4-benzoxazepine hydrochloride (186 mg, 0.1 mmol), diisopropylethylamine (0.4 mL) and 5 mL of N-methyl-2-pyrrolidone was heated with stirring at 100° C. overnight. The mixture was cooled to room temperature, diluted with brine, and extracted with ethyl acetate (30 mL×3). The organic layers were combined and washed with brine. The solvent was dried over sodium sulfate and removed under reduced pressure to give a residue which was purified by column chromatography on silica gel to give 119 mg of product as a white solid. MS obsd. (ESI+) [(M+H)+] 311.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH:4]([CH2:12][OH:13])[CH2:3]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>ClCCl>[CH3:21][S:22]([O:13][CH2:12][CH:4]1[CH2:3][N:2]([CH3:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CN1CC(CO)Oc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CN1CC(COS(C)(=O)=O)Oc2ccccc21
Reaction time: 10 h
Yield: 42.9 %

Procedure:
To a solution of 4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-methanol (6.0 g, 33.51 mmol) in dichloromethane (20 mL) was added triethylamine (10.15 g, 100.5 mmol) under nitrogen atmosphere at 25° C. Methanesulfonyl chloride (5.75 g, 50.25 mmol) was added to the above reaction mixture at 0° C. and stirring was continued for further 10 h at 25° C. Water (50 mL) was added and extracted with chloroform (2×25 mL). The combined organic extracts were washed with water (50 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed over silica gel using a mixture of ethyl acetate and hexane (2:8) to yield (4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl methanesulfonate (3.7 g, 43%) as a syrup.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([CH2:13][CH3:14])[N:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](=[O:15])[NH:8]2)[CH3:2].[H-].[Na+].Cl.[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22]Cl>CN(C)C=O>[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][N:8]1[C:9]2[C:4](=[C:3]([CH2:1][CH3:2])[CH:12]=[C:11]([CH2:13][CH3:14])[N:10]=2)[CH:5]=[CH:6][C:7]1=[O:15]
Reactant: CN(C)CCCl
Reactant: CCc1cc(CC)c2ccc(=O)[nH]c2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc(CC)c2ccc(=O)n(CCN(C)C)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 5,7-diethyl-1,8-naphthyridin-2(1H)-one (4.04 g., 0.02 mole) in 25 ml. of dry dimethylformamide under nitrogen atmosphere is added a 57% suspension of sodium hydride in mineral oil (0.84 g., 0.02 mole). This mixture is stirred at room temperature for 0.5 hours. Then a mixture of 2-dimethylaminoethyl chloride hydrochloride (3.17 g., 0.022 mole) and a 57% suspension of sodium hydride in mineral oil (0.93 g., 0.022 mole) in 25 ml. of dry dimethylformamide is added to the above suspension. The mixture is stirred at steam bath temperature overnight (16 hours). After the mixture is cooled to room temperature it is filtered to remove salt (2.6 g., theory 2.45 g.). Removal of the solvent under reduced pressure gives a pale tan waxy solid (4.8 g.). Several recrystalizations from hexane gives 1-(2-dimethylaminoethyl)-5,7-diethyl-1,8-naphthyridin-2(1H)-one melting at 59.5°-61° C.
Reaction SMILES: CS(O[CH2:6][C@H:7]([NH:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]([O:10][CH3:11])=[O:9])(=O)=O.[I-:32].[Na+]>CC(C)=O>[I:32][CH2:6][C@H:7]([NH:12][C:13]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: [I-]
Reactant: COC(=O)[C@H](COS(C)(=O)=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)[C@H](CI)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of methyl (2S)-3-[(methylsulfonyl)oxy]-2-(tritylamino)propanoate CII (22 g; 0.05 mol) in acetone (700 mL) was added sodium iodide (150 g; 1.0 mol) and stirred at r.t. for one week under argon. The acetone was evaporated and the residue was dissolved in diethyl ether (1.5 L). The solids were filtered and the solvent reduced to 1 L before washing with 10% aq Na2S2O3 (3×) and water (200 mL). The solvent was removed under reduced pressure and the residue purified on a silica gel column (10:1→2:1 hexane/EtOAc) and then crystallized from hexane. The methyl (2R)-3-iodo-2-(tritylamino)propanoate CIII was obtained as yellow foam (21 g; 0.045 mol; 89% yield). 1H NMR (CDCl3) [2.25-2.28 (m, 1st rotamer), 2.89 (d, J=10 Hz, 2nd rotamer), 1H], [2.54 (dd, J=13 Hz, J=6 Hz), 3.21 (dd, J=10 Hz, J=8 Hz), 1st rotamer, 1H], [2.69 (dd, J=12 Hz, J=8 Hz), 3.35 (dd, J=10 Hz, J=3 Hz), 2nd rotamer, 1H], [3.31 (s, 1st rotamer), 3.77 (s, 2nd rotamer), 3H], [3.48 (ddd, J=10 Hz, J=7 Hz, J=3 Hz, 2nd rotamer), 4.39 (dd, J=8 Hz, J=6 Hz, 1st rotamer), 1H], 7.18-7.22 (m, 3H), 7.29 (dd, J=8 Hz, J=7 Hz, 6H), [7.45 (d, J=8 Hz, 1st rotamer), 7.50 (d, J=8 Hz, 2nd rotamer), 6H].
Reaction SMILES: [NH2:1][CH:2]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.O>ClCCl>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:1][CH:2]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:3][C:4]2[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: COC(=O)Cc1ccc(CC(N)c2cccnc2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)Cc1ccc(CC(NS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
To 0.11 g of methyl 4-[2-amino-2- (3-pyridyl)ethyl]phenylacetate in 10 ml of dichloromethane were added 0.07 ml of triethylamine (0.07 ml) and 0.11 g of p-chlorobenzenesulfonyl chloride, and stirred overnight at room temperature. After completion of reaction, water was added to the reaction mixture, which was then extracted with dichloromethane, followed by washing in saturated aqueous sodium chloride solution and dried over magnesium sulfate to obtain residue of 0.31 g. The residue was subjected to chromatography on a silica gel column, which was then eluted with chloroform-methanol (10:1 v/v) to produce 0.1 g of methyl 4-[2-(4-chlorobenzenesulfonamido)-2-(3-pyridyl)ethyl]phenylacetate. The spectrometric data thereof supports the structure of [28] as follows.
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[N:5]=[CH:6][C:7]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[NH2:16])=[N:8][CH:9]=1.[F:19][CH:20]([F:30])[C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24].C(N(CC)CC)C.O1POPOP1>C(Cl)Cl>[F:19][CH:20]([F:30])[C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:16][C@H:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[NH:10][C:7]1[CH:6]=[N:5][C:4]([C:3]([F:2])([F:17])[F:18])=[CH:9][N:8]=1)=[O:24]
Reactant: O=C(O)c1ccccc1C(F)F
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Agent: O1POPOP1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ccccc1C(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 100 mg, 0.35 mmol), 2-(difluoromethyl)benzoic acid (CAS number 799814-32-7; 61 mg, 0.35 mmol) and triethylamine (0.148 ml, 1.06 mmol) in DCM (2 ml) was added 1,3,5,2,4,6-trioxatriphosphorinane, 2,4,6-tripropyl-, 2,4,6-trioxide (CAS number 68957-94-8; 50% in ethyl acetate, 0.417 ml, 0.71 mmol). The reaction mixture was stirred at room temperature for 3 hours. To this was then added further 1,3,5,2,4,6-trioxatriphosphorinane, 2,4,6-tripropyl-, 2,4,6-trioxide (CAS number 68957-94-8; 50% in ethyl acetate, 0.417 ml, 0.71 mmol) and stirred at room temperature overnight. The reaction was partitioned between DCM and a saturated solution of sodium bicarbonate, filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) and then triturated with diethyl ether to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:20]([C@@H:23]3[CH2:27][CH2:26][CH2:25][N:24]3[CH3:28])=[N:21][N:22]=2)[CH:5]=[C:6]([O:8][C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@@H:12]([NH2:19])[CH2:11][CH2:10]2)[CH:7]=1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[N:36]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:40]([C:38]1[CH:39]=[C:35]([NH:34][C:33]([NH:19][C@@H:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:9]([O:8][C:6]3[CH:7]=[C:2]([CH3:1])[C:3]4[N:4]([C:20]([C@@H:23]5[CH2:27][CH2:26][CH2:25][N:24]5[CH3:28])=[N:21][N:22]=4)[CH:5]=3)[CH2:10][CH2:11]2)=[O:32])[N:36]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[N:37]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: Cc1cc(O[C@@H]2CC[C@H](N)c3ccccc32)cn2c([C@@H]3CCCN3C)nnc12
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3cc(C)c4nnc([C@@H]5CCCN5C)n4c3)c3ccccc32)cc1
Temperature: 25 °C
Yield: 74 %

Procedure:
A mixture of Intermediate 105e (53 mg, 0.14 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (for reference procedure see Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 67 mg, 0.168 mmol) and DIPEA (49 μL, 0.28 mmol) in DMF (2 mL) was stirred at 100° C. for 1.5 h under argon atmosphere. After cooling to RT, the reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-100% EtOAc in cyclohexane followed by 10% [2M NH3 in MeOH] in EtOAc. The product containing fractions were concentrated in vacuo and the resultant residue was purified by HPLC (C18 Phenomenex Gemini column, 5-98% gradient MeCN in H2O, 0.1% NH4OH), to afford the title compound (52 mg, 74%). LCMS (Method 5): Rt 3.76 min, m/z 633 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.23 (9H, s), 1.75-2.30 (13H, m), 2.32 (3H, s), 2.48 (3H, s), 3.19 (1H, br s), 4.72-4.83 (1H, m), 5.30-5.38 (1H, m), 6.28 (1H, s), 7.03-7.11 (2H, m), 7.20-7.36 (8H, m), 8.00 (1H, s), 8.11 (1H, s).
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[OH-].[K+].[Cl:10][C:11]1[CH:12]=[C:13]([C:17](=[O:19])[CH3:18])[CH:14]=[CH:15][CH:16]=1.OS(O)(=O)=O>CO.O>[Cl:10][C:11]1[CH:12]=[C:13]([C:17](=[O:19])[CH2:18][C:2]([CH2:6][CH3:7])([OH:1])[C:3]([OH:5])=[O:4])[CH:14]=[CH:15][CH:16]=1
Reactant: CCC(=O)C(=O)O
Reactant: CC(=O)c1cccc(Cl)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(O)(CC(=O)c1cccc(Cl)c1)C(=O)O
Temperature: 0 °C
Reaction time: 48 h

Procedure:
A RBF was charged with 2-oxobutanoic acid (2.50 g, 24.5 mmol) and 3.2 mL of water and the mixture was cooled to 0° C. The acid was neutralized by slow addition of 20% aqueous KOH. 3′-chloroacetophenone (3.79 g, 24.5 mmol) was added, followed by a 1.3 M solution of KOH (2.20 g, 39.2 mmol) in MeOH. The reaction mixture was stirred at 0° C. for 48 h. The mixture was brought to pH 2 by dropwise addition of conc. H2SO4. The MeOH was removed in vacuo, and 25 mL of water was added. The heterogeneous mixture was filtered through Celite, and the filter cake was washed with water and CH2Cl2. The layers of the filtrate were separated, and the aqueous portion was extracted with additional CH2Cl2. The combined organics were dried with MgSO4, filtered and concentrated to a volume of ˜25 mL. Hexane was added until the mixture became cloudy, and upon standing a white crystalline solid formed. The mother liquor was decanted and the solids were washed with hexane and dried to provide 4-(3-chlorophenyl)-2-ethyl-2-hydroxy-4-oxobutanoic acid as a white crystalline solid. MS m/z=279 [M+Na]+. Calc'd for C12H13ClO4: 256.69.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.ON1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=N1.CN1CC[O:25]CC1.CCN=C=NCCCN(C)C>>[OH:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:20]([C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[O:25])=[CH:4][CH:5]=1
Reactant: CN1CCOCC1
Reactant: NCc1ccc(CO)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Product: O=C(NCc1ccc(CO)cc1)c1ccccn1
Yield: 95 %

Procedure:
Using General Procedure F: Reaction of (4-aminomethyl-phenyl)-methanol (200 mg, 1.46 mmol, 1-hydroxybenzotriazole (218 mg, 1.61 mmol), 4-methyl morpholine (241 uL, 2.19 mmol), and EDCI (309 mg, 1.61 mmol) for 2 h at room temperature gave the title compound (335 mg, 95%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 4.67 (d, 2H, J=6.0 Hz), 4.69 (s, 2H), 7.36 (br s, 4H), 7.43-7.44 (m, 1H), 7.85-7.86 (m, 1H), 8.24 (d, 1H, J=9.0 Hz), 8.52 (br s, 1H), 8.52 (d, 1H, J=3.0 Hz). ES-MS m/z 243 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:10])=[C:4]([F:22])[CH:3]=1.[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28](B(O)O)=[CH:27][N:26]=1>>[F:8][C:6]1[CH:7]=[C:2]([C:28]2[CH:27]=[N:26][C:25]([O:24][CH3:23])=[N:30][CH:29]=2)[CH:3]=[C:4]([F:22])[C:5]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:10]
Reactant: COc1ncc(B(O)O)cn1
Reactant: O=C(c1c(F)cc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Product: COc1ncc(-c2cc(F)c(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)cn1

Procedure:
The title compound is prepared in a manner substantially analogous to Example 14 via Procedure F′ from (4-bromo-2,6-difluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 2-methoxypyrimidine-5-boronic acid (CAS 628692-15-9). MS (FIA) 403 (MH+)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:12]=1[CH2:13]Br.[H-].[Na+]>CN(C)C=O>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:12]=1[CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Clc1cccc(Cl)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2c(Cl)cccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 107.6 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (3.59 g, 24.39 mmol) and 2,6-dichlorobenzyl bromide (7.05 g, 29.39 mmol) in dimethylformamide (20 mL) at 0° C. was added 60% sodium hydride (1.176 g, 29.39 mmol). After stirring at ambient temperature for 16 h, the reaction was partitioned between ethyl acetate and water. The organic layer was washed with aqueous sodium chloride and dried (MgSO4). Purification by flash column chromatography (silica gel, hexane/ethyl acetate) yielded an off-white solid (7.38 g, 89%). MS(ES) m/e 281.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4]Br.C([O-])([O-])=[O:12].[Ca+2]>O1CCOCC1.O>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4][OH:12]
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(Br)c(CBr)c1
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: OCc1cc(F)ccc1Br

Procedure:
2-Bromo-5-fluorobenzylbromide (2.0 g, 7.46 mmol) was dissolved in dioxane (25 mL) and H2O (25 mL), and CaCO3 (3.84 g, 38.39 mmol) was added. The mixture was heated to reflux overnight. The solution was concentrated, and the residue was partitioned between H2O and CH2Cl2. The organic phase was washed with 1N HCl and brine, dried (MgSO4), filtered, and concentrated to afford the title compound. 1H NMR (CDCl3): δ2.00 (t, 1 H), 4.72 (d, 2 H), 6.85-6.92 (m, 1 H), 7.26 (dd, 1 H), 7.48 (dd, 1 H).
Reaction SMILES: [C:1]([N:8](C)[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:28][C:29]2[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=2[O:35][CH3:36])[C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])[CH2:11][CH2:10]1)(OC(C)(C)C)=O.[NH2:41][C:42]1[N:47]=[C:46]([CH3:48])[C:45](Br)=[CH:44][CH:43]=1>>[ClH:27].[ClH:27].[NH2:41][C:42]1[N:47]=[C:46]([CH3:48])[C:45]([C:31]2[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:29]([CH:30]=2)[CH2:28][N:15]([CH:12]2[CH2:13][CH2:14][CH:9]([NH:8][CH3:1])[CH2:10][CH2:11]2)[C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])=[CH:44][CH:43]=1
Reactant: Cc1nc(N)ccc1Br
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: CNC1CCC(N(Cc2cc(-c3ccc(N)nc3C)ccc2OC)C(=O)c2sc3ccccc3c2Cl)CC1
Product: Cl

Procedure:
The title compound was prepared from boronic acid (5) (25 mg, 43 μmol) and 6-amino-3-bromo-2-methylpyridine (6.6 mg, 41 μmol) in accordance with Method L2.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.I[CH2:26][CH2:27][CH3:28].C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CCC)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:26][CH2:27][CH3:28])[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: CCCI
Agent: CCCn1nc2c(c1-c1ccc(Cl)cc1)CCN(C(=O)OC(C)(C)C)CC2
Product: CCCn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2

Procedure:
The title compound (0.031 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 g) using 1-iodopropane (0.33 mL) in place of benzyl chloride. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-propyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C16H20ClN3, 289.13. found, m/z 290.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.39-7.35 (m, 4H), 4.03 (t, J=7.2 Hz, 2H), 3.37-3.35 (m, 2H), 3.27-3.24 (m, 2H), 3.15-3.13 (m, 2H), 2.95-2.93 (m, 2H), 1.76-1.69 (m, 2H), 0.84 (t, J=7.4 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[N:11][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([CH:34]=3)[CH2:19][CH2:20][C:21]3[CH:29]=[C:25]([NH:26][C:27]=1[N:28]=2)[CH:24]=[C:23]([C:30]([O:32]C)=[O:31])[CH:22]=3.O>C(#N)C.[OH-].[Na+]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[N:11][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([CH:34]=3)[CH2:19][CH2:20][C:21]3[CH:29]=[C:25]([NH:26][C:27]=1[N:28]=2)[CH:24]=[C:23]([C:30]([OH:32])=[O:31])[CH:22]=3
Reactant: COC(=O)c1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Yield: 36.6 %

Procedure:
A solution of methyl 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene-11-carboxylate trifluoroacetate (45 mg, 90.9 μmol) in acetonitrile (5 mL) and 2.0 M of sodium hydroxide in water (227 μL, 0.455 mmol) were stirred at 25° C. overnight. Purification by preparative LCMS gave the desired product as a white solid (16 mg, 48%). LCMS for C19H16ClN4O2 (M+H)+: m/z=367.1. 1H NMR (400 MHz, DMSO-d6): δ 9.33 (s, 1H), 9.28 (s, 1H), 8.12 (s, 1H), 8.01 (m, 1H), 7.86 (m, 1H), 7.71 (m, 1H), 7.58 (m, 1H), 7.11 (t, 1H), 6.91 (m, 1H), 6.82 (m, 1H), 2.93 (m, 2H), 2.87 (m, 2H).
Reaction SMILES: C(O[C@@H:5]1[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:6]1[O:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.[CH:38]1[C:43]([N+:44]([O-:46])=[O:45])=[CH:42][CH:41]=[C:40]([OH:47])[CH:39]=1.B(F)(F)F.CCOCC>ClCCl>[C:8]([O:7][C@@H:6]1[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:27][C@H:5]1[O:47][C:40]1[CH:41]=[CH:42][C:43]([N+:44]([O-:46])=[O:45])=[CH:38][CH:39]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(OC[C@H]1O[C@@H](Oc2ccc([N+](=O)[O-])cc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 71.7 %

Procedure:
A solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (10 g), p-nitrophenol (5.6 g, 2 eq) and boron trifluoride diethyl etherate (1.2 ml, 0.5 eq) in dry dichloromethane (100 ml) was allowed to stand at room temperature overnight. Thin-layer chromatography on silica gel [Eluant EtOAc:CHCl3:Hexanes 1:2:4] then indicated essentially complete conversion to a slightly less polar material. The solution was washed with aq bicarbonate and processed conventionally. Flash chromatography on silica gel [eluant EtOAc:CHCl3:Hexanes 1:2:8] then afforded 8.29 g of title compound.