Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]([C:7]([CH2:23][C:24]1[CH:29]=[C:28]([F:30])[C:27]([O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])=[C:26]([F:42])[CH:25]=1)([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])C(OCC=C)=O)=[O:6])C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C(O)=O>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH:7]([CH2:23][C:24]1[CH:29]=[C:28]([F:30])[C:27]([O:31][Si:32]([CH:33]([CH3:35])[CH3:34])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:37])[CH3:38])=[C:26]([F:42])[CH:25]=1)[C:5]([OH:6])=[O:4])[CH3:22]
Reactant: C=CCOC(=O)C(CCCCC(=O)OCC)(Cc1cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1)C(=O)OCC=C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O=CO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCC(Cc1cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1)C(=O)O
Temperature: 100 °C

Procedure:
4.2 g (6.88 mmol) of 1-allyl 7-ethyl 2-allyloxycarbonyl-2-(3,5-difluoro-4-triisopropylsilanyloxy-benzyl)heptanedioate, 39 mg (0.17 mmol) of palladium(II)acetate and 135 mg (0.52 mmol) of triphenylphosphine are stirred in 30 ml of dioxane under argon. A solution of 2.3 g (22.69 mmol) of triethylamine and 0.79 g (17.19 mmol) of formic acid in 20 ml of dioxane is then added dropwise, and the mixture is heated at 100° C. overnight. The cooled mixture is concentrated and the crude product is chromatographed on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1, 3:1). 2.07 g (52% of theory) of the title compound are obtained.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1[CH2:25][N:26]([CH2:39][C:40]1[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[C:42]([C:50]([F:53])([F:52])[F:51])[CH:41]=1)[C:27]1[N:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:29][N:28]=1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[F:53][C:50]([F:51])([F:52])[C:42]1[CH:41]=[C:40]([CH:45]=[C:44]([C:46]([F:47])([F:49])[F:48])[CH:43]=1)[CH2:39][N:26]([CH2:25][C:16]1[CH:17]=[C:18]([C:21]([F:22])([F:23])[F:24])[CH:19]=[CH:20][C:15]=1[C:10]1[C:9]([OH:8])=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:27]1[N:32]=[CH:31][C:30]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)=[CH:29][N:28]=1
Reactant: FC(F)(F)c1cc(CN(Cc2cc(C(F)(F)F)ccc2-c2ccccc2OCc2ccccc2)c2ncc(N3CCOCC3)cn2)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccccc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 70.2 %

Procedure:
(2′-Benzyloxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (606 mg) is dissolved in ethanol (10 ml), and thereto is added 10% palladium-carbon (100 mg) and the mixture is stirred under hydrogen atmosphere at room temperature for 3.5 hours. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→7:3) to give 2′-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4′-trifluoromethyl-biphenyl-2-ol (374 mg). MS (m/z): 657 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH3:14])[CH:12]=[N:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[CH2:23][C@@H:22]3[C:24](OCC)=[O:25])=[CH:17][CH:16]=2)=[N:6][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH3:14])[CH:12]=[N:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[CH2:23][C@@H:22]3[CH2:24][OH:25])=[CH:17][CH:16]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(-c2ncn(C)c2Sc2ccc(Cl)cn2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1cnc(-c2ccc([C@H]3C[C@@H]3CO)cc2)c1Sc1ccc(Cl)cn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The product of Step 1 (150 mg, 0.362 mmol) was dissolved in THF (2 mL), to which was added 100 mg of LAH (2.63 mmol) at 0° C. The reaction was stirred at 0° C. for 10 min and was quenched by Fischer work up: careful successive dropwise addition of 0.1 mL of water, 0.1 mL of 15% NaOH solution, and 0.3 mL of water provided a granular inorganic precipitate that was easy to rinse and filter. The granular precipitate was filtered and washed with EtOAc. The combined organic solution was concentrated to give the crude product that was purified by column (95-100% EtOAc in hexanes) to afford the title compound. 1H NMR (500 MHz, (CDCl3): 8.39 (s, 1H), 8.05 (s, 1H), 7.86 (d, 2H), 7.48 (d, 1H), 7.06 (d, 2H), 6.81 (d, 1H), 3.67 (s, 3H), 3.61 (d, 2H), 3.02 (broad s, 1H), 1.83 (m, 1H), 1.45 (m, 1H), 0.97 (m, 2H). LCMS: m/z 372 (M+H)+. Human FAAH lysate assay: IC50=88.4 nM.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:3]1.C(OC([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33]O)[CH2:29][CH2:28]1)=O)(C)(C)C>>[F:19][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[C:8]([O:10][CH2:33][CH:30]2[CH2:31][CH2:32][NH:27][CH2:28][CH2:29]2)=[O:9])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: O=C(O)[C@](O)(c1ccc(Cl)cc1)[C@@H]1CCC(F)(F)C1
Product: O=C(OCC1CCNCC1)[C@](O)(c1ccc(Cl)cc1)[C@@H]1CCC(F)(F)C1

Procedure:
Using (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)acetic acid and N-t-butoxycarbonyl-4-piperidine-methanol, the title compound was prepared by a method similar to Steps 2 and 3 of Referential Example 12.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([N:11]2[CH2:16][CH2:15][C:14]3([C:25](=[CH:26]O)[C:24](=O)[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[O:17]3)[CH2:13][CH2:12]2)=[O:10])=[CH:7][C:6]=1[O:31][CH3:32])([CH3:4])([CH3:3])[CH3:2].[CH3:33][NH:34][NH2:35]>C(O)C>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([N:11]2[CH2:16][CH2:15][C:14]3([C:25]4[C:24](=[N:35][N:34]([CH3:33])[CH:26]=4)[C:23]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:17]3)[CH2:13][CH2:12]2)=[O:10])=[CH:7][C:6]=1[O:31][CH3:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNN
Reactant: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2C(=O)C3=CO)ccc1C(C)(C)C
Solvent: CCO
Product: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2nn(C)cc23)ccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 15 %

Procedure:
A mixture of 1′-(4-tert-butyl-3-methoxy-benzoyl)-3-(hydroxymethylene)-spiro[chromane-2,4′-piperidine]-4-one (50 mg, 0.12 mmol) and methylhydrazine (6.7 μL, 0.13 mmol) in ethanol (1.6 mL) was allowed to stir at 25° C. for 3 h. The mixture was filtered and then purified by reverse phase HPLC to provide (4-tert-butyl-3-methoxy-phenyl)-(2-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (8 mg, 15%) (peak 1) and (4-tert-butyl-3-methoxy-phenyl)-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (peak 2). (4-tert-Butyl-3-methoxy-phenyl)-(2-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone: ESI-MS m/z calc. 445.2. found 446.3 (M+1)+; Retention time: 1.87 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.33 (t, J=7.5 Hz, 1H), 7.2-7.20 (m, 1H), 7.17-7.10 (m, 1H), 7.06-6.94 (m, 2H), 6.93-6.83 (m, 2H), 4.25-4.05 (m, 1H), 4.02-3.93 (m, 1H), 3.85-3.75 (m, 1H), 3.79 (s, 3H), 3.63 (s, 3H), 3.55-3.40 (m, 1H), 2.37-2.18 (m, 2H), 1.35 (s, 9H), 1.30-1.15 (m, 2H). (4-tert-Butyl-3-methoxy-phenyl)-(1-methylspiro-[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone: ESI-MS m/z calc. 445.2. found 446.3 (M+1)+; Retention time: 2.10 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=7.5 Hz, 1H), 7.32-7.25 (m, 2H), 7.18 (t, J=7.7 Hz, 1H), 7.08-6.88 (m, 3H), 6.84 (t, J=7.5 Hz, 1H), 4.43-4.32 (m, 1H), 4.20-4.05 (m, 1H), 3.93 (s, 3H), 3.84 (s, 3H), 3.76-3.55 (m, 2H), 2.26-2.25 (m, 2H), 1.80-1.50 (m, 2H), 1.36 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:4]=2[C:3]=1[C:12]([O:14][CH3:15])=[O:13].F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24]>CS(C)=O>[N+:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[NH:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:4]=2[C:3]=1[C:12]([O:14][CH3:15])=[O:13])([O-:25])=[O:24]
Reactant: COC(=O)c1c(N)sc2ccc(C)cc12
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CS(C)=O
Product: COC(=O)c1c(Nc2ccccc2[N+](=O)[O-])sc2ccc(C)cc12

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using methyl 2-amino-5-methylbenzo[b]thiophene-3-carboxylate, 2-fluoronitrobenzene and dimethyl sulfoxide, methyl 2-(2-nitroanilino)-5-methylbenzo[b]thiophene-3-carboxylate was obtained.
Reaction SMILES: [CH:1]([C@:4]1([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[N:28]=[CH:27][N:26]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH:9][C:10](=O)OC(C)(C)C)[CH2:5]1)([CH3:3])[CH3:2].O1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.[CH2:41](Cl)Cl>Cl>[CH:1]([C@:4]1([C:17]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[N:28]=[CH:27][N:26]=3)[CH2:23][CH2:24]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:10]2[CH2:36][CH2:37][O:38][CH2:39][CH:40]2[CH3:41])[CH2:5]1)([CH3:2])[CH3:3]
Reactant: ClCCl
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ncn3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: C1COCCO1
Agent: Cl
Product: CC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCN(c3cc(C(F)(F)F)ncn3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A solution of tert-butyl [(1R,3S)-3-isopropyl-3-(4-[6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-ylcarbonyl)cyclopentyl]carbamate (800 mg, 1.65 mmol) dissolved in 4 M of HCl in 1,4-dioxane (10 mL, 40 mmol) was stirred at room temperature for 2 h. The reaction mixture was diluted with methylene chloride, washed with saturated NaHCO3 solution, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (0.6 g, 99%). LCMS calculated for C18H27F3N5O: (M+1) 386.2; found 386.2.
Reaction SMILES: [C:1]([Mg]Br)#[C:2][CH3:3].[Si:6]([O:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:39]=[CH:40][CH:41]=1)[CH:28]=[C:29]1[C:34](=[O:35])[O:33][C:32]([CH3:37])([CH3:36])[O:31][C:30]1=[O:38])([C:19]([CH3:22])([CH3:21])[CH3:20])([C:13]1C=CC=CC=1)[C:7]1C=CC=CC=1.[Cl-].[NH4+]>C1COCC1>[Si:6]([O:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:28]([CH:29]2[C:30](=[O:38])[O:31][C:32]([CH3:37])([CH3:36])[O:33][C:34]2=[O:35])[C:1]#[C:2][CH3:3])[CH:39]=[CH:40][CH:41]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:13])[CH3:7]
Reactant: CC#C[Mg]Br
Reactant: CC1(C)OC(=O)C(=Cc2cccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)C(=O)O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CC(c1cccc(CO[Si](C)(C)C(C)(C)C)c1)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, a solution (0.5 M, 12.0 mL) of 1-propynylmagnesium bromide in THF was added to a solution of 5-(3-(((tert-butyldiphenylsilyl)oxy)methyl)benzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.0 g) in THF (10 mL) at 0° C., and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound. This compound was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[O:7][C:6]([CH:8]=[O:9])=[CH:5][CH:4]=1.[CH3:12][Mg+].[Br-].[NH4+].[Cl-]>C1COCC1>[F:11][C:2]([F:10])([F:1])[C:3]1[O:7][C:6]([CH:8]([OH:9])[CH3:12])=[CH:5][CH:4]=1
Reactant: C[Mg+]
Reactant: O=Cc1ccc(C(F)(F)F)o1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc(C(F)(F)F)o1
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To 5-trifluoromethyl-furan-2-carbaldehyde (0.76 g, 4.6 mmol) in THF (20 mL) at 0° C. was added MeMgBr (3M in Et2O, 3 mL, 6 mmol) dropwise over 1 h. After an additional 1 h, ½ saturated NH4Cl (aq.) was added and the mixture extracted with EtOAc (2×). The combined organics were washed with brine and dried to give 0.81 g (97%) of the title compound. 1H NMR (CDCl3): 6.74-6.73 (m, 1H), 6.32-6.31 (m, 1H), 4.91 (q, J=6.5 Hz, 1H), 1.57 (d, J=6.6 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].Cl[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.O>>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([N:20]2[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][CH2:14][O:1][C:2]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:3]=3[CH2:4][CH2:5][CH2:6][C:7]4=[O:12])[CH2:22][CH2:21]2)=[CH:28][CH:27]=1
Reactant: O=C1CCCc2c(O)cccc21
Reactant: ClCCCN1CCN(c2ccc(Cl)cc2)CC1
Solvent: O
Product: O=C1CCCc2c(OCCCN3CCN(c4ccc(Cl)cc4)CC3)cccc21
Yield: 70 %

Procedure:
from 5-hydroxy-1-oxotetraline and 1-(3-chloropropyl)-4-(4-chlorophenyl)-piperazine; yield 70.0% of theory; the hydrochloride, after recrystallization from 96% ethanol and drying in a vacuum desiccator, still contained 0.55 mol water; m.p. 189°-191°C;
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH2:12]Br)[CH:9]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=1)=[O:5])[CH3:2].[F-].[CH2:20]([N+:24](CCCC)(CCCC)CCCC)CCC>CC#N>[C:20]([CH2:12][C:10]1[CH:9]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=1)#[N:24]
Reactant: CCOC(=O)c1cc(CBr)cc(C(=O)OCC)c1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Product: CCOC(=O)c1cc(CC#N)cc(C(=O)OCC)c1
Reaction time: 0.5 h

Procedure:
To a solution of diethyl-5-(bromomethyl)benzene-1,3-dioate (1.9 g, 6.0 mmol) in 69 mL MeCN was added trimethylsilyl cyamide (1.2 mL, 9.0 mmol) and tetrabutylammonium fluoride (1M in THF, 9.0 mL, 9.0 mmol). The reaction was stirred for 0.5 h and concentrated. Flash chromatography (silica gel, 0-30% EtOAc/hexanes) gave diethyl 5-(cyanomethyl)benzene-1,3-dioate. 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.20 (app t, J=0.7 Hz, 2H), 4.43 (q, J=7.1 Hz, 4H), 3.86 (s, 2H), 1.43 (t, J=7.1 Hz, 6H).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[CH:7].[Li]CCCC.[CH3:15][Si:16](Cl)([CH3:18])[CH3:17]>C1COCC1>[CH3:15][Si:16]([CH3:18])([CH3:17])[C:7]#[C:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:9])=[O:8]
Reactant: C#CCCCCC(=O)O
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CCCCCC(=O)O
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 91.9 %

Procedure:
A solution of hept-6-ynoic acid (1.90 g, 14.8 mmol) in anhydrous THF (90 mL) at −78° C. was treated with n-BuLi (2.3 M in hexanes, 14.5 mL, 33.3 mmol). After stirring for 2 min, TMSCl (5.8 mL, 46.0 mmol) was added. The reaction mixture was allowed to warm slowly to 25° C. and was stirred for 1 h. The reaction was quenched with the addition of aqueous 2 N HCl and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated. Column chromatography (SiO2, 4×6 cm, 20% EtOAc-hexanes) afforded 7-(trimethylsilyl)hept-6-ynoic acid (2.7 g, 13.6 mmol, 92%) as a white solid: 1NMR (CDCl3, 500 MHz) δ 2.40 (t, 2H, J=7.4 Hz), 2.24 (t, 2H, J=7.3 Hz), 1.78-1.72 (m, 2H), 1.62-1.56 (m, 2H), 0.15 (s, 9H).
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]I.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[I-:1].[I-:1].[CH2:2]([N+:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N+:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ICCCCCCI
Reactant: c1ccncc1
Product: [I-]
Product: c1cc[n+](CCCCCC[n+]2ccccc2)cc1
Temperature: 65 °C

Procedure:
1,6-Diiodohexane (mmol) was added to a solution (30 mL) of dry pyridine, and the solution heated for 24 hours at 65° C. The resulting precipitate was filtered, and the product washed five times with dry diethyl ether. The resulting yellow solid was isolated. 1H NMR (300 MHz, DMSO-D6) δ 9.11 (2H, d, C2&C6-H), 8.63 (1H, t, C4-H), 8.18 (2H, t, C3&C5-H), 4.59 (2H, t, C′1-CH2), 1.89 (2H, m, C′2-CH2), 1.28 (2H, m, C′3-CH2).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[CH:7]=[C:8]([CH3:10])[O:9][C:4]=2[CH:3]=1.Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.[OH-].[K+].CN(C)C=O>C1(C)C=CC=CC=1>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([O:1][C:2]2[CH:14]=[CH:13][C:5]3[C:6]([CH3:11])([CH3:12])[CH:7]=[C:8]([CH3:10])[O:9][C:4]=3[CH:3]=2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CC1=CC(C)(C)c2ccc(O)cc2O1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC1=CC(C)(C)c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
One hundred grams of 7-hydroxy-2,4,4-trimethyl-4H-1-benzopyran (synthesized by the method of Japanese Laid-Open Patent Publication No. 5475/1981), 79 g of p-chloronitrobenzene, 42 g of potassium hydroxide, 500 ml of N,N-dimethylformamide and 500 ml of toluene were introduced into a flask equipped with the Dean-Stark condenser, and heated at 110° to 116° C. While removing the distilled water as an azeotrope with toluene, the mixture was stirred for 2 hours. The reaction mixture was cooled to room temperature, and 1 liter of water, 500 ml of ethyl acetate and 120 ml of 2N-HCl were added. The insoluble materials were separated by filtration. The filtrate was subjected to oil-water separation. The oil layer was washed with 500 ml of brine, and dried over magnesium sulfate. The solvent was evaporated. Methanol (650 ml) was added to the residue, and crystals that precipitated were collected, washed with 650 ml of hexane, and dried to give 106 g (yield 67%) of the desired product as a brown powder (melting point 80° C.).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:11][CH:10]=1)(=O)CCCCC.[Cl-].[Al+3].[Cl-].[Cl-].Cl>CCOCC>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:13][C:14]=1[C:9](=[O:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCc1ccc(OC(=O)CCCCC)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CCCCCCCCCCCCCCc1ccc(O)c(C(=O)CCCCC)c1
Yield: 170.1 %

Procedure:
To a melted liquid of 38.8 g of hexanoic acid, 4-tetradecylphenyl ester at 80°-95° C. was added 26.67 g of aluminum chloride in small portions over a period of 2 hours. This mixture was heated for an additional hour, then allowed to cool, diluted with ether and poured onto ice containing 10 ml of concentrated hydrochloric acid. The organic layer was washed with water, dried and the solvent evaporated. The residue was chromatographed on silica gel, eluting with hexane:ethyl acetate (50:1), giving 33 g of the desired compound, mp 41°-42° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([S:11]([O:14][C:15]3[CH:16]=[C:17]([OH:22])[CH:18]=[C:19]([CH3:21])[CH:20]=3)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(P(CCCC)CCCC)CCC.[CH2:36](O)[CH2:37][CH2:38][OH:39].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[CH:1]1[C:10]2[C:5](=[C:6]([S:11]([O:14][C:15]3[CH:16]=[C:17]([CH:18]=[C:19]([CH3:21])[CH:20]=3)[O:22][CH2:36][CH2:37][CH2:38][OH:39])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: OCCCO
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc3cnccc23)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc3cnccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of 3-(5-isoquinolinylsulfonyloxy)-5-methylphenol (630 mg, 2.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (607 mg, 3.0 mmol), and 1,3-propanediol (760 mg, 10 mmol) in tetrahydrofuran (20 mL) was added 1,1′-(azodicarbonyl)dipiperidine (757 mg, 3.0 mmol). The mixture was stirred at room temperature overnight. Hexane (30 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, the residue was purified by flash column chromatography (4:1 ethyl acetate/CH2Cl2) to give the title compound as a colorless oil (620 mg, 82%). 1H-NMR (300 MHz, CDCl3) δ9.41 (s, 1H), 8.80 (d, J=6.1 Hz, 1H), 8.54 (d, J=6.1 Hz, 1H), 8.33 (d, J=7.2 Hz, 1H), 8.29 (d, J=7.6 Hz, 1H), 7.67 (t, J=7.7 Hz, 1H), 6.56 (s, 1H), 6.29 (s, 1H), 6.24 (s, 1H), 3.89 (t, J=6.1 Hz, 2H), 3.75 (t, J=6.0 Hz, 2H), 2.16 (s, 3H), 2.05 (m, 2H), 1.90 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.CN.[C:24]([BH3-])#[N:25].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)(=O)C.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH3:1][O:2][C:3]1[C:10]([O:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][CH2:24][NH2:25]
Reactant: [BH3-]C#N
Reactant: COc1c(C=O)cccc1Oc1cc(C)ccc1[N+](=O)[O-]
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1c(CCN)cccc1Oc1cc(C)ccc1[N+](=O)[O-]
Yield: 38.8 %

Procedure:
2-Methoxy-3-(5-methyl-2-nitrophenoxy)benzaldehyde (0.36 g, 1.3 mmol), methylamine (2M in methanol, 3.0 mL, 6.0 mmol) and sodium cyanoborohydride (100 mg, 1.6 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (50 mL) for 18 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.14 g, 1.2 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with hot methanol and allowed to cool overnight. The filtrate was collected, the solvent removed in vacuo. The residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give [2-methoxy-3-(5-methyl-2-nitrophenoxy)benzyl]methylamine fumarate (195 mg, 38%) as a beige solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:27][CH2:26][C@H:25]([OH:28])[C@@H:24]2[CH2:29][OH:30])[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3N(C4CC4)N=N[N:16]=3)[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CC[C@H](OC(=O)C(F)(F)F)[C@@H]2COC(=O)C(F)(F)F)C2N=NNC=2N=1)(C)(C)C.Br[CH2:65][C:66]1C(C)=N[O:68][N:67]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:27][CH2:26][C@H:25]([OH:28])[C@@H:24]2[CH2:29][OH:30])[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:66]([CH3:65])=[N:67][O:68][N:16]=3)[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nonc1CBr
Reactant: CC(C)(C)c1nc(N2CC[C@H](O)[C@@H]2CO)c2nn(Cc3nnnn3C3CC3)nc2n1
Agent: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)[C@@H]2COC(=O)C(F)(F)F)c2nn[nH]c2n1
Product: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)[C@@H]3CO)c2n1

Procedure:
In analogy to the procedure described for the synthesis of (2S,3S)-1-[5-tert-Butyl-2-(1-cyclopropyl-1H-tetrazol-5-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-2-hydroxymethyl-pyrrolidin-3-ol (example 97), the title compound was prepared from Trifluoro-acetic acid (2S,3S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-2-(2,2,2-trifluoro-acetoxymethyl)-pyrrolidin-3-yl ester and 3-(bromomethyl)-4-methyl-1,2,5-oxadiazole and isolated as white solid. MS (m/e): 389.3 (MH+).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C:12]1[CH:16]=[CH:15][NH:14][N:13]=1.O=[C:18]([CH2:25][CH2:26][CH3:27])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH2:25][CH2:26][CH3:27])[NH:11][C:12]2=[N:13][NH:14][CH:15]=[C:16]12
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1cccc(F)c1F
Reactant: CCCC(=O)CC(=O)OCC
Product: CCCC1=C(C(=O)OCC)C(c2cccc(F)c2F)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2,3-difluorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.