Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH3:19])=[C:9]2[C:20]([O:22][CH3:23])=[O:21])[CH:5]=[CH:6][CH:7]=1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[S:25]>CN(C=O)C>[CH3:19][C:10]1[NH:11][C:12]([CH3:18])=[C:13]([C:14]([O:16][CH3:17])=[O:15])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([N:1]=[C:24]=[S:25])[CH:3]=2)[C:9]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)N1c1cccc(N)c1
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)N1c1cccc(N=C=S)c1
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
4-(3-Aminophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyrazinedicarboxylic acid, dimethyl ester (3.8 mmol) in 16 mL of DMF was slowly added into a DMF solution (20 mL) of 1,1′-thiocarbonyldiimidazole (5.2 mmol) and the reaction went to completion in 0.5 hours. After DMF was removed in vacuo, the residue was purified by chromatography on silica gel eluted with 50% (v/v) ethyl acetate in hexanes to give the title compound as a yellow powder (1.19 g, 87%); 1H-NMR (CDCl3) δ 7.09 (t, 1H, J=8.1 Hz), 6.73 (dd, 1H, J=7.8, 1.9 Hz), 6.59 (dd, 1H, J=8.3, 2.4 Hz), 6.47 (t, 1H, J=2.1 Hz), 6.06 (s, 1H), 3.79 (s, 6H), and 2.43 (s, 6H); 13C-NMR (CDCl3) δ 166.0, 151.7, 149.1, 131.3, 129.6, 117.7, 112.6, 110.3, 108.9, 52.0, and 18.1.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34].C(OCC)(=O)C>CN(C=O)C>[CH3:34][CH:33]([CH3:35])[CH2:32][CH2:31][CH2:30][CH2:29][N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1
Reactant: CC(C)CCCCBr
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CCCCN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 50 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 1-bromo-5-methylhexane (0.199 g, 1.05 mmol) in DMF (5.3 mL). Heat at 50° C. overnight, then increase the temperature to 80° C. for 3.5 hours. Cool die reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1×30 mL), brine (1×30 mL), dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 382.2 (M+H)+, HRMS calcd for C23H31N3O2 382.2492 (M+H)+, found 382.2495, time 0.46 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=12.4 min, 97.7% purity.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[Na].Cl[C:7]1[N:12]=[C:11]([N:13]([CH2:16][C:17]2[S:21][C:20]([Cl:22])=[N:19][CH:18]=2)[CH2:14][CH3:15])[C:10]([N+:23]([O-:25])=[O:24])=[CH:9][CH:8]=1>ClCCl>[CH2:1]([O:4][C:7]1[N:12]=[C:11]([N:13]([CH2:16][C:17]2[S:21][C:20]([Cl:22])=[N:19][CH:18]=2)[CH2:14][CH3:15])[C:10]([N+:23]([O-:25])=[O:24])=[CH:9][CH:8]=1)[C:2]#[CH:3]
Reactant: C#CCO
Reactant: CCN(Cc1cnc(Cl)s1)c1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Na]
Solvent: ClCCl
Product: C#CCOc1ccc([N+](=O)[O-])c(N(CC)Cc2cnc(Cl)s2)n1
Temperature: 25 °C
Yield: 23.8 %

Procedure:
0.52 g of sodium propargyl alcohol and 10 mL of anhydrous dichloromethane were added into a 100 mL three-necked flask equipped with a magnetic stirrer, a condenser and a drying tube, under stirring at room temperature, 1.15 g of 6-chloro-N-((2-chlorothiazole-5-yl)methyl)-N-ethyl-3-nitropyridin-2-amine, prepared according to the example 1, in 5 mL of dichloromethane was added dropwise. After that, the reaction mixture was stirred at room temperature for 1 to 2 hours, and then stirred at reflux temperature for 2 to 5 hours. After cooling down to the room temperature, the reaction mixture was treated by the method according to example 1 to obtain 0.29 g of 6-propargyloxy-N-((2-chlorothiazole-5-yl)methyl)-N-ethyl-3-nitropyridine-2-amine, as a viscous yellow-green solid in a yield of 23.8%. GC-MS (M+) (EI, 70 eV, m/z) calc: 352. found: 352. 1H NMR (CDCl3/TMS, 300 MHz) δ (ppm): (CDCl3) 1.212 (t, J=7.2 Hz, 3H, CH3), 2.497 (t, J=2.4 Hz, 1H, CH), 3.265 (q, J=7.2 Hz, 2H, CH2), 4.850 (s, 2H, CH2), 4.969 (s, 2H, CH2), 6.263 (d, J=8.7 Hz, 1H, Py H), 7.489 (s, 1H, Thiazole-H), 8.182 (d, J=8.7 Hz, 1H, Py H).
Reaction SMILES: [O:1]([C@H:8]([CH3:11])[CH2:9][NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:20][C@@H:21]1[C@H:25]([O:26]C(=O)C2C=CC=CC=2)[C@@H:24]([CH2:35][O:36]C(=O)C2C=CC=CC=2)[O:23][C@H:22]1[N:45]1[CH:53]=[N:52][C:51]2[C:46]1=[N:47][C:48]([Cl:55])=[N:49][C:50]=2Cl)(=O)C1C=CC=CC=1.C(N(CC)CC)C>O1CCOCC1>[Cl:55][C:48]1[N:49]=[C:50]([NH:10][CH2:9][C@H:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:11])[C:51]2[N:52]=[CH:53][N:45]([C:46]=2[N:47]=1)[C@@H:22]1[O:23][C@H:24]([CH2:35][OH:36])[C@@H:25]([OH:26])[C@H:21]1[OH:20]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: C[C@H](CN)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C[C@H](CNc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.9 %

Procedure:
(R)-2-Phenoxy-1-propylamine (0.6 g, 2.9 mmol)(prepared by the method described in example 2) was reacted with 9-(2,3,5-tri- O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.5 g, 2.4 mmol) in dioxan (20 ml) in the presence of triethylamine (0.5 g, 5.3 mmol). The reaction mixture was stirred at room temperature for 72 h before being filtered and evaporated. The product, following purification by flash chromatography, was treated with saturated methanolic ammonia (30 ml) for 18 h and evaporated to provide a solid residue. This solid was washed thoroughly with dichloromethane to provide the title 2-chloro- N-[(R)-2-phenoxy-1-propyl]adenosine (0.7 g, 65%), mp 175°-177° C., 1H NMR (DMSO-d6)δ 1.39 (3H, d, --CH3), 3.56 (1H, ABX, H-5'a), 3.68 (1H, m, H-5'b), 3.33-3.40 (1H, m, --C--H), 3.83-3.92 (1H, --C--H), 3.96 (1H, q, H-4'), 4.14 (1H, m, H-3'), 4.53 (1H, dd, H-2'), 4.70 (1H, q, --C--H), 5.08, 5.34, 5.50 (3H, 3 br, 2', 3' and 5'-OH), 5.85 (1H, d, H-1'), 6.90 (1H, t, Ar--H), 7.11 (2H, d, Ar--H), 7.28 (2H, t, Ar--H), 8.45 (1H, s, H-8), 8.63 (1H, t, N--H).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([F:22])=[C:18]([C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[NH:17][C:16]2=O)=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].P(Cl)(Cl)([Cl:33])=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([F:22])=[C:18]([C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[N:17]=[C:16]2[Cl:33])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c(C(F)(F)C(F)(F)F)c(F)c2=O)c(F)cc1Cl
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)OC(=O)c1cc(-n2c(Cl)nc(C(F)(F)C(F)(F)F)c(F)c2=O)c(F)cc1Cl

Procedure:
using isopropyl 2-chloro-5-[3,6-dihydro-2,6-dioxo-5-fluoro-4-pentafluoroethyl-1(2H)-pyrimidinyl]-4-fluorobenzoate with phosphorus oxychloride and pyridine within 6 hours at room temperature there is obtained isopropyl 2-chloro-5-[2-chloro-5-fluoro-6-oxo-4-pentafluoroethyl-1(6H) -pyrimidinyl]-4-fluorobenzoate, 1H-NMR (CDCl3, 400 MHz): 7.88 ppm (d,1H), 7.48 ppm (d,1H), 5.28 ppm (m,1H), 1.39 ppm (d,6H),
Reaction SMILES: [CH2:1]([CH:8]1[C:14](=[O:15])[N:13]([S:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:12][C:11](=[O:28])[NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](OC(C1C=CC(S(N)(=O)=O)=CC=1)=O)(C)(C)C.C(C1C(=O)N(S(C2C=C(C=CC=2)C(O)=O)(=O)=O)CC(=O)NC1)C1C=CC=CC=1.C(OC(C1C=C(S(N)(=O)=O)C=CC=1)=O)(C)(C)C.ClC1C=CC(S(N2C(=O)/C(=C/C3C=C(Cl)C=CC=3OC)/CNC(=O)C2)(=O)=O)=CC=1C(OC)=O>>[CH2:1]([CH:8]1[C:14](=[O:15])[N:13]([S:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([O:25][CH3:29])=[O:24])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:12][C:11](=[O:28])[NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(S(=O)(=O)c2ccc(C(=O)O)cc2)C(=O)C(Cc2ccccc2)CN1
Reactant: CC(C)(C)OC(=O)c1ccc(S(N)(=O)=O)cc1
Agent: CC(C)(C)OC(=O)c1cccc(S(N)(=O)=O)c1
Agent: COC(=O)c1cc(S(=O)(=O)N2CC(=O)NC/C(=C\c3cc(Cl)ccc3OC)C2=O)ccc1Cl
Agent: O=C1CN(S(=O)(=O)c2cccc(C(=O)O)c2)C(=O)C(Cc2ccccc2)CN1
Product: COC(=O)c1ccc(S(=O)(=O)N2CC(=O)NCC(Cc3ccccc3)C2=O)cc1

Procedure:
4-[(6-benzyl-3,7-dioxo-1,4-diazepan-1-yl)sulfonyl]benzoic acid, synthesized by using 4-(tert-butoxycarbonyl) benzenesulfonamide instead of the starting material compound of Example 198, that is, 3-(tert-butoxycarbonyl) benzenesulfonamide for the similar procedure as in Example 198, was used instead of the starting material of Example 208, that is, the compound 196, for the similar procedure as with Example 208 to obtain the title compound.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[K+].[Br:11][CH2:12][CH2:13]Br>CO>[Br:11][CH2:12][CH2:13][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: BrCCBr
Reactant: Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1ccc(OCCBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.9 %

Procedure:
To a solution of hydroquinone (1.0 g, 9 mmol) in MeOH (15 mL), KOH (1.02 g, 9 mmol) was added and stirred at room temperature for 30 minutes under argon. 1,2-dibromoethane (0.98 mL, 11.3 mmol) was added dropwise over 10 min. After the addition was complete, the mixture was refluxed for 12 hours. The reaction mixture was concentrated and was then quenched with water (50 mL) and the aqueous layer was extracted with EtOAc (2×25 mL). The combined organic layer was washed with water, brine, and dried over Na2SO4. The solvent was evaporated to give a colorless oil, which was purified by column chromatography to isolate the intermediate 5a as a white solid (0.39 g, 1.79 mmol, 20% yield). 1H NMR (CDCl3, 400 MHz) δ 6.78-6.85 (m, 4H), 4.53 (s, 1H), 4.26 (t, J=6.4 Hz, 2H), 3.63 (t, J=6.4 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:14]3([CH2:20][NH2:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[S:12][CH:13]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[F:22][C:23]([F:39])([F:38])[C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32](O)=[O:33])[N:25]=1>>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[N:10]=[C:11]([C:14]3([CH2:20][NH:21][C:32](=[O:33])[C:31]4[CH:35]=[CH:36][CH:37]=[C:29]([C:26]5[N:25]=[C:24]([C:23]([F:39])([F:38])[F:22])[O:28][N:27]=5)[CH:30]=4)[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[S:12][CH:13]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NCC1(c2nc(-c3cc(F)cc(F)c3)cs2)CCOCC1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCC1(c2nc(-c3cc(F)cc(F)c3)cs2)CCOCC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 10 %

Procedure:
This compound was synthesized from (4-(4-(3,5-difluorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (20 mg, 10% yield). 1H NMR (300 MHz, CDCl3) δ 8.45 (s, 1H), 8.24 (d, J=8.3 Hz, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.64-7.54 (m, 2H), 7.35 (d, J=5.5 Hz, 1H), 6.73 (m, 2H), 3.95 (m, 2H), 3.85 (d, J=5.5 Hz, 2H), 3.70 (m, 2H), 2.28 (m, 2H), 2.05 (m, 2H). MS (ESI) m/z: Calculated for C25H19F5N4O3S: 550.11. found: 551.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][Br:12])=[N:7][C:6]=2[CH:11]=1
Reactant: Cc1nc2cc(Cl)ccc2o1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc2oc(CBr)nc2c1
Reaction time: 24 h

Procedure:
A solution of the benzoxazol (1.3 ) (Step 2) in CCl4 (15 mL) was treated with N-bromo-succinimide (NBS) (1.5 ) and benzoyl peroxide (38 mg) at reflux using a U.V. lamp for 24 hours. Filtration, evaporation, and flash chromatography of the residue using 1:1 hexane/toluene afforded the title compound which was used as such for the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[Br:9]Br>[Fe]>[Br:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(C)cc1
Reactant: BrBr
Agent: [Fe]
Product: Cc1ccc(C)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
p-Xylene (934.4 g; 8.8 mol) and Fe powder (16 g) were placed in the reaction vessel and about 20 ml of bromine were slowly added dropwise. The commencement of the reaction (after about 10 minutes) could be recognized by gas evolution. After the reaction had begun, the remaining bromine (total: 1278.4 g; 8.0 mol) was added dropwise at RT, with water bath cooling (4 hours). The mixture was stirred further for 2 hours at RT. The slightly brownish reaction solution was filtered off and stirred first with water, and then with 480 ml of saturated aqueous Na2SO3 solution, subsequently shaken once with dilute aqueous NaOH and twice with H2O; the organic phase (clear and colorless) was dried over MgSO4, filtered and purified by being vacuum-distilled twice (diaphragm pump/oil bath, about 100-120° C./60 cm column).
Reaction SMILES: [C:1]1([CH3:31])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[OH:22])[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[OH:30])[N:10]=1.[CH2:32]([O:36][CH2:37][CH:38]([CH2:43][CH3:44])[CH2:39][CH2:40][CH2:41][CH3:42])[CH:33]1[O:35][CH2:34]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1(C)C=C(C)C=C(C)C=1.C(OCC)(=O)C>[C:1]1([CH3:31])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[N:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:34][CH:33]([OH:35])[CH2:32][O:36][CH2:37][CH:38]([CH2:43][CH3:44])[CH2:39][CH2:40][CH2:41][CH3:42])=[CH:25][C:24]=2[OH:30])[N:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:34][CH:33]([OH:35])[CH2:32][O:36][CH2:37][CH:38]([CH2:43][CH3:44])[CH2:39][CH2:40][CH2:41][CH3:42])=[CH:17][C:16]=2[OH:22])[N:14]=1
Reactant: CCCCC(CC)COCC1CO1
Reactant: Cc1cc(C)c(-c2nc(-c3ccc(O)cc3O)nc(-c3ccc(O)cc3O)n2)c(C)c1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: Cc1cc(C)cc(C)c1
Product: CCCCC(CC)COCC(O)COc1ccc(-c2nc(-c3ccc(OCC(O)COCC(CC)CCCC)cc3O)nc(-c3c(C)cc(C)cc3C)n2)c(O)c1
Temperature: 140 °C
Reaction time: 16 h
Yield: 81.9 %

Procedure:
A mixture of 39.5 g (0.095 mol) of 2-mesityl-4,6-bis(2,4-dihydroxyphenyl)-1,3,5-triazine (compound 1b), 40.7 g (0.2185 mol) of 2-ethylhexyl glycidyl ether (purity 98%) and 3.5 g (9.5 mmol) of ethyltriphenylphosphonium bromide (purity 97%) in 250 ml of mesitylene (purity 99%) is stirred at 140° C. under nitrogen for 16 hours. The clear solution is freed from solvent under reduced pressure. The crude product is dissolved in 200 ml of ethyl acetate and filtered through a 6.0 cm layer of silica gel 60 (230-400 mesh) of diameter 8.0 cm, with elution with 1000 ml of ethyl acetate. Removal of the solvent and drying for 2 hours at 100° C. and a pressure of 0.6 mmHg (80 Pa) give 61.3 g (yield 81.8%) of the title product (compound 7; Tg 54.4° C.) of the formula ##STR106## where R=CH2 --CH(OH)--CH2O--CH2 --CH(C2 H5)--CH2CH2CH2CH3.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[C:12](O)(=[O:22])[C:13]1[CH:21]=[CH:20][C:19]2[O:18][CH2:17][O:16][C:15]=2[CH:14]=1.N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:12]([C:13]3[CH:21]=[CH:20][C:19]4[O:18][CH2:17][O:16][C:15]=4[CH:14]=3)=[O:22])[CH2:2]1)[CH2:8]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc2c(c1)OCO2

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and piperonylic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.86-2.63 (m, 7H), 3.46-3.86 (m, 6H), 4.35 (s, 1H), 6.02-6.05 (m, 2H), 6.90 (d, J=8 Hz, 1H), 7.32 (d, J=2 Hz, 1H), 7.44 (dd, J=8, 2 Hz, 1H); MS (APCI/NH3) m/z 301 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[C:10]=1I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25](N(CC)CC)C.C[Sn](C)(C)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[C:10]=1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=c1c(I)c(OCc2ccccc2)ccn1Cc1cccc(F)c1
Agent: C[Sn](C)(C)C
Solvent: CN(C)C=O
Product: Cc1c(OCc2ccccc2)ccn(Cc2cccc(F)c2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
To a degassed solution of 4-(benzyloxy)-1-(3-fluorobenzyl)-3-iodopyridin-2(1H)-one (1.03 g, 2.36 mmol) in anhydrous DMF (15 mL) under argon atmosphere was added triethylamine (1.11 g, 11 mmol). The reaction mixture was chilled in an ice bath for 15 minutes before adding tetramethyl tin (2.10 g, 11.75 mmol) followed by bistriphenylphosphine-palladium chloride (0.166 g, 0.24 mmol). The reaction was stirred at room temperature for 30 minutes before heating at 950 C under an atmosphere of argon for 3 hours. The reaction mixture was filtered through a bed of celite and the filtrate was concentrated under reduced pressure. The dark brown residue was diluted with ethyl acetate (100 mL) and washed with water. The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The dark brown residue was purified by flash chromatography (30% ethyl acetate in hexane). The appropriate fractions were combined and concentrated under reduced pressure to afford the desired product (0.1758 g, 22%) as a light yellow solid. The product was further purified by reverse phase HPLC using a 10-90% acetonitrile/water (30 minute gradient) at a 100 mL/min flow rate, to afford a cleaner product as a light yellow solid (0.0975 g, 8%). 1H-NMR (CD3OD, 400 MHz) δ 7.58 (d, 1H, J=7.6 Hz)), 7.35 (m, 6H), 6.98 (m, 3H), 6.46 (d, 1H, J=7.6 Hz), 5.19 (s, 2H), 5.15 (s, 2H), 2.0 (s, 3H); ES-HRMS m/z 324.1366 (M+H calculated for C20H19NO2F requires 324.1394).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH2:44][C:45]([NH:47][CH2:48][CH:49]2[CH2:53][CH2:52][CH2:51][O:50]2)=[O:46])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:41]3[CH2:40][CH2:39][N:38]([CH2:44][C:45]([NH:47][CH2:48][CH:49]4[CH2:53][CH2:52][CH2:51][O:50]4)=[O:46])[CH2:43][CH2:42]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(CN1CCNCC1)NCC1CCCO1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NCC2CCCO2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 2-piperazin-1-yl-N-(tetrahydro-furan-2-ylmethyl)-acetamide (Enamine) to give the title compound as a mixture of diastereomers. HR-MS (ES, m/z) calculated for C40H51Cl2N6O4 [(M+H)+] 749.3344, observed 749.3341.
Reaction SMILES: N#N.Br[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([F:14])=[CH:6][CH:5]=1.C([Li])CCC.[B:20](OCC)([O:24]CC)[O:21]CC>CCCCCC.O1CCCC1>[F:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([B:20]([OH:24])[OH:21])=[CH:5][CH:6]=1
Reactant: Fc1ccc(Br)c2ccccc12
Reactant: CCOB(OCC)OCC
Agent: N#N
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(F)c2ccccc12
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
To a 250 mL three-necked round-bottomed flask equipped with septum and N2 (nitrogen) inlet were added 4.62 g (20.53 mmol) 4-bromo-1-fluoronaphthalene and 100 mL dry tetrahydrofuran. The solution was cooled to −70° C., and 15.4 mL (24.64 mmol) of a 1.6 M solution of butyl lithium in hexane was added dropwise over 5 min. The reaction was stirred at −70° C. for 10 min, then 4.2 mL (3.59 g, 24.64 mmol) triethyl borate was added, and the reaction stirred at −70° C. for 20 min and warmed to room temperature. After stirring overnight at room temperature, the reaction was quenched with saturated aqueous ammonium chloride solution, acidified with 1 N hydrochloric acid, and extracted into ethyl acetate (twice). The combined organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was triturated with hexane to give an off-white powder, 1.97 g (51%), as a mixture of monoaryl and diaryl boronic acids. 1H-NMR (δ, CDCl3): 7.2-7.4 (m, 1H), 7.5-7.7 (m, 3H), 8.0-8.5 (m, 1H), 8.5 and 9.2 (m, 1H); APCI (−) (%): 189 (parent−1, 60).
Reaction SMILES: [C:1]([O:4][C:5]([CH3:15])([CH2:8][CH2:9][C:10]([CH3:14])=[C:11]([CH3:13])[CH3:12])[C:6]#[CH:7])(=[O:3])[CH3:2].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[C:1]([O:4][C:5]([CH3:15])([CH2:8][CH2:9][C:10]([CH3:14])=[C:11]([CH3:13])[CH3:12])[CH2:6][CH3:7])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: C#CC(C)(CCC(C)=C(C)C)OC(C)=O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Product: CCC(C)(CCC(C)=C(C)C)OC(C)=O
Temperature: 45 °C

Procedure:
409.0 g of 3,6,7-trimethyl-6-octen-1-in-3-yl acetate and 20.0 g of Lindlar catalyst (5% Pd+3.5% Pb on CaCO3) are put in an autoclave and heated under nitrogen to a temperature of 45° C. Nitrogen is exchanged by hydrogen (H2) and the reaction mixture put at an absolute pressure of 2 bar. After the calculated amount of hydrogen has been consumed the reaction mixture is filtered and distilled (2 mbar, 130° C.) to obtain 3,6,7-trimethyl-6-octen-3-yl acetate (=compound of formula (Ib)).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[NH:7][C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[C:36]([F:39])[C:37]=1[F:38]>>[F:29][C:27]([F:30])([F:28])[C:4]1[CH:3]=[C:2]([C:34]2[CH:33]=[C:32]([F:31])[C:37]([F:38])=[C:36]([F:39])[CH:35]=2)[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[NH:7][C:6]=2[CH:5]=1
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Reactant: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1
Product: Fc1cc(-c2cc(C(F)(F)F)cc3[nH]c(N4CCN(c5ncccc5C(F)(F)F)CC4)nc23)cc(F)c1F

Procedure:
4-Bromo-6-trifluoromethyl-2-[4-(3-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1H-benzoimidazole (1.99 g, 4 mmol, Example 7) reacted with 3,4,5-trifluorophenylboronic acid (1.1 g, 6 mmol, Lancaster) under the conditions of Example 51a to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 546 (M+1).