Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[Cl:14][C:15]1[C:16]2[CH2:27][CH2:26][C:25](=O)[C:17]=2[C:18]2[C:22]([CH:23]=1)=[N:21][N:20]([CH3:24])[CH:19]=2>O1CCCC1.C(=O)([O-])O.[Na+]>[Cl:14][C:15]1[C:16]2[CH2:27][CH2:26][C:25](=[CH:5][C:3]#[N:4])[C:17]=2[C:18]2[C:22]([CH:23]=1)=[N:21][N:20]([CH3:24])[CH:19]=2
Reactant: CCOP(=O)(CC#N)OCC
Reactant: Cn1cc2c3c(c(Cl)cc2n1)CCC3=O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc2c3c(c(Cl)cc2n1)CCC3=CC#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.1 %

Procedure:
To a suspension of 60% sodium hydride (34.8 mg, 0.870 mmol) in tetrahydrofuran (3 mL) was added diethyl cyanomethylphosphonate (152 μL, 0.94 mmol), and the mixture was stirred at room temperature for 15 min. A suspension of 5-chloro-2-methyl-6,7-dihydrocyclopenta[e]indazol-8(2H)-one (160 mg, 0.725 mmol) in tetrahydrofuran (3 mL) was added thereto, and the mixture was stirred at 50° C. for 4 hr. A solution prepared by adding diethyl cyanomethylphosphonate (152 μL, 0.94 mmol) to a suspension of 60% sodium hydride (34.8 mg, 0.870 mmol) in tetrahydrofuran (3 mL), and stirring the mixture at room temperature for 15 min was added to the reaction solution, and the mixture was further stirred at 50° C. for 4 hr. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was washed with diisopropyl ether to give the title compound (131 mg, yield 74%).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].O.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([OH:20])=[CH:18][C:17]([C:21]([O:23][CH3:24])=[O:22])=[N:16]1.S(OC)(OC)(=O)=O>C(C(C)=O)C(C)C>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([O:20][CH3:1])=[CH:18][C:17]([C:21]([O:23][CH3:24])=[O:22])=[N:16]1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)n(-c2ccccc2F)n1
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cc(OC)n(-c2ccccc2F)n1
Reaction time: 2.5 h
Yield: 81.7 %

Procedure:
Potassium carbonate (27.8 g, 201 mmol) and water (3.62 g, 201 mmol) were added to a suspension of methyl 1-(2-fluoro-phenyl)-5-hydroxy-1H-pyrazole-3-carboxylate (31.6 g, 134 mmol) in methyl isobutyl ketone (323 ml) at room temperature. Then dimethyl sulfate (16.9 g, 134 mmol) was added slowly and the mixture was stirred for 2.5 h. Water was added and the phases were separated. The organic phase was evaporated to give 27.4 g of the title compound as a white solid.
Reaction SMILES: [CH:1]1([C:6]2[CH:33]=[CH:32][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:16]5=[CH:15][C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:34]([F:37])([F:36])[F:35])[CH2:5][CH2:4][CH2:3][CH2:2]1.[I:38]N1C(=O)CCC1=O>C(Cl)Cl>[CH:1]1([C:6]2[CH:33]=[CH:32][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])[C:16]5=[C:15]([I:38])[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:34]([F:37])([F:35])[F:36])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC1CCn2c1c(I)c1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a solution of tert-butyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (100 mg, 0.195 mmol) in DCM (2 mL) was added 1-iodopyrrolidine-2,5-dione (43.8 mg, 0.195 mmol) at 0° C. and the reaction was allowed to continue at 0° C. for 30 min in a 20 mL sealed scintillation vial. After 30 min, the reaction mixture was diluted with DCM, washed with water (3×10 mL), sodium thiolsulfate pentahydrate (aq) (2×10 mL), dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound as an off-white solid (118 mg). LCMS m/z=640.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (s, 9H), 1.55-1.73 (m, 4H), 1.79-1.89 (m, 2H), 1.95-2.05 (m, 2H), 2.26-2.38 (m, 1H), 2.51-2.56 (m, 1H), 2.77-2.88 (m, 1H), 2.94 (dd, J=15.92, 3.41 Hz, 1H), 3.20-3.28 (m, 1H), 3.50-3.60 (m, 1H), 3.99-4.08 (m, 1H), 4.12-4.21 (m, 1H), 5.18 (s, 2H), 6.79 (d, J=2.27 Hz, 1H), 6.87 (dd, J=8.78, 2.46 Hz, 1H), 7.26 (d, J=8.84 Hz, 1H), 7.63 (d, J=8.59 Hz, 1H), 7.70-7.77 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[CH2:11](Br)[CH:12]=[CH2:13].[Li+].CC([N-]C(C)C)C.C(OCC)(=O)C>C1COCC1.O>[CH2:1]([C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1)[CH2:13][CH:12]=[CH2:11]
Reactant: Cc1noc2ccccc12
Reactant: C=CCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCCc1noc2ccccc12
Reaction time: 0.5 h
Yield: 103.1 %

Procedure:
3.0 mL dry THF was added to an oven-dried 25 mL flask and cooled to −78° C. on a dry ice/isopropanol bath. Diisopropylamine (840 μl, 6.0 mmol) was added followed by n-BuLi (3.8 mL, 1.6 M, 6.0 mmol). The LDA-solution that was obtained was left at room temperature. Compound 25 (666 mg, 5.0 mmol) was dissolved in 10 mL dry THF and added to an oven-dried 50 mL flask followed by allylbromide (476 μl, 5.5 mmol). The freshly prepared LDA-solution was slowly added at −78° C. and the mixture was left at room temperature for 30 min. Ethyl acetate and water were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate and evaporated to dryness to produce 893 mg of a light brown oil. Crude product was purified by column chromatography (heptane:ethyl acetate; 9:1; isocratic) to produce pure 26 (355 mg, 41%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:12]Br)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]C)=O.Cl.[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].C(N(CC)CC)C>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]2[C:3]=1[CH2:12][N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:5]2=[O:7]
Reactant: COC(=O)CCCCCN
Reactant: COC(=O)c1cccc(Br)c1CBr
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCN1Cc2c(Br)cccc2C1=O
Reaction time: 20 h
Yield: 99 %

Procedure:
The procedure of the step 2 in Example 1 was repeated except that methyl 3-bromo-2-(bromomethyl)benzoate instead of methyl 3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate, methyl 6-aminohexanoate hydrochloride instead of methyl 4-(aminomethyl)benzoate hydrochloride, triethylamine (2.4 equiv.), and THF as a solvent were used and the reaction was conducted for 20 hrs, to obtain the title compound (99%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([CH3:11])([OH:10])[C:4]#[C:5][Si](C)(C)C.[H-].[Na+].[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17]>CN(C=O)C>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:10][C:3]([CH3:11])([C:2]([F:13])([F:12])[F:1])[C:4]#[CH:5])=[O:24])=[CH:26][CH:27]=1)([O-:18])=[O:17]
Reactant: CC(O)(C#C[Si](C)(C)C)C(F)(F)F
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CC(C)(OC(=O)c1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reaction time: 0.5 h

Procedure:
A solution of crude 1,1,1-trifluoro-2-methyl-4-(trimethylsilyl)but-3-yn-2-ol from Step 1 (˜20.2 mmol) in DMF (10 mL) was added dropwise to a suspension of NaH (60% disp., 850 mg, 21.2 mmol) in DMF (25 mL) at 0° C. The mixture was allowed to reach room temperature, stirred for 30 min. and recooled to 0° C. A solution of 4-nitrobenzoyl chloride (3.94 g, 21.2 mmol) in DMF (10 mL) was added dropwise and the resulting mixture was stirred at room temperature. After 30 min., the mixture was poured in 1:1 25% NH4OAc/H2O and extracted with Et2O (3×). The combined organic layers were washed with H2O (3×) and brine, dried (Na2SO4) and concentrated. The residue was subjected to chromatography on silica gel (toluene/hexane 40:60 to 60:40) affording the title compound. 1H NMR (400 MHz, acetone-d6): 8.44 (d, 2H), 8.28 (d, 2H), 3.65 (s, 1H), 2.09 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.Cl.[C:15]([C:19]1[S:23][C:22]([NH:24][C:25](=[O:31])[CH:26]([NH2:30])[CH2:27][CH2:28][CH3:29])=[N:21][N:20]=1)([CH3:18])([CH3:17])[CH3:16].S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C.C(N(CC)CC)C>[C:15]([C:19]1[S:23][C:22]([NH:24][C:25](=[O:31])[C@@H:26]([NH:30][CH:7]2[CH2:6][CH2:5][C:4]3[C:9](=[C:10]([F:12])[CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)[CH2:27][CH2:28][CH3:29])=[N:21][N:20]=1)([CH3:17])([CH3:16])[CH3:18]
Reactant: CCCC(N)C(=O)Nc1nnc(C(C)(C)C)s1
Reactant: O=C1CCc2cc(F)cc(F)c2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCC[C@H](NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1nnc(C(C)(C)C)s1
Reaction time: 0.25 h
Yield: 76.2 %

Procedure:
A mixture of 6,8-difluoro-3,4-dihydro-1H-naphthalen-2-one (182 mg, 1.0 mmol), 2-amino-pentanoic acid (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide HCl (293 mg, 1.0 mmol) in methylene chloride (25 mL) was treated with triethyl amine (0.14 mL), then acetic acid (0.27 mL) and sodium sulfate. After stirring for 15 min, 95% pure sodium triacetoxy borohydride (424 mg, 2.0 mmol) was added and the resulting mixture was stirred at rt overnight. The mixture was quenched with dilute water and extracted with methylene chloride. The organic layer was washed with dilute sodium bicarbonate to pH 8, separated, dried and concentrated to give 322 mg of the title compound as a yellow glass foam, LC-MS, RT=2.2 min, M+1=423.0. The glass foam was purified by HPLC to give the trifluoroacetic acid salt of the title compound as a brown solid, LC-MS, RT=2.3 min, M+1=423.0.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:8]([F:18])([F:17])C(C1C=CC=CC=1)=O.[OH:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([O:28][CH3:29])=[O:27])=[N:24][CH:25]=1.[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[F:17][CH:8]([F:18])[O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([O:28][CH3:29])=[O:27])=[N:24][CH:25]=1
Reactant: O=C(c1ccccc1)C(F)(F)Cl
Reactant: COC(=O)c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(F)F)cn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 22.9 %

Procedure:
Cesium carbonate (7.45 g) and 2-chloro-2,2-difluoroacetophenone (5.75 g) were added to a solution of methyl 5-hydroxypyridine-2-carboxylate (2.5 g) in DMF, and the mixture was stirred at 100° C. for three hours. The reaction solution was returned to room temperature. Aqueous ammonium chloride and ethyl acetate were added and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (760 mg).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[Cl:18][C:19]1[N:20]=[C:21](Cl)[C:22]2[O:27][CH:26]=[CH:25][C:23]=2[N:24]=1.O.CCOC(C)=O>O1CCOCC1>[Cl:18][C:19]1[N:20]=[C:21]([N:8]2[CH2:7][CH2:6][C:5]3([CH2:1][N:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][CH2:4]3)[CH2:10][CH2:9]2)[C:22]2[O:27][CH:26]=[CH:25][C:23]=2[N:24]=1
Reactant: Clc1nc(Cl)c2occc2n1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3nc(Cl)nc4ccoc34)CC2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.6 %

Procedure:
A mixture of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (0.83 g, 3.4 mmol, Alfa Aesar), 2,4-dichlorofuro[3,2-d]pyrimidine (0.65 g, 3.4 mmol, ArkPharm) and TEA (0.96 mL, 6.9 mmol) in 1,4-dioxane (35 mL) was stirred at about 25° C. for about 12 h. Water (4 mL) and EtOAc (25 mL) were added and the layers were separated. The organic layer was concentrated under reduced pressure to give tert-butyl 8-(2-chlorofuro[3,2-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (1.25 g, 55%): LC/MS (Table 2, Method f) Rt=2.12 min; MS m/z: 393 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][CH2:11][C@H:12]1[CH2:14][O:13]1)[CH3:9].[F:15][C:16]1[CH:17]=[C:18]([CH:25]=[CH:26][C:27]=1[CH3:28])[CH2:19][C@@H:20]1[CH2:24][CH2:23][CH2:22][NH:21]1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][CH2:11][C@H:12]([OH:13])[CH2:14][N:21]1[CH2:22][CH2:23][CH2:24][C@H:20]1[CH2:19][C:18]1[CH:25]=[CH:26][C:27]([CH3:28])=[C:16]([F:15])[CH:17]=1)[CH3:9]
Reactant: Cc1ccc(C[C@@H]2CCCN2)cc1F
Reactant: C[C@@H](OC[C@H]1CO1)c1ccccc1Br
Product: Cc1ccc(C[C@@H]2CCCN2C[C@@H](O)CO[C@H](C)c2ccccc2Br)cc1F
Yield: 92 %

Procedure:
By using (2R)-2-{[(1R)-1-(2-bromo phenyl)ethoxy]methyl}oxirane described in WO 2004/106280 and (2S)-2-(3-fluoro-4-methylbenzyl)pyrrolidine which had been obtained in Example 1 (1e), the reaction was carried out in the same manner as the method described in Example 1 (1f) to give the title compound as a colorless oily substance (yield 92%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:12][C:13]1[CH:14]=[C:15]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[NH:4][N:3]=2)[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: COc1cc(F)cc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc(F)cc(-c2n[nH]c3ncnc(N)c23)c1
Yield: 18.2 %

Procedure:
3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.52 g, 5.82 mmol), 3-fluoro-5-methoxyphenylboronic acid (1.4 g, 8.24 mmol), Pd(dppf)Cl2 (0.18 g, 0.246 mmol) and 8.7 mL of 1M NaOHaqueous (8.73 mmol) were reacted in DMF (13 mL) under Ar at 120° C. for 48 hrs. The reaction was quenched by the addition of 1M HClaqueous (10 mL), dried under reduced pressure and the dark crude oil purified via flash chromatography on silica gel using a Biotage 100G SNAP with a gradient of DCM and iPrOH to give the title compound (275 mg, 18.2%) as yellowish solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:21]=[CH:22][CH:23]=1)[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([CH2:19][NH2:20])[N:14]=1)[CH3:3].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:21]=[CH:22][CH:23]=1)[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([CH2:19][NH:20][S:25]([CH3:24])(=[O:27])=[O:26])[N:14]=1)[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)Cc1cccc(OCCCNc2nc(CN)nn2C)c1
Solvent: c1ccncc1
Product: CN(C)Cc1cccc(OCCCNc2nc(CNS(C)(=O)=O)nn2C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5-[[3-[3-[(Dimethylamino)methyl]phenoxy]propyl]amino]-1-methyl-1H-1,2,4-triazole-3-methanamine (0.75 g) and methane sulphonyl chloride (0.18 ml) in dry pyridine (15 ml) was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was dissolved in aqueous sodium carbonate and extracted with ethyl acetate. The organic solution was evaporated leaving the title compound (0.5 g). T.l.c. System B, Rf 0.6.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:18])=[CH:5][CH2:6][CH2:7]/[C:8](/[CH3:17])=[CH:9]/[CH2:10][CH2:11]/[C:12](/[CH3:16])=[CH:13]/[CH2:14][OH:15]>C1COCC1>[CH2:14]([O:15][CH2:14][CH:13]=[C:12]([CH2:11][CH2:10][CH:9]=[C:8]([CH2:7][CH2:6][CH:5]=[C:4]([CH3:3])[CH3:18])[CH3:17])[CH3:16])[CH:13]=[C:12]([CH2:11][CH2:10][CH:9]=[C:8]([CH2:7][CH2:6][CH:5]=[C:4]([CH3:18])[CH3:3])[CH3:17])[CH3:16]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)=CCCC(C)=CCOCC=C(C)CCC=C(C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
To 81 mg (2.03 mmole, 2 eq) of 60% sodium hydride (washed with anhydrous hexanes to remove mineral oil) in 1 mL of anhydrous THF under an argon atmosphere at 0° C., 228 mg (1.02 mmol) of trans,trans-farnesol in 1 mL of anhydrous THF was added. The mixture was stirred for 10 min, then 438 mg (1.53 mmol, 1.5 eq) of trans,trans-farnesol bromide was added in 0.5 ml of anhydrous THF. The mixture was stirred for 20 h and allowed to warm to 25° C. The reaction was quenched with 2 mL of 1M HCl, diluted with EtOAc, washed successively with water and brine and dried over anhydrous MgSO4. The crude product was chromatographed on silica gel F254 preparative TLC plates (Merck) in 1:10 EtOAc:hexanes to afford 174 mg (40%) of bisfarnesyl ether that had NMR and mass spectral data identical to that of material produced in enzymatic reactions (FIG. 7).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([OH:10])=[O:9].C(N(CC)CC)C.[CH3:18][O:19][C:20]1[C:29]([O:30][CH3:31])=[N:28][C:27]2[C:26]([CH:32]=O)=[CH:25][C:24]([N+:34]([O-:36])=[O:35])=[CH:23][C:22]=2[N:21]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+]>ClCCl.C(O)C>[CH3:18][O:19][C:20]1[C:29]([O:30][CH3:31])=[N:28][C:27]2[C:22](=[CH:23][C:24]([N+:34]([O-:36])=[O:35])=[CH:25][C:26]=2[CH2:32][NH:1][C@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[C:8]([OH:10])=[O:9])[N:21]=1
Reactant: COc1nc2cc([N+](=O)[O-])cc(C=O)c2nc1OC
Reactant: N[C@H]1CCCC[C@H]1C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1nc2cc([N+](=O)[O-])cc(CN[C@H]3CCCC[C@H]3C(=O)O)c2nc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
105 mg (0.588 mmol) of cis-2-amino-cyclohexanecarboxylic acid and 82 μl (0.588 mmol) of triethylamine are added in succession to a solution of 129 mg (0.490 mmol) of 2,3-dimethoxy-7-nitro-quinoxaline-5-carbaldehyde in 1 ml of dichloromethane and 2 ml of ethanol. After 3 hours' stirring at room temperature, 1 g of anhydrous sodium sulfate is added to the suspension and the mixture is stirred for a further 20 hours at room temperature. The thick suspension is diluted with 0.5 ml of ethanol and 46 mg (1.23 mmol) of sodium borohydride are added. After 3 hours' stirring, there are added 0.5 ml of acetone and 10 minutes later 0.3 ml of acetic acid and filtration is carried out. The filter residue is washed with ethanol and dichloromethane. The filtrate is chromatographed on silica gel first with dichloromethane/ethyl acetate (97:3) and then with dichloromethane/methanol/glacial acetic acid (90:9:1). The title compound is obtained in the form of a white powder.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:20](=[O:22])[CH3:21])=[C:6]([CH3:19])[N:7]([C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([OH:17])=[CH:12][C:11]=2[CH3:18])[C:8]=1[CH3:9])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:30][CH3:31]>>[C:1]([C:4]1[C:5]([C:20](=[O:22])[CH3:21])=[C:6]([CH3:19])[N:7]([C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([O:17][CH2:30][CH3:31])=[CH:12][C:11]=2[CH3:18])[C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: CCBr
Reactant: CC(=O)c1c(C(C)=O)c(C)n(-c2cc(C)c(O)cc2C)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1cc(C)c(-n2c(C)c(C(C)=O)c(C(C)=O)c2C)cc1C

Procedure:
Utilizing the general procedure outlined in Example 7, 1-[4-acetyl-1-(4-hydroxy-2,5-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (100 mg, 0.3 mmol) reacted with bromoethane (300 μL, excess), in the presence of K2CO3 (50 mg), to afford 1-[4-acetyl-1-(4-ethoxy-2,5-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone: MS (ESI) 328 (M+H)+. Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-1-(4-ethoxy-2,5-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (108 mg, 0.3) and hydrazine (50 μL) reacted to give 6-(4-Ethoxy-2,3-dimethyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]-pyridazine as an off-white solid: 1H NMR (CDCl3, 500 MHz) δ 6.88 (s, 1H), 6.77 (s, 1H), 4.14 (q, 2H), 2.85 (s, 6H), 2.39 (s, 6H), 2.26 (s, 3H), 1.83 (s, 3H, 1.50 (t, 3H); MS (ESI) 324 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]3([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:23][CH:22]=2)[C:10]=1[CH3:35])C1C=CC=CC=1>C(O)C.C1COCC1.[Pd]>[OH:34][C:29]1([CH2:28][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][CH2:19][C:11]3[NH:12][C:13]4[C:18]([C:9](=[O:8])[C:10]=3[CH3:35])=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:22][CH:23]=2)[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: Cc1c(COc2ccc(CCC3(O)CCCC3)cc2)nc2ccccc2c1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(COc2ccc(CCC3(O)CCCC3)cc2)[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.4 %

Procedure:
To a solution of 1-[2-(4-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}phenyl)ethyl]cyclopentanol (128 mg) in ethanol-THF (1:1, 4 mL) was added 10% palladium-activated carbon (30 mg) under nitrogen atmosphere, followed by stirring at room temperature under hydrogen atmosphere for 3 hours. The catalyst was removed by filtration, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=92/8). The resulting solid was washed with ether and dried to obtain 2-({4-[2-(1-hydroxycyclopentyl)ethyl]phenoxy}methyl)-3-methylquinolin-4(1H)-one (51 mg) as a crystal.
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:23]3[C:22](=[O:26])[CH2:21][CH2:20][CH2:19][C:18]=3[CH:17]=2)[N:10]=[CH:9]1)=O)(C)(C)C.[OH-:27].[K+]>CCO>[O:27]1[CH:18]=[CH:17][CH:16]=[C:25]1[CH:24]=[C:21]1[CH2:20][CH2:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]([O:15][CH2:14][CH2:13][C:11]3[N:10]=[CH:9][NH:8][CH:12]=3)[CH:17]=2)[C:22]1=[O:26]
Reactant: CC(C)(C)OC(=O)n1cnc(CCOc2ccc3c(c2)CCCC3=O)c1
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: O=C1C(=Cc2ccco2)CCc2cc(OCCc3c[nH]cn3)ccc21
Yield: 76 %

Procedure:
According to the method of Example 32, 4-[2-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-imidazole-1-carboxylic acid tert-butyl ester (0.270 g, 0.75 mmol) was reacted with 2-furylaldehyde (0.095 mL, 1.14 mmol) in 5 mL of 4% KOH in EtOH overnight to afford 0.190 g (76%) of the title compound as a foam which solidified on standing to give a dark red powder, mp 57-60° C.: CI-MS m/e 335 (M+ +1).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]2[N:21]([CH2:22][CH3:23])[C:20](=[O:24])[N:19]([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[C:16]2=[N:17][CH:18]=1.[H-].[Na+]>CN(C=O)C.CO>[Cl:12][C:13]1[CH:14]=[C:15]2[N:21]([CH2:22][CH3:23])[C:20](=[O:24])[N:19]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:2]4[N:6]([CH3:7])[C:5]5[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=5[N:3]=4)=[CH:27][CH:26]=3)[C:16]2=[N:17][CH:18]=1
Reactant: Cn1c(Cl)nc2ccccc21
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4n3C)cc2)c2ncc(Cl)cc21
Temperature: 180 °C
Yield: 79.4 %

Procedure:
2-Chloro-1-methyl-1H-benzimidazole (50 mg) was added to a solution of 6-chloro-1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (90 mg) and NaH (13.2 mg) in DMF (2 mL) at room temperature. The mixture was heated at 180° C. for 30 min under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 6-chloro-1-ethyl-3-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) as colorless crystals.