Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([C:23]([OH:25])=O)=[CH:18][CH:17]=[CH:16]2.[C:26]1([NH2:33])[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:32]>>[NH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[NH:33][C:23]([C:19]1[C:20]2[C:15](=[CH:14][C:13]([O:12][C:7]3[C:6]4[C:11](=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=4)[N:10]=[CH:9][CH:8]=3)=[CH:22][CH:21]=2)[CH:16]=[CH:17][CH:18]=1)=[O:25]
Reactant: Cc1cccc2c(Oc3ccc4c(C(=O)O)cccc4c3)ccnc12
Reactant: Nc1ccccc1N
Product: Cc1cccc2c(Oc3ccc4c(C(=O)Nc5ccccc5N)cccc4c3)ccnc12
Yield: 89.9 %

Procedure:
The title compound (37.7 mg, 90% yield) was prepared as a brown solid from 6-(8-methylquinolin-4-yloxy)-1-naphthoic acid (32.9 mg, 0.1 mmol) and o-phenylenediamine (43.2 mg, 0.4 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) δ 2.76 (s, 3H, Ar—CH3), 4.97 (s, 2H, benzene-NH2), 6.64 (t, J=7.1 Hz, 1H, Ar—H), 6.78 (d, J=5.0 Hz, 1H, Ar—H), 6.82 (d, J=7.8 Hz, 1H, Ar—H), 6.99 (t, J=7.3 Hz, 1H, Ar—H), 7.38 (d, J=7.5 Hz, 1H, Ar—H), 7.55-7.58 (m, 2H, Ar—H), 7.65 (t, J=7.6 Hz, 1H, Ar—H), 7.71 (d, J=7.0 Hz, 1H, Ar—H), 7.87-7.89 (m, 2H, Ar—H), 8.07 (d, J=8.2 Hz, 1H, Ar—H), 8.20 (d, J=7.9 Hz, 1H, Ar—H), 8.44 (d, J=9.2 Hz, 1H, Ar—H), 8.76 (d, J=5.0 Hz, 1H, Ar—H), 9.84 (s, 1H, benzene-NH). LC-MS (m/z) 420 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=O)=[CH:4][CH:3]=1.[C:15]([Mg]Cl)([CH3:18])([CH3:17])[CH3:16].CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]2[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Reactant: CC(C)(C)[Mg]Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C1=CCC(C)(C)c2ccc(Br)cc21
Temperature: -20 °C
Reaction time: 1 h

Procedure:
In a flame dried round bottom flask 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G, 2.0 g, 7.93 mmol) was dissolved in anhydrous THF (50 ml) and 3,4,5,6,-tetrahydro-2(H)-pyrimidinone (DMPU) (11.5 ml, 95.16 mmol) was added, under argon atmosphere. The reaction was then cooled to −20° C. and a solution of t-butyl magnesium chloride (16 ml, 31.7 mmol) (2 M in Et2O) was added dropwise and stirred at −20° C. for 2 h and at ambient temperature for 1 h, under argon atmosphere. The reaction was quenched at 0° C. with saturated ammonium chloride solution (20 ml) and extracted with EtOAc (2×50 ml). The combined extract was washed with water (20 ml), brine (20 ml) and dried over MgSO4. The solvent was evaporated under reduced pressure to afford a yellow oil. To this yellow oil were added MeOH (50 ml) and p-tolylsulfonic acid (100 mg). The resultant reaction solution was heated in an oil bath (60° C.) for 3 h. The reaction was cooled and quenched with water (20 ml), extracted with EtOAc (2×50 ml). The combined extract was washed with saturated NaHCO3 (20 ml), water (20 ml), brine (20 ml), and dried over MgSO4. The solvent was concentrated in vacuo and the title compound was obtained as a colorless oil after purification by flash chromatography (silica, hexane).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:16][C:17]([O:19][CH2:20][CH:21]1[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([CH:42](O)[C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([NH2:49])[CH:44]=1)(OC(C)(C)C)=O>>[C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:16][C:17]([O:19][CH2:20][CH:21]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[C:28]2[C:33]1=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:18])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([NH:49][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:34])[CH:44]=2)=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)C(O)c1cccc(N)c1
Product: CC(C)(C)OC(=O)Nc1cccc(COc2ccc(C[C@H](NC(=O)OCC3c4ccccc4-c4ccccc43)C(=O)OC(C)(C)C)cc2)c1
Yield: 111.4 %

Procedure:
In a manner similar to that described in Example H, the product from Example G (0.50 g, 1.08 mmol) and BOC-3-aminobenzylalcohol (0.24 g, 1.08 mmol) were converted to the title compound (0.40 g, 60%).
Reaction SMILES: [OH-:1].[Li+].[C:3]([O:7][C:8]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=2)[C:13]([CH3:22])([CH3:21])[CH2:12][C:11]1=[O:23])=[O:9])([CH3:6])([CH3:5])[CH3:4]>C1COCC1>[C:3]([O:7][C:8]([NH:10][C:19]1[CH:18]=[CH:17][C:16]([F:20])=[CH:15][C:14]=1[C:13]([CH3:22])([CH3:21])[CH2:12][C:11]([OH:23])=[O:1])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC(C)(C)c2cc(F)ccc21
Reactant: [OH-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(F)cc1C(C)(C)CC(=O)O
Reaction time: 24 h

Procedure:
375 ml (0.75 mol) of an aqueous 2 M lithium hydroxide solution is added to a solution of 44 g (0.15 mol) of 1-tert-butoxycarbonyl-3,4-dihydro-4,4-dimethyl-6-fluoro-2-quinolone in 1l of THF. After 24 hours at room temperature, the batch is concentrated by evaporation, brought to pH 4 with 10% citric acid and extracted with ether. The combined organic extracts are washed with saturated NaCl, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography of the residue on silica gel with hexane-ethyl acetate yields 34.0 g of 3-(2-tert-butoxycarbonylamino-5-fluorophenyl)-3-methylbutyric acid [1H-NMR (CDCl3), δ (ppm)=1.62 (br.s, 15H), 2.77 (s, 2H), 6.41 (br, 1H), 6.93 (td, 1H), 7.07 (dd, 1H), 7.20 (br, 1H)], which dissolves in 1 l of THF and is mixed at 0° C. with 17 ml (121 mmol) of triethylamine and 11.5 ml (121 mmol) of ethyl chloroformate. After 10 minutes at 0° C., 20.7 g (546 mmol) of sodium borohydride is added to it, and 1 l of MeOH is slowly added in drops to it. The batch is stirred for another 30 minutes at 0° C., concentrated by evaporation and diluted with ethyl acetate. It is washed with saturated NaCl, dried on Na2SO4 and purified by column chromatography on silica gel with hexane-ethyl acetate. Yield: 6.7 g.
Reaction SMILES: [C:1]([O:9][C:10]([C:14]([F:17])([F:16])[F:15])=[C:11]([F:13])[F:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:18]([O-:21])([OH:20])=[O:19].[Na+:22].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1(C)C=CC=CC=1>O>[F:13][C:11]([F:12])([S:18]([O-:21])(=[O:20])=[O:19])[CH:10]([O:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]([F:16])([F:15])[F:17].[Na+:22]
Reactant: O=S([O-])O
Reactant: O=C(OC(=C(F)F)C(F)(F)F)c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-])c1ccccc1
Reaction time: 65 h
Yield: 43 %

Procedure:
10.0 g of 1,1,3,3,3-pentafluoropropen-2-yl benzoate which had been synthesized by a conventional technique, was dispersed in 72 g of water, after which 12.0 g of sodium hydrogen sulfite and 1.24 g of benzoyl peroxide were added. Reaction occurred at 85° C. for 65 hours. The reaction solution was allowed to cool, after which toluene was added, followed by separatory operation to separate a water layer. A saturated sodium chloride aqueous solution was added to the water layer whereupon white crystals settled out. The crystals were collected by filtration, washed with a small volume of saturated sodium chloride aqueous solution and then dried in vacuum, obtaining the target compound, sodium 1,1,3,3,3-pentafluoro-2-benzoyloxypropane-1-sulfonate. White crystals, 5.85 g (yield 43%).
Reaction SMILES: S([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:13][CH2:12]1)(C1C=CC(C)=CC=1)(=O)=O.[BrH:22].C(O)(=O)C.Br>C1(C)C=CC=CC=1>[BrH:22].[BrH:22].[F:21][C:18]([F:19])([F:20])[CH2:17][N:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(CC(F)(F)F)CC2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: FC(F)(F)CN1CCNCC1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 55 %

Procedure:
A suspension of 1-tosyl-4-(2,2,2-trifluoroethyl)piperazine (700 mg, 2.2 mmol) in a 30% HBr/acetic acid solution was stirred at 90° C. for 90 minutes. Toluene was added to the suspension. An orange solid was filtered off and washed with diethyl ether to afford the desired compound (400 mg, 55% yield) as a bis HBr salt.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)#[N:2].[H-].[Na+].[CH3:14][Si:15]([CH2:18][CH2:19][O:20][CH2:21]Cl)([CH3:17])[CH3:16]>CN(C=O)C>[CH3:14][Si:15]([CH3:17])([CH3:16])[CH2:18][CH2:19][O:20][CH2:21][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[C:1]#[N:2])[CH:8]=[CH:9]1
Reactant: N#Cc1cccc2cc[nH]c12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2cccc(C#N)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
7-Cyanoindole (1.0 g, 7.0 mmol) was stirred in DMF (10 mL) at 0° C. Sodium hydride (60%, 310 mg, 7.7 mmol) was added, and the reaction stirred 30 min at rt. SEM-chloride was added, and the reaction stirred 16 h. The solution was concentrated in vacuo and purified by silica gel chromatography (10-40% EtOAc/hexanes) to give 1.5 g (78%) of the title compound as a clear oil. 1H NMR (400 MHz, CDCl3): δ 7.85 (dd, 1H, J=7.9, 0.9 Hz), 7.56 (d, 1H, J=7.5 Hz), 7.26 (d, 1H, J=6.3 Hz), 7.17 (t, 1H, J=7.7 Hz), 6.62 (d, 1H, J=3.3 Hz), 5.79 (s, 2H), 3.58 (t, 2H, J=8.1 Hz), 0.92 (t, 2H, J=8.2 Hz), −0.05 (s, 9H). [M+H] calc'd for C15H20N2OSi, 273; found 273.
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]3[N:23]([CH3:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[CH3:26])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl[CH2:32][C:33]1[CH:48]=[CH:47][C:36]([C:37]([N:39]2[CH2:44][CH2:43][N:42]([CH:45]=[O:46])[CH2:41][CH2:40]2)=[O:38])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:24][N:23]1[C:22](=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH3:26])[N:15]=[C:14]1[S:13][CH2:12][C:11]1[CH:27]=[CH:28][C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:32][C:33]3[CH:48]=[CH:47][C:36]([C:37]([N:39]4[CH2:44][CH2:43][N:42]([CH:45]=[O:46])[CH2:41][CH2:40]4)=[O:38])=[CH:35][CH:34]=3)=[CH:30][CH:29]=2)=[CH:9][CH:10]=1
Reactant: O=CN1CCN(C(=O)c2ccc(CCl)cc2)CC1
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCc5ccc(C(=O)N6CCN(C=O)CC6)cc5)cc4)cc3)n(C)c(=O)c12
Yield: 49.7 %

Procedure:
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (402 mg), 1-(4-chloromethylbenzoyl)-4-formylpiperazine (354 mg) and potassium carbonate (261 mg) in DMF (5 ml) was stirred at room temperature for 24 hours. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The solution was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to provide the title compound as colorless solid (310 mg).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]=[C:11]=[S:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.[CH3:14][NH:15][O:16][CH2:17][C:18]([OH:20])=[O:19].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]([N:15]([CH3:14])[O:16][CH2:17][C:18]([OH:20])=[O:19])=[S:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CNOCC(=O)O
Reactant: S=C=Nc1ccc2c(c1)CCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(OCC(=O)O)C(=S)Nc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.8 %

Procedure:
A mixture of 5-indanyl-isothiocyanate (18.5 g), N-methyl aminooxy acetic acid hydrochloride (16.2 g), triethylamine (25 g) and chloroform (150 mL) was heated at reflux for one half hour, stirred at ambient temperature for one hour, then evaporated to dryness. The residue was dissolved in ethyl acetate (500 mL) and washed with 2N HCl (2×400 mL) then with water (400 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness affording (31.3 g) of [[[[(5-indanyl)amino]thioxomethyl]methylamino]oxy]acetic acid as an oil. 1H-NMR (DMSO-d6; 300 MHz) δ13.1 (br s, 1H), 10.5 (s, 1H), 7.38 (s, 1H), 7.18 (m, 2H), 4.62 (s, 2H), 3.50 (s, 3H), 2.82 (m, 4H), and 2.03 ppm (m, 2H). The acid (26.1 g) was dissolved in benzene (200 mL). Phosphorus pentachloride (25 g) was added in portions. The mixture was heated at reflux for one half hour then evaporated to dryness. The residue was dissolved in ethyl acetate (400 mL) and washed with sodium bicarbonate saturated solution (2×300 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel (10% ethyl acetate in hexane). Crystallization from ether afforded the title compound (4.3 g) as a solid, m.p. 135-137° C. Mass spectrum (El, M.+) m/z 262. 1H-NMR (CDCl3; 400 MHz) δ7.31 (d, 1H), 7.04 (s, 1H), 6.96 (d, 1H), 4.84 (ABq, 2H), 3.75 (s, 3H), 2.96 (t, 4H), and 2.11 ppm (m, 2H).
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[N:15]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C@@H:25]([C:39]([OH:41])=O)[CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[C:30]([NH2:37])=[C:29]([Cl:38])[CH:28]=3)=[O:23])[CH2:18][CH2:17]2)[CH2:14][CH2:13][C:12]2[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=2[NH:10]1.[CH3:46][N:47]1[CH2:52][CH2:51][CH:50]([N:53]2[CH2:58][CH2:57][NH:56][C@H:55]([C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:54]2)[CH2:49][CH2:48]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[NH2:37][C:30]1[C:31]([C:33]([F:36])([F:35])[F:34])=[CH:32][C:27]([CH2:26][C@@H:25]([O:24][C:22]([N:19]2[CH2:20][CH2:21][CH:16]([N:15]3[CH2:14][CH2:13][C:12]4[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=4[NH:10][C:9]3=[O:8])[CH2:17][CH2:18]2)=[O:23])[C:39]([N:56]2[CH2:57][CH2:58][N:53]([CH:50]3[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]3)[CH2:54][C@H:55]2[C:59]([O:61][CH2:62][CH3:63])=[O:60])=[O:41])=[CH:28][C:29]=1[Cl:38]
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Reactant: CCOC(=O)[C@@H]1CN(C2CCN(C)CC2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CN(C2CCN(C)CC2)CCN1C(=O)[C@@H](Cc1cc(Cl)c(N)c(C(F)(F)F)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.30 mL (2.16 mmol) triethylamine were added to a mixture of 700 mg (1.26 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1f), 430 mg (1.41 mmol) ethyl(S)-4-(1-methyl-piperidin-4-yl)-piperazine-2-carboxylate (Example A11b) and 450 mg (1.40 mmol) TBTU in 7 mL DMF and the reaction mixture was stirred for 18 h at RT. It was evaporated down i. vac., the residue was stirred with saturated NaHCO3 solution, extracted exhaustively with EtOAc and the combined organic phases were dried over Na2SO4. After elimination of the desiccant and solvent the residue was purified by HPLC; the fractions containing the product were combined and lyophilised.
Reaction SMILES: N#N.Br[C:4]1[CH:5]=[C:6]([C:9]2([CH3:14])[O:13][CH2:12][CH2:11][O:10]2)[S:7][CH:8]=1.[Li]CCCC.CN([CH:23]=[O:24])C>CCOCC.CCCCCC>[CH3:14][C:9]1([C:6]2[S:7][CH:8]=[C:4]([CH:23]=[O:24])[CH:5]=2)[O:13][CH2:12][CH2:11][O:10]1
Reactant: CN(C)C=O
Reactant: CC1(c2cc(Br)cs2)OCCO1
Agent: N#N
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1(c2cc(C=O)cs2)OCCO1
Reaction time: 0.17 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 2-(4-bromo-thiophen-2-yl)-2-methyl-[1,3]dioxolane (1.00 g, 4.01 mmol) in Et2O (36.0 mL) at −78° C. was added dropwise n-BuLi (2.5 mL of a 1.6M solution in hexane, 4.00 mmol) over 15 min. The reaction mixture was then stirred at −78° C. for 15 min before DMF (3.1 mL, 40.14 mmol) was added dropwise. The cooling bath was removed and the reaction mixture was stirred for 10 min. Sat. aq. NaH4Cl (40 mL) was added and the aqueous layer was extracted with EA (2×100 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give crude 5-(2-methyl-[1,3]dioxolan-2-yl)-thiophene-3-carbaldehyde as an yellow oil. LC-MS-conditions 02: tR=0.84 min. The crude material was dissolved, under inert atmosphere (N2) in MeOH (9.98 mL) and treated at 0° C., portionwise with NaBH4 (284 mg, 7.21 mmol). The reaction mixture was stirred at rt for 2 h. The reaction mixture was poured in water (16 mL) and the aq. layer was extracted with EA (2×100 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound as a yellow oil. TLC:rf (50:50 EA-Hept)=0.21. LC-MS-conditions 02: tR=0.71 min; [M+H]+=201.49.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[C:5]([C:8]1[C:9]([C:29]([F:32])([F:31])[F:30])=[N:10][N:11]([CH2:13][C:14]([NH:16][C:17]2[S:21][C:20]3[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=3[C:18]=2[C:26]([NH2:28])=[O:27])=[O:15])[CH:12]=1)(=O)[CH3:6].C([BH3-])#N.[Na+]>CO.CC(O)=O>[OH:4][CH2:3][CH2:2][NH:1][CH:5]([C:8]1[C:9]([C:29]([F:31])([F:32])[F:30])=[N:10][N:11]([CH2:13][C:14]([NH:16][C:17]2[S:21][C:20]3[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=3[C:18]=2[C:26]([NH2:28])=[O:27])=[O:15])[CH:12]=1)[CH3:6]
Reactant: CC(=O)c1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Reactant: NCCO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(NCCO)c1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Temperature: 100 °C
Yield: 14.9 %

Procedure:
To a solution of 2-aminoethanol (103 mg, 1.689 mmol) in MeOH (1.5 mL), AcOH was added until the pH reached 5. 2-(2-(4-acetyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (50 mg, 0.121 mmol) was added before the addition of (7.6 mg, 0.121 mmol) of sodium cyanoborohydride. The reaction was heated by microwave irradiation to 100° C. for 20 min. The reaction mixture was filtered before purification by preparative reverse phase HPLC. The product fractions were acidified to pH 4 before applying to a strong cation exchange cartridge (500 mg). The cartridge was washed with DCM/MeOH (1:1) before eluting the product with 2M NH3 in MeOH. The solvent was removed in vacuo to give the title compound (8.3 mg, 0.018 mmol, 15%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH:20]=[CH:19]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][CH:14]([O:17][CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[CH2:15][CH2:16]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(N2CCC(OC3C=CCCC3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1ccc(N2CCC(OC3CCCCC3)CC2)cc1
Yield: 61.9 %

Procedure:
To a solution of 4-[4-(2-cyclohexenyloxy)piperidin-1-yl]benzoic acid ethyl ester (3.82 g) in methanol (80 ml) was added 10% palladium on carbon (1.0 g), and hydrogen gas at atmosphere pressure for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated by evaporation under reduced pressure to give 4-(4-cyclohexyloxypiperidin-1-yl)benzoic acid ethyl ester (2.38 g).
Reaction SMILES: [C:1]1([N:7]2[C:16]([OH:17])=[C:10]3[N:11]=[CH:12][N:13]=[C:14]([SH:15])[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.C(=O)([O-])[O-].[K+].[K+].Br[C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>O>[C:1]1([N:7]2[C:16]([OH:17])=[C:10]3[N:11]=[CH:12][N:13]=[C:14]([S:15][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH3:35])[CH3:34])[C:9]3=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1c2ncnc(S)c2nn1-c1ccccc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C)(C)Sc1ncnc2c(O)n(-c3ccccc3)nc12
Temperature: 80 °C
Reaction time: 6 h

Procedure:
3.66 g of 2-phenyl-3-hydroxy-7-mercapto-pyrazolo [4,3-d]pyrimidine was suspended in a solvent mixture comprising 150 ml of ethanol and 30 ml of water, and 2.5 g of anhydrous potassium carbonate was added thereto. While heating the mixture to 80° C., 3.5 g of ethyl α-bromoisobutyrate was dropwise added thereto, and the heating was continued for further 6 hours. Then, the solvent was distilled off. Water was added to the residue and the residue was dissolved. The solution was acidified with hydrochloric acid, and then extracted with chloroform. The starting material insoluble in both the aqueous layer and the chloroform layer was collected by filtration and recovered (recovered amount: 1.5 g). The chloroform layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The remaining solid was recrystallized from acetone.
Reaction SMILES: [OH:1][C:2]1[C:23]([CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])=[C:22]([O:29][CH3:30])[CH:21]=[C:20]([O:31][CH3:32])[C:3]=1[C:4](=[O:19])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1.[H][H]>[Pd].C(OCC)(=O)C>[OH:1][C:2]1[C:23]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[C:22]([O:29][CH3:30])[CH:21]=[C:20]([O:31][CH3:32])[C:3]=1[C:4](=[O:19])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1
Reactant: COCOc1ccc(C=CC(=O)c2c(OC)cc(OC)c(CC=C(C)C)c2O)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCOc1ccc(CCC(=O)c2c(OC)cc(OC)c(CCC(C)C)c2O)cc1OC
Yield: 87.8 %

Procedure:
An ethyl acetate solution of 7.0 g of the so-obtained 2'-hydroxy-3,4',6'-trimethoxy-4-methoxymethoxy3'-(3-methyl-2-butenyl)chalcone was added to an ethyl acetate solution of 1.0 g of 5% palladium/carbon, in which hydrogen had been adsorbed in advance, and the mixture was strongly stirred and hydrogen was adsorbed. Then, the mixture was stirred overnight, the palladium/carbon was removed by using Celite and the solvent was removed by distillation. The residue was dissolved in diethyl ether and crystallization was effected by addition of hexane to obtain 6.2 g (yield= 92%) of 1-(2-hydroxy-4,6-dimethoxy-3-isopentylphenyl)3-(3-methoxy-4-methoxymethoxyphenyl)-1-propanone in the form of a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=[O:16])[CH2:12][CH:11]([C:22]([OH:24])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:26]=[C:27]([NH2:32])[CH2:28][CH2:29][O:30][CH3:31]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:22]3[O:24][N:32]=[C:27]([CH2:28][CH2:29][O:30][CH3:31])[N:26]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: COCCC(N)=NO
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CC(O)C3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(CCOC)no3)CN(C(=O)N3CC(O)C3)C2)cc1

Procedure:
60 mg (0.18 mmol) of the compound from Example 138A and 43 mg (0.27 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted according to the General Method 2. Yield: 25 mg (33% of theory)
Reaction SMILES: [CH2:1]=[CH:2][CH:3]1[CH2:8][CH:7]=[CH:6][CH2:5][CH2:4]1.[CH3:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[C:16](=[O:21])[CH:15]=[CH:14][C:13]2=[O:22].C1C=CC=CC=1>[Pd].CO>[CH2:4]([CH:5]1[C:14]2[C:13](=[O:22])[C:12]3[C:17](=[CH:18][C:19]([CH3:20])=[C:10]([CH3:9])[CH:11]=3)[C:16](=[O:21])[C:15]=2[CH2:8][CH2:7][CH2:6]1)[CH2:3][CH2:2][CH3:1]
Reactant: Cc1cc2c(cc1C)C(=O)C=CC2=O
Reactant: C=CC1CC=CCC1
Agent: [Pd]
Solvent: c1ccccc1
Solvent: CO
Product: CCCCC1CCCC2=C1C(=O)c1cc(C)c(C)cc1C2=O
Reaction time: 4 h
Yield: 36 %

Procedure:
A 3.0 g. sample of the butadiene dimer-6,7-di-methylnaphthoquinone adduct was dissolved in 100 ml. benzene. After the addition of 0.30 g 10% Pd/C catalyst, the mixture was hydrogenated at 35 psi for four hours. After removal of catalyst by filtration, five drops DBN were added and the mixture was stirred overnight while exposed to air. The benzene was then blown off with air and the residue chromatographed on acidic alumina with a 9:1 benzene-ethyl acetate solution. The crude product (1.1 g.; 36% yield) was recrystallized from methanol to give an analytical sample with m.p. 88°-90° C.