Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[O:13][C:14]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25]Br)[C:15]=3[C:16]=2[CH3:17])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][NH2:34])[CH:28]=1>CN1CCCC1=O.C(OCC)(=O)C>[CH:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[O:13][C:14]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][NH:34][CH2:33][C:29]4[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=4)[C:15]=3[C:16]=2[CH3:17])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCc1cccnc1
Reactant: Cc1c(C(=O)NCCC2CCCCC2)oc2cccc(OCCCBr)c12
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)NCCC2CCCCC2)oc2cccc(OCCCNCc3cccnc3)c12
Temperature: 100 °C

Procedure:
4-(3-Bromo-propoxy)-3-methyl-benzofuran-2-carboxylic acid (2-cyclohexyl-ethyl)-amide (100 mg) and 3-picolyl amine (250 μl) were dissolved in 1-methylpyrrolidone (2 ml) and heated at 100° C. for two hours. The reaction mixture was dissolved in ethyl acetate and washed with saturated ammonium chloride solution and water. The organic solvent was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography (dichloromethane-MeOH) to afford 3-methyl-4-{3-[(pyridin-3-ylmethyl)-amino]-propoxy}-benzofuran-2-carboxylic acid (2-cyclohexyl-ethyl)-amide. ESI-MS: m/z 450 (MH+); 1H-NMR (CDCl3): δ 0.85-1.85 (13H, m), 2.05 (2H, quintet, J=6.5 Hz), 2.72 (3H, s), 2.90 (2H, t, J=6.5 Hz), 3.46 (2H, m), 3.85 (2H, s), 4.15 (2H, t, J=6.5 Hz), 6.53 (1H, t, J=6 Hz), 6.62 (1H, d, 8 Hz), 7.01 (1H, d, J=8 Hz), 7.26 (2H, m), 7.68 (1H, dd, J=1.5 Hz, 8 Hz), 8.49 (1H, br d, J=3.5 Hz), 8.56 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:19][C:18]([CH2:20]Cl)=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([OH:37])[CH2:34][NH:35][CH3:36])=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:19][C:18]([CH2:20][N:35]([CH2:34][CH:33]([OH:37])[C:30]4[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=4)[CH3:36])=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CNCC(O)c1ccc(OC)cc1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CCl)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(O)CN(C)Cc2cc3c(s2)c(=O)c(C(=O)NCc2ccc(Cl)cc2)cn3C)cc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 48.9 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (80 mg, 0.21 mmol), 1-(4-methoxyphenyl)-2-(methylamino)ethanol (Tetrahedron 1999, 55, 4831-4842) (58 mg, 0.32 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 7 hours at that temperature. After cooling to room temperature, the solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight in the refrigerator. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (5 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (54 mg) as a white solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH2:14])(=[O:13])=[O:12].[CH3:17][N:18]=[C:19]=[O:20].C(N(CC)CC)C>C(Cl)Cl>[F:16][C:2]([F:1])([F:15])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:19]([NH:18][CH3:17])=[O:20])(=[O:13])=[O:12]
Reactant: CN=C=O
Reactant: NS(=O)(=O)c1ccccc1C=CC(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)NS(=O)(=O)c1ccccc1C=CC(F)(F)F
Yield: 96.2 %

Procedure:
5.0 g of 2-(3,3,3-trifluoro-1-propen-1-yl)phenylsulfonamide and 1.7 g of methyl isocyanate are suspended in 25 ml of methylene chloride and 3.0 g of triethylamine are added dropwise for 10 minutes, whereupon a clear solution forms. The solution is concentrated, the residue is dissolved in a 5% sodium carbonate solution, and insoluble constituents are removed by filtration. The clear solution is acidified with 10% hydrochloric acid, to give 5.9 g of N-[2-(3,3,3-trifluoro-1-propen-1-yl)phenylsulfonyl]-N'-methylurea is a colorless precipitate with a melting point of 190°-192° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[N:6]2.[C-:13]#[N:14].[Na+]>C(O)C>[N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH2:2][C:13]#[N:14])=[CH:12][CH:11]=2)[N:6]=[CH:7][CH:8]=1
Reactant: [C-]#N
Reactant: BrCc1ccc2nccnc2c1
Agent: [Na+]
Solvent: CCO
Product: N#CCc1ccc2nccnc2c1
Temperature: 50 °C
Yield: 28.9 %

Procedure:
To a solution of crude 6-bromomethylquinoxaline (36.0 g) in 95% ethanol (200 mL) was added NaCN (30.9 g, 0.63 mol) at room temperature. The mixture was heated at 50° C. for 3 hours and then concentrated under vacuum. Water (100 mL) and ethyl acetate (100 mL) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column (Petroleum Ether/EtOAc 10:1) to give 2-(quinoxalin-6-yl)acetonitrile (7.9 g, 23% over two steps). 1H NMR (300 MHz, CDCl3) δ 8.88-8.90 (m, 2H), 8.12-8.18 (m, 2H), 7.74 (dd, J=2.1, 8.7 Hz, 1H), 4.02 (s, 2H). MS (ESI) m/z (M+H)+ 170.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([OH:15])=[O:14])[CH:7]=[CH:6]2.[Si](C=[N+]=[N-])(C)(C)[CH3:17]>C1C=CC=CC=1.CO>[CH3:17][O:14][C:13]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)=[O:15]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1ccc2cc(C(=O)O)ccc2c1
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1ccc2cc(OC)ccc2c1
Reaction time: 1 h
Yield: 81 %

Procedure:
To a stirred solution of 6-methoxy-2-naphthoic acid (10.0 g, 49.5 mmol) in benzene:MeOH (4:1, 200 mL) at 0° C. was added TMS diazomethane (29.7 mL, 2.0 M in hexnae, 59.4 mmol) dropwise. After initial addition of reagent, TLC showed reaction was not quite complete, so another 4 mL of TMS diazomethane added. The reaction was then stirred for 1 h before total completion. After concentration, the residue was recrystallized from MeOH:H2O to afford the product (8.67 g, 81%) as a solid; 1H NMR (DMSO-d6) δ3.85 (s, 3H), 3.87 (s, 3H), 7.22 (dd, J=2.6, 9.0 Hz, 1H), 7.37 (d, J=2.4 Hz, 1H), 7.85-7.92 (m, 2H), 8.00 (d, J=9.0 Hz, 1H), 8.51 (s, 1H); mass spectrum [(+) ESI], m/z 217 (M+H)+.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CC(C1COC(=O)N1[C:23](=[O:29])[CH:24]([CH3:28])[CH2:25][CH:26]=[CH2:27])C>O1CCCC1.CCCCCC.[Cl-].[NH4+].C(Cl)Cl>[C:2]1([CH2:1][O:8][C:23](=[O:29])[C@@H:24]([CH3:28])[CH2:25][CH:26]=[CH2:27])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCC(C)C(=O)N1C(=O)OCC1C(C)C
Reactant: OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CC[C@H](C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of 5.1 g of benzyl alcohol in 50 ml of tetrahydrofuran is added, dropwise, 3.8 ml of 2.5M n-butyl lithium in hexane. To this mixture is added, via cannula, a solution of 3.5 g of S-(R*,R*)]4-(1-methylethyl)-3-(2-methyl-1-oxo-4-pentenyl)-2-oxazolidinone in 100 ml of tetrahydrofuran. The resulting solution is stirred at 0° C. for 2 hours. The reaction is diluted with saturated aqueous ammonium chloride and methylene chloride. The organic layer is washed with water, dried and concentrated in vacuo. The residue is purified by chromatography (silica gel, methylene chloride) to give 2.9 g of the desired product as a colorless oil. [α]D26 =+3° (methylene chloride).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][OH:16])[O:11][CH:12]=2)=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].O>N1C=CC=CC=1>[C:17]([O:16][CH2:15][CH2:14][CH2:13][C:10]1[O:11][CH:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]=1)(=[O:19])[CH3:18]
Reactant: OCCCc1nc(-c2ccc(Cl)cc2)co1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCCCc1nc(-c2ccc(Cl)cc2)co1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution 3-[4-(4-chlorophenyl)-2-oxazolyl] propanol (0.5 g) in pyridine (5 ml) was added acetic anhydride (1.0 ml), followed by stirring for 30 minutes at 50° to 60° C. The reaction mixture was poured into water. The precipitated crystals were collected by filtration to obtain 3-[4-(4-chlorophenyl)-2-oxazolyl]propyl acetate (0.535 g, 91%). Recrystallization from ether-hexane gave colorless prism crystals of mp 37°-37.5° C.
Reaction SMILES: [OH-:1].[K+].O[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.[I-].[K+].[CH2:15](Br)[CH:16]=[CH2:17]>C(O)C>[CH2:15]([O:1][C:11]1[CH:12]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9])[CH:16]=[CH2:17]
Reactant: [OH-]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: C=CCBr
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: C=CCOc1ccccc1C(=O)O
Temperature: 25 °C

Procedure:
3750 ml of ethanol and 98.75 grams of potassium hydroxide (1.75 mol) were combined in a 5000 ml three-necked reaction flask, equipped with a magnetic stirrer, a thermometer, a condenser and an addition funnel. After the potassium hydroxide dissolved, 93.75 grams of 4-hydroxybenzoic acid (0.675 mol) and 1.25 grams of potassium iodide were added to the solution. The solution was then heated to reflux, and 81.75 grams of allyl bromide (0.675 mol) was added dropwise to the solution and refluxed overnight. A total of 2000 ml of solvent was then distilled out of the reactor. A layer of solid potassium bromide collected on the internal wall of the flask. The remaining mixture was cooled to room temperature, poured into 2500 ml of water, and neutralized with 6 N aqueous hydrochloric acid. The product precipitated, was filtered, and was washed with deionized water. The crude product was dried under vacuum at 110° C., recrystallized from ethanol (400 ml), and dried again under vacuum, to provide allyloxy benzoic acid.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:19]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO>O>[N:24]1([C:19]2[C:18]([C:16]([NH:15][C:6]3([C:4]([OH:5])=[O:3])[CH2:14][C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[CH2:7]3)=[O:17])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)C1(NC(=O)c2cccnc2N2CCCCC2)Cc2ccccc2C1
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1cccnc1N1CCCCC1
Reaction time: 62 h
Yield: 97.7 %

Procedure:
A 100 mL round bottom flask which contains 2-[(3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-3′-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (343, 330 mg, 0.84 mmol) is charged with 1,4-dioxane (4 mL) and MeOH (4 mL). A stirring bar is added and stirring is initiated. After dissolution, water (1.5 mL) is added followed by the LiOH monohydrate (89 mg, 2.12 mmol). After 62 h, tlc analysis (silica, 50% EtOAc/heptanes) indicates that the starting material is completely consumed. Amberlyst highly acidic exchange resin (0.5 g) is added to the reaction flask. The reaction is capped and allowed to stir at ambient temperature. After 38 h, the contents of the flask are filtered through a pad of Celite. The solvent is removed from the filtrate. The residue is reconstituted with iPrOH/toluene (20+20 mL) and the solvent is removed. This process is repeated 1 time. Pumping to constant weight provides 0.3 g of a white solid.
Reaction SMILES: Cl[C:2](OC1C=CC=CC=1)=[O:3].[NH2:11][C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:27]2[C:32]3[N:33]=[C:34]4[C:39]([C:31]=3[CH2:30][CH2:29][NH:28]2)=[CH:38][CH:37]=[CH:36][NH:35]4)[CH:24]=[CH:25][CH:26]=1.FC1C=C(C=CC=1)C(O)=O.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.O1CCCC1>[CH3:19][C:14]1[CH:15]=[C:16]([CH3:18])[N:17]=[C:12]([NH:11][C:2]([N:28]2[CH2:29][CH2:30][C:31]3[C:39]4[C:34]([NH:33][C:32]=3[CH:27]2[C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([F:20])[CH:22]=2)=[N:35][CH:36]=[CH:37][CH:38]=4)=[O:3])[CH:13]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Fc1cccc(C2NCCc3c4ccc[nH]c-4nc32)c1
Reactant: Cc1cc(C)nc(N)c1
Agent: O=C(O)c1cccc(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C)nc(NC(=O)N2CCc3c([nH]c4ncccc34)C2c2cccc(F)c2)c1
Reaction time: 1 h

Procedure:
To a tetrahydrofuran (1 mL) solution of phenyl chloroformate (157 mg), a tetrahydrofuran (1 mL) solution of 6-amino-2,4-lutidine (122 mg) and triethylamine (0.14 mL) were added under ice cooling, followed by stirring for one hour. The resulting mixture was added to a tetrahydrofuran (0.5 mL) solution of 8-(3-fluorophenyl)-5,6,7,8-tetrahydro-1H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridine (prepared by conducting the operation having the same purpose as that in Example 8→Example 9→Example 10 using 3-fluorobenzoic acid in place of 3-methoxybenzoic acid) (60 mg) and triethylamine (31 μL), followed by stirring at 70° C. for 2 hours. To the reaction mixture, an aqueous saturated sodium hydrogen carbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution and saturated saline, dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (parallel separation purification system) and recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the titled compound having the following physical properties (38.7 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]2[C:8](=[O:15])[O:9][C:10]([O:12][CH2:13][CH3:14])=[N:11][C:6]=2[CH:5]=1)([O-])=O.C1CCCCC1>C1C=CC=CC=1.[Pd]>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]2[C:8](=[O:15])[O:9][C:10]([O:12][CH2:13][CH3:14])=[N:11][C:6]=2[CH:5]=1
Reactant: CCOc1nc2cc([N+](=O)[O-])ccc2c(=O)o1
Agent: [Pd]
Solvent: c1ccccc1
Solvent: C1CCCCC1
Product: CCOc1nc2cc(N)ccc2c(=O)o1
Yield: 47 %

Procedure:
7-Nitro-2-ethoxy-4H-3,1-benzoxazin-4-one (1 gm, 4.2 m mol.), 10% Pd-C (1 gm), and cyclohexane (2.5 ml) were refluxed in dry benzene (50 ml) under anhydrous conditions for 3 hours. The hot reaction mixture was filtered immediately through celite and the catalyst on celite was washed with hot benzene (25 ml). The combined filtrate was evaporated to dryness under reduced pressure. The residue was stirred in anhydrous ether (30 ml) to give 410 mg (47%) of the title compound, 7-amino-2-ethoxy-4H-3,1-benzoxazin-4-one, as a pale yellow powder, after filtration. The product can be further purified by chromatography on silica gel column, if necessary (silica gel 60; EtOAc:pet. ether=1:2); m. p. 185°-187° C.; IR (KBr): νmax 3425, 3330 cm-1 (NH2), 1740 cm-1 (C=O), 1640 cm-1 (C=N); H'NMR (CDCl3): δ1.43 ppm (t, J=7.1 Hz, 3H, OCH2CH3), 4.30 ppm (b, 2H, NH2), 4.75 ppm (q, J=7.1 Hz, 2H, OCH2CH3), 6.5-7.98 ppm (m, 3H, aromatic protons).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C@@H:11]([N:13]1[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]1)[CH3:12].C(N(C(C)C)CC)(C)C.[Cl:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[O:36][C:35](=[O:40])[CH:34]=[C:33]2OS(C(F)(F)F)(=O)=O>C1COCC1>[Cl:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[O:36][C:35](=[O:40])[CH:34]=[C:33]2[NH:19][CH:16]1[CH2:17][CH2:18][N:13]([C@H:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH3:12])[CH2:14][CH2:15]1
Reactant: O=c1cc(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2o1
Reactant: C[C@@H](c1ccc2ccccc2c1)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@@H](c1ccc2ccccc2c1)N1CCC(Nc2cc(=O)oc3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.8 %

Procedure:
To a mixture of (S)-1-(1-naphthalen-2-yl-ethyl)-piperidin-4-ylamine (0.24 g, 0.94 mmol) and diisopropylethylamine (0.34 mL, 2 mmol) in 5 mL THF was added trifluoromethanesulfonic acid 6-chloro-2-oxo-2H-chromen-4-yl ester (0.30 g, 0.93 mmol). The reaction was stirred at room temperature for about 3 hours. The reaction mixture was then washed with water, dried with MgSO4 and evaporated. The residue was purified by chromatography on silica gel with methanol/dichloromethane (2:98) to give the title compound (0.1 g, 25%). The final product was converted to the mono-HCl salt by addition of 1.0N HCl in ether to a suspension of the compound in dichloromethane. The solvent was removed by evaporation. 1H NMR of the mono-HCl salt (300 MHz, DMSO-d6) δ 1.20-1.28 (2H, m), 1.81 (3H, d, J=6.97 Hz), 1.74-2.18 (4H, m), 2.83-3.05 (2H, m), 3.30-3.80 (2H, m), 4.65-4.78 (1H, br), 5.37 (1H, s), 7.30-7.79 (5H, m), 7.92-8.16 (4H, m), 8.32 (1H, d, J=2.64 Hz), 10.09 (1H, br, s).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[C:10]([O:12]C)[CH:9]=[CH:8][C:7]=1[C:14]1[N:18]([CH3:19])[C:17]([C:20]23[CH2:27][CH2:26][C:23]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])([CH2:24][CH2:25]2)[CH2:22][CH2:21]3)=[N:16][N:15]=1>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:7]=1[C:14]1[N:18]([CH3:19])[C:17]([C:20]23[CH2:27][CH2:26][C:23]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])([CH2:24][CH2:25]2)[CH2:22][CH2:21]3)=[N:16][N:15]=1
Reactant: CCCCCC12CCC(c3nnc(-c4ccc(OC)cc4Cl)n3C)(CC1)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCC12CCC(c3nnc(-c4ccc(O)cc4Cl)n3C)(CC1)CC2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Boron tribromide (135 μL, 1.43 mmol) was added dropwise to a solution of 3-(2-chloro-4-methoxyphenyl)-4-methyl-5-(4-pentylbicyclo[2.2.2]oct-1-yl)4H-1,2,4-triazole (3-F) (287 mg, 0.714 mmol) in methylene chloride (5 mL) at 0° C. The mixture was stirred at room temperature for 2.5 h. The solution was washed with water, 10% NaHCO3, dried (MgSO4) and concentrated in vacuo and the residue purified by column chromatography (silica gel, 5% MeOH/methylene chloride) to provide 3-chloro-4-[4-methyl-5-(4-pentylbicyclo[2.2.2]oct-1-yl)--4H-1,2,4-triazol-3-yl]phenol (3-G). Mass spectrum: 388 (M+1); 1H NMR (500 MHz, CDCl3): δ 0.93 (t, 3H); 1.26 (m, 8H); 1.56 (m, 6H); 2.13 (m, 6H); 3.58 (s, 3H); 6.69 (dd, 1H); 6.92 (d, 1H); 7.09 (d 1H) ppm.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[CH3:19][C:20]([CH3:23])([O-:22])[CH3:21].[K+]>C1COCC1.O>[Cl:8][C:6]1[CH:7]=[C:2]([O:22][C:20]([CH3:23])([CH3:21])[CH3:19])[N:3]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:5]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step ii) (2 g) in THF (20 mL) was added potassium tert-butoxide (0.8 g) and the reaction mixture was stirred at ambient temperature for 20 h. Further potassium tert-butoxide (0.8 g) was added and the reaction mixture was stirred at ambient temperature for 4 h. The mixture was diluted with H2O and extracted with EtOAc (×3). The combined organic layers were washed with H2O and dried (MgSO4), filtered and evaporated. The resulting oil was purified by column chromatography on silica gel using MeOH/DCM (99:1 to 98:2 gradient) as eluent to give the subtitle compound as a clear, colourless oil. Yield: 0.68 g
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH2:60])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1>C1COCC1.C(Cl)(Cl)Cl>[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH:60][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=3[CH3:1])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1
Reactant: Cc1ccc(C(=O)O)c(C)c1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccc(C)cc3C)nc12

Procedure:
From 2,4-dimethylbenzoic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+7.4° (c=0.77, CHCl3), ES-MS m/e (%): 399 (M+H+, 100).
Reaction SMILES: [C:1]([N:4]1[CH2:8][C@@H:7]([O:9]CC2C=CC=CC=2)[C@@H:6]([O:17]CC2C=CC=CC=2)[C@@:5]1([CH3:33])OCC1C=CC=CC=1)(=[O:3])[CH3:2].[CH2:34]([OH:36])[CH3:35].Cl.C([O:45][C@H:46]1[C@H:50]([O:51]CC2C=CC=CC=2)[CH2:49][NH:48][C@@H:47]1[CH2:59][O:60]CC1C=CC=CC=1)C1C=CC=CC=1>[Pd].CO>[C:1]([N:4]1[CH2:8][C@@H:7]([OH:9])[C@H:6]([OH:17])[C@H:5]1[CH2:33][OH:36])(=[O:3])[CH3:2].[C:34]([N:48]1[CH2:49][CH:50]([OH:51])[CH:46]([OH:45])[CH:47]1[CH2:59][OH:60])(=[O:36])[CH3:35]
Reactant: CC(=O)N1C[C@@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@]1(C)OCc1ccccc1
Reactant: c1ccc(COC[C@H]2NC[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Reactant: CCO
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(=O)N1CC(O)C(O)C1CO
Product: CC(=O)N1C[C@@H](O)[C@H](O)[C@H]1CO
Yield: 86 %

Procedure:
The title compound was synthesized as described for compound 9 using (2R,3R,4R)-1-acetyl-3,4-dibenzyloxy-2-benzyloxy-methylpyrrolidine (Compound 12) (0.595 g, 1.3 mmol), ethanol (30 ml), methanol (10 ml), 10% Pd/C (0.10 g) and a catalytic amount of 1 M hydrochloric acid. Purification of the product on silica gel (Eluent: Ethyl acetate/methanol (1:1))afford-ed(2R,3R,4R)-1-acetyl-3,4-dihydroxy-2-hydroxymethylpyrrolidine(0.2 g, yield: 86%) as an oil.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][C:7]1([C:13]#[N:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl.[C:19]([C:21]1[CH:34]=[CH:33][C:24]([CH2:25][N:26]2[C:30]([CH2:31]Cl)=[CH:29][N:28]=[CH:27]2)=[CH:23][CH:22]=1)#[N:20].C(N(C(C)C)CC)(C)C>C(#N)C>[C:19]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:26]2[C:30]([CH2:31][N:10]3[CH2:11][CH2:12][C:7]([CH2:6][C:5]4[CH:15]=[CH:16][CH:17]=[C:3]([CH3:2])[CH:4]=4)([C:13]#[N:14])[CH2:8][CH2:9]3)=[CH:29][N:28]=[CH:27]2)=[CH:33][CH:34]=1)#[N:20]
Reactant: Cc1cccc(CC2(C#N)CCNCC2)c1
Reactant: N#Cc1ccc(Cn2cncc2CCl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccc(CC2(C#N)CCN(Cc3cncn3Cc3ccc(C#N)cc3)CC2)c1

Procedure:
A solution of 4-(3-methylbenzyl)piperidine-4-carbonitrile hydrochloride salt (129 mg, 0.51 mmol), 1-(4-cyanobenzyl)-5-chloromethylimidazole hydrochloride salt (135 mg, 0.51 mmol; Example 52, Step D), and diisopropylethylamine (440 mL, 2.5 mmol) in anhydrous acetonitrile (5 mL) was heated under reflux overnight. The resultant mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 85:15 v/v mixture of chloroform saturated with ammonia gas and hexhne. After collection and concentration of appropriate fractions, the residue was triturated with a mixture of ethyl acetate and diethyl ether. The white solid precipitated was filtered to provide the title compound.