Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Cl:4])[CH:2]=[CH2:3].[CH3:5][N:6]([CH3:23])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Cl-]>>[Cl-:4].[CH2:1]([N+:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:5])[CH3:23])[CH:2]=[CH2:3]
Reactant: CCCCCCCCCCCCCCCCN(C)C
Reactant: C=CCCl
Agent: [Cl-]
Product: C=CC[N+](C)(C)CCCCCCCCCCCCCCCC

Procedure:
Allyl hexadecyl dimethyl ammonium chloride was prepared by reacting allyl chloride and dimethyl hexadecyl amine as set forth in Example 1. 17.8 grams of the chloride in 23.5% aqueous solution were treated with a stoichiometric excess of AgF in aqueous solution until analysis of the filtrate showed only a trace of chloride ion present. Excess silver ion was removed by the careful addition of NaCl, AgCl being removed by filtration.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([C:14](=[O:19])[CH2:15][CH2:16][CH2:17]Cl)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:21][C:22]1[CH:36]=[CH:35][C:25]2[C:26]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][O:28][C:24]=2[CH:23]=1>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([C:14](=[O:19])[CH2:15][CH2:16][CH2:17][N:32]3[CH2:31][CH2:30][CH:29]([C:26]4[C:25]5[CH:35]=[CH:36][C:22]([F:21])=[CH:23][C:24]=5[O:28][N:27]=4)[CH2:34][CH2:33]3)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)N1CCc2c(sc(C)c2C(=O)CCCCl)C1
Agent: Cl
Product: CC(=O)N1CCc2c(sc(C)c2C(=O)CCCN2CCC(c3noc4cc(F)ccc34)CC2)C1
Yield: 62 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.4 g of 6-acetyl-3-(4-chlorobutyryl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine and 1.3 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 1.4 g of 6-acetyl-3-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil.
Reaction SMILES: Cl.[I:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[CH3:11][C:12]([O:15][C:16]([NH:18][C@H:19]([C:26](O)=[O:27])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:17])([CH3:14])[CH3:13].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:12]([O:15][C:16]([NH:18][C@H:19]([C:26]([NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([I:2])=[CH:4][CH:5]=1)=[O:27])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:17])([CH3:13])([CH3:11])[CH3:14]
Reactant: COC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCc1ccc(I)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.7 %

Procedure:
A solution of 4-iodobenzylamine hydrochloride (2.965 g, 11.0 mmol), Boc-Glu(OMe)-OH.DCHA (4.426 g, 10.0 mmol), EDCI (2.301 g, 10.0 mmol), HOBt (1.351 g, 10.0 mmol) in DCM (100 mL) containing DIPEA (5.23 mL) was stirred at room temperature under nitrogen for 20 h. The reaction mixture was diluted with DCM, washed with 1N HCl, sat. NaHCO3 solution, and brine. The solvent was evaporated under reduced pressure to give a crude product, which was purified by flash chromatography eluting with hexane/ethyl acetate (3:1) to give (S)-methyl 4-(tert-butoxycarbonylamino)-5-(4-iodobenzylamino)-5-oxopentanoate (3.653 g, 77%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 6.65 (s, 1H), 5.24 (brs, 1H), 4.39 (t, J=5.4 Hz, 2H), 4.15 (m, 1H), 3.70 (s, 3H), 2.57-2.37 (m, 2H), 2.20-2.11 (m, 1H), 1.99-1.90 (m, 1H), 1.44 (s, 9H); MS (ESI), 499 (M+Na)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:16][CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]([CH:23]=O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1([CH2:31][CH2:32][CH2:33][CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:16][CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]([CH2:23][N:37]2[CH2:38][CH2:39][CH:34]([CH2:33][CH2:32][CH2:31][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:35][CH2:36]2)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC1CC(NC(=O)OCc2ccccc2)CC1c1ccccc1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NC1CC(CN2CCC(CCCc3ccccc3)CC2)C(c2ccccc2)C1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.2 %

Procedure:
To a solution of 1-((SR)-(benzyloxycarbonylamino)-3-(SR)-(formyl)-4-(SR)-phenylcyclopentane (from Step F, derived from Higher Rf isomer in Step D) (450 mg, 0.1.4 mmol) in 1,2-dichloroethane (10 mL) was added 4-(3-phenylprop-1-yl)piperidine (424 mg, 2.1 mmol) and acetic acid (0.125 mL, 2.1 mmol). After 15 min, sodium triacetoxyborohydride (890 mg, 4.2 mmol) was added in portions over 30 min and the reaction was stirred at RT for 16 h. The reaction was diluted with methylene chloride, quenched with aq. sodium carbonate and extracted 3 times with methylene chloride. The organic layers were each washed with brine, dried over sodium sulfate, combined and concentrated in vacuo. The residue was purified by FC (30-40% ethyl acetate in hexanes) to give the title product (698 mg) as the free amine.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(O[C:17]1(O[Si](C)(C)C)[CH2:19][CH2:18]1)C.C(O)(=O)C.C([BH3-])#N.[Na+]>O1CCCC1.CO>[CH:17]1([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C2CC2)CC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 68.3 %

Procedure:
A solution of tert-butyl piperazine-1-carboxylate (9.31 g, 50 mmol), [(1-ethoxycyclopropyl)oxy]trimethylsilane (20.11 mL, 100.00 mmol) and acetic acid(14.31 mL, 250.00 mmol) in tetrahydrofuran (100 mL), methanol (10 mL) was treated with sodium cyanoborohydride (4.71 g, 75.00 mmol) at 20° C. The resulting solution was stirred at 60° C. for 18 h. The reaction mixture was cooled, filtered and evaporated to dryness. 1N HCl (40 ml) and water (60 ml) were added and the solution extracted with ethyl acetate (3×50 ml). The aqueous layer was basified to pH 10 with solid potassium carbonate and extracted with ethyl acetate (4×50 ml). The organic extracts were washed with saturated sodium chloride solution (50 ml) and dried over MgSO4, filtered and evaporated to dryness to give tert-butyl 4-cyclopropylpiperazine-1-carboxylate (7.73 g, 68.3%) as a white waxy solid.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[CH3:10][N:11]([CH:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1=[O:20])[CH3:12].[Cl-:27].[NH4+]>CCOCC>[ClH:27].[CH3:12][N:11]([CH:13]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1)[OH:20])[CH3:10]
Reactant: CN(C)C(c1ccccc1)C1CCCCC1=O
Reactant: [Cl-]
Reactant: Cc1ccc(Br)cc1
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1ccc(C2(O)CCCCC2C(c2ccccc2)N(C)C)cc1
Product: Cl
Temperature: 25 °C
Yield: 27.8 %

Procedure:
0.50 g (20.7 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 2.55 ml (20.7 mmole) of 4-bromotoluene dissolved in 20 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 4.0 g (17.3 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction solution was worked up by adding 30 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with in each case 80 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 5.35 g of crude base (95.7%) of theory) were obtained. 1.73 g of 2-(dimethylaminophenylmethyl)-1-p-tolylcyclohexanol, hydrochloride (27.8% of theory) with a melting point of 168-169° C. were obtained from the crude base according to the procedure described in Example 1 (3rd stage) with chlorotrimethylsilane/water in 2-butanone.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH:15][CH3:16])[C:12]([N+:17]([O-])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>CO.[Zn]>[NH2:17][C:12]1[C:13]([NH:15][CH3:16])=[N:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1
Reactant: CNc1nc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: CNc1nc(OCc2ccccc2)ccc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
21.4 g of zinc were added to a solution of 8.50 of 6-benzyloxy-2-methylamino-3-nitropyridine (prepared as described in Preparation 92) in 360 ml of methanol, and then 8.5 ml of acetic acid were added dropwise. The resulting mixture was then stirred at room temperature for one hour. At the end of this time, the reaction mixture was filtered to remove insoluble material. The filtrate was freed from the solvent by distillation under reduced pressure, and the resulting residue was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure, to give 7.50 g of the title compound having Rf=0.63 (on silica gel thin layer chromatography using ethyl acetate as the developing solvent).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][O:6][C@H:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH3:8])[CH2:3][OH:4].C([O-])([O-])=O.[K+].[K+].[N:22]#[C:23]Br.O>C1COCC1>[F:15][C:12]1[CH:11]=[CH:10][C:9]([C@@H:7]([O:6][CH2:5][C@H:2]2[CH2:3][O:4][C:23]([NH2:22])=[N:1]2)[CH3:8])=[CH:14][CH:13]=1
Reactant: C[C@H](OC[C@H](N)CO)c1ccc(F)cc1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](OC[C@H]1COC(N)=N1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.5 %

Procedure:
To a stirred solution of (R)-2-amino-3-[(S)-1-(4-fluoro-phenyl)-ethoxy]-propan-1-ol (1.40 g) in THF (80 ml) were added sequentially K2CO3 (1.82 g) and cyanogen bromide (0.83 g). The mixture was stirred at room temperature for 18 hours, then water was added. The mixture was extracted twice with ethyl acetate and the combined organic layers were dried over MgSO4 and evaporated over Isolute® Flash-NH2 silica gel. Chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: heptane/ethyl acetate=25:75) yielded the title compound as a white solid, (1.15 g, 73%). MS (ISP): 239.0 ([M+H]+).
Reaction SMILES: Br[CH2:2][C:3](=[O:26])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C@@H:11]([CH2:12][C@:13]([C:24]#[CH:25])([OH:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[SH:27][CH2:28][CH2:29][OH:30].C(N(CC)CC)C>CCCCCC.CC(C)=O>[C:24]([C@@:13]1([OH:23])[CH2:14][CH2:15][C@@:16]2([CH3:17])[C@H:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:18]2[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@H:7]3[CH2:6][CH2:5][C@@H:4]2[C:3](=[O:26])[CH2:2][S:27][CH2:28][CH2:29][OH:30])[CH2:12]1)#[CH:25]
Reactant: C#C[C@@]1(O)CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]32)C1
Reactant: OCCS
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: CCCCCC
Product: C#C[C@@]1(O)CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(=O)CSCCO)CC[C@@H]32)C1

Procedure:
A solution of 21-bromo-3β-ethynyl-3α-hydroxy-5β-pregnan-20-one (150 mg, 0.356 mmol), 2-mercaptoethanol (31 μL, 0.445 mmol), and triethylamine (62 μL, 0.445 mmol) in 5 mL of TBF was stirred at room temperature overnight. The mixture was partitioned between EtOAc and water. The organic layer was washed with sat. aq. NaCl, dried with Na2SO4 and concentrated in vacuo resulting in 3β-ethynyl-3α-hydroxy-21-hydroxyethylthio-5β-pregnan-20-one (141 mg) as a white solid; mp 122-126° C.; TLC Rf (hexane:acetone 3:1)=0.11.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14].N1C=CN=C1>C(Cl)(Cl)Cl>[C:1]([Si:5]([CH3:8])([CH3:7])[O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
t-Butyldimethylchlorosilane (26.01 g; 172.56 mmol) was added to a solution of 3-hydroxybenzaldehyde (20.7 g; 164.35 mmol) and imidazole (27.97 g; 410.9 mmol) in CHCl3 (300 mL) at 0° C. via a funnel. The reaction was stirred under N2 overnight while it warmed to room temperature. The reaction mixture was washed by water (100 mL×3) and brine (100 mL×1), dried over Na2SO4 and concentrated to give crude product (29.56 g), which was purified by column chromatography eluted by (i) pentane and (ii) 3% EtOAc in pentane to give 3-(t-butyl-dimethyl-silanyloxy)-benzaldehyde (21 g; 54%). 1H NMR (300 MHz, CDCl3) δ 9.93 (s, 1H), 7.45 (d, 1H, J=7.5 Hz), 7.38 (dd, 1H, J=7.5, 7.5 Hz), 7.31 (d, 1H, J=1.0 Hz), 7.09 (1H, dd, J=7.5, 1.0 Hz), 0.98 (s, 9H), 0.20 (s, 6H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[C:6]12([NH2:16])[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2.C(N(CC)CC)C>C(OCC)C>[C:6]12([NH:16][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:13][CH:12]3[CH2:11][CH:10]([CH2:9][CH:8]([CH2:14]3)[CH2:7]1)[CH2:15]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: C=CC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CC(=O)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of acryloyl chloride (4.05 ml, 0.05 mole) in ethyl ether (25 ml) was added to a cold (+5° C.) solution of 1-adamantaneamine (7.65 g, 0.05 mole) and triethylamine (15.3 ml, 0.11 mole) in ethyl ether (300 ml) and the solution stirred for 72 hours at room temperature. The solvent was removed on a rotary evaporator. The residue was dissoled in ethyl acetate (100 ml), washed with 10 percent hydrochloric acid (100 ml) and water (50 ml), dried over sodium sulfate, filtered and the solvent removed in vacuo leaving an oily solid which was crystallized from methanol-ethyl acetate-hexane. The structure was confirmed by NMR.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[CH2:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CS(C)=O.[OH-].[K+]>O>[ClH:5].[ClH:5].[CH2:6]([N:13]1[CH2:18][CH2:17][N:16]([CH2:2][CH2:3][CH2:4][Cl:5])[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: ClCCCBr
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cl
Product: ClCCCN1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 163.9 %

Procedure:
31.5 g of 1-bromo-3-chloropropane were added to a mixture of 35 g of 1-benzylpiperazine, 150 ml of dimethyl sulfoxide and 25 g of potassium hydroxide. The resulting mixture was stirred at room temperature for 3 hours. Water was added to the resulting solution, the reaction product was extracted with ether, dried (magnesium sulfate), and the salt was precipitated with ethereal hydrochloric acid to give 35.6 g (55% of theory) of 1-benzyl-4-(3-chloropropyl)piperazine dihydrochloride as a white crystalline solid.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([CH3:16])[N:6](COCC[Si](C)(C)C)[CH:7]=1)#[CH:2].C(=O)([O-])[O-].[K+].[K+].[CH3:23][C:24]1[N:25](COCC[Si](C)(C)C)[CH:26]=[C:27]([CH:29]=O)N=1.[CH3:39]C1N(COCC[Si](C)(C)C)C(C=O)=CN=1>CO>[CH3:39][C:24]1[CH:23]=[C:29]([C:2]#[C:1][C:3]2[N:4]=[C:5]([CH3:16])[NH:6][CH:7]=2)[CH:27]=[CH:26][N:25]=1
Reactant: C#Cc1cn(COCC[Si](C)(C)C)c(C)n1
Reactant: Cc1ncc(C=O)n1COCC[Si](C)(C)C
Reactant: Cc1nc(C=O)cn1COCC[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Ethynyl-2-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole and 5-ethynyl-2-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole(1-Diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (10.4 g, 54 mmol) was dissolved in 150 mL methanol. Potassium carbonate (12.6 g, 90 mmol) was added. A solution of crude 2-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbaldehyde and 2-methyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazole-4-carbaldehyde (45 mmol) in 150 mmol methanol was added dropwise at RT. The reaction mixture was stirred at RT overnight. The solvent was evaporated. The residue was taken up in 150 mL water and extracted three times with ethyl acetate (150 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography on silica gel (cyclohexane/ethyl acetate 1:1) and the desired compound was obtained as a mixture of 2 isomers (8.36 g, 78%), MS: m/e=237.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[C:17]([F:18])=[C:16]([F:19])[CH:15]=[CH:14][C:13]=2[F:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:21]([O:26][CH3:27])(=[O:25])/[CH:22]=[CH:23]/[CH3:24].CC(C)([O-])C.[K+].O>C1COCC1.C(OCC)(=O)C>[CH3:27][O:26][C:21](=[O:25])[CH2:22][CH:23]([CH3:24])[CH:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])[C:12]1[C:13]([F:20])=[CH:14][CH:15]=[C:16]([F:19])[C:17]=1[F:18]
Reactant: C/C=C/C(=O)OC
Reactant: O=S(=O)(Cc1c(F)ccc(F)c1F)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CC(C)C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-(4-Chloro-phenylsulfanylmethyl)-1,3,4-trifluoro-benzene (Example 8, step 2, 1.0 g, 3.1 mmol) and methyl crotonate (1.55 g, 15.5 mmol) were dissolved in 50 mL of THF and potassium t-butoxide (1M in THF, 6.2 mL) was added. The reaction mixture was stirred at room temperature for five hours. 100 mL of water and 100 mL of EtOAc were added. The organic layer was washed with brine (100 mL), dried over Na2SO4 and concentrated. The product was purified by column chromatography using EtOAc/hexane as the eluent (gradient from 0/100 to 50/50 in 40 min, 0.79 g, 60%). The product is a mixture of diastereomers. 1H NMR (CDCl3 400 MHz) δ 7.60 (m, 2H), 7.37 (m, 2H), 7.07 (m, 1H), 6.83 (m, 0.5H), 6.63 (m, 0.5H), 5.03 (t, J=10.2 Hz, 0.5H), 4.80 (d, J=10.2 Hz, 0.5H), 3.71 (s, 1.5H), 3.60 (s, 1.5H), 3.33 (m, 1H), 3.10 (m, 0.5H), 2.89 (m, 0.5H), 2.42 (m, 0.5H), 2.15 (m, 0.5H), 1.49 (t, J=6.6 Hz, 1.5H), 0.95 (dd, J=8.8 and 7.3 Hz, 1.5H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:40]=[CH:39][C:16]([CH2:17][N:18]([C:30](=[O:38])[CH2:31][CH2:32][CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].O[Li].O>O1CCOCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([C:30](=[O:38])[CH2:31][CH2:32][CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:28][CH:29]=3)=[CH:39][CH:40]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(C(=O)CCC3CCCC3)c3ccc(C(=O)OCC)cc3)cc2)cc1
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)CCC3CCCC3)c3ccc(C(=O)O)cc3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure F using ethyl 4-[{4-[(4-butylphenyl)ethynyl]benzyl}(3-cyclopentylpropanoyl)amino]benzoate and LiOH.H2O in the presence of dioxane as a yellow powder (79%). 1H NMR (CDCl3, 300 MHz) δ 8.08 (m, 2H), 7.49-7.35 (m, 4H), 7.23-7.02 (m, 6H), 4.91 (br s, 2H), 2.66-2.53 (m, 2H), 2.18-2.05 (m, 2H), 1.70-1.20 (m, 13H), 1.30-0.82 (m, 5H). M− (ESI): 506.4; M+ (ESI): 508.4. HPLC, Rt: 5.67 min (Purity: 98.5%).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8](Cl)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[SH:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:20][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CO>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:14][CH2:15][C:16]2[CH:21]=[N:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:25])[F:26])=[CH:18][CH:17]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(F)COc1ccc(CS)cn1
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)n1ncc(SCc2ccc(OCC(F)(F)F)nc2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
In 40 ml of methanol were dissolved 2.2 g of 2-t-butyl-4,5-dichloro-3(2H)-pyridazinone and 2.4 g of 5-mercaptomethyl(2,2,2-trifluoro-ethoxy)-pyridine, and thereto was added 1.2 g of sodium carbonate. The reaction mixture was stirred overnight at room temperature and then poured into water. Then, procedures similar to those in Preparation Example 24 were conducted to obtain 3.6 g of 2-t-butyl-4-chloro-5-[{6-(2,2,2-trifluoroethoxy)-3-pyridyl}-methylthio]-3(2H)-pyridazinone, m.p. 109.0°~110.0° C.
Reaction SMILES: [I-].COC(=O)C(C)C1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13]C=2)C=CC=1.[C:19](=[O:22])([O-])[O-:20].[K+].[K+].CN(C)C=[O:28]>>[CH3:15][C:10]([CH2:11][C:12]([CH2:13][C:19]([OH:20])=[O:22])=[O:16])=[O:28]
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C(C)c1cccc2cc(O)ccc12
Agent: [I-]
Agent: [K+]
Product: CC(=O)CC(=O)CC(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 64 %

Procedure:
The iodide 2 (286.6 mg) and 6-hydroxy-α-methylnaphthaleneacetic acid methyl ester (154.0 mg) were dissolved in dimethylformamide (3 ml) and potassium carbonate (277,6 mg) was added. The reaction was stirred at room temperature for 12 hours, after which it was partitioned between water (10 ml) 15 and ethyl acetate (50 ml). The layers were separated and the organics were washed with water (3×10 ml) and brine (10 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. Purification of the residue on silica gel (25% ethyl acetate/hexane) gave the desired triacetate (225.8 mg, 64% yield).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([OH:17])=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH3:29][N:30]1[CH2:34][CH2:33][C@@H:32](O)[CH2:31]1>C(Cl)(Cl)Cl>[CH3:29][N:30]1[CH2:34][CH2:33][C@@H:32]([O:16][C:15]([CH:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:6][C:7]3[C:12]2=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:17])[CH2:31]1
Reactant: CN1CC[C@@H](O)C1
Reactant: O=C(O)C1c2ccccc2Oc2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CN1CC[C@@H](OC(=O)C2c3ccccc3Oc3ccccc32)C1
Temperature: 0 °C
Yield: 92.9 %

Procedure:
2 g of 9H-Xanthene-9-carboxylic acid (0.0088 mol) were dissolved in 30 ml of CHCl3 (ethanol free). The solution was cooled at 0° C. and 1.08 ml (0.0123 mol) of oxalyl chloride and a drop of DMF was added. The mixture was stirred and allowed to warm to room temperature. After an hour at this temperature the solvents were evaporated and the residue was dissolved in CHCl3 and evaporated again. This procedure was repeated two times. The solid obtained (2.19 g) was dissolved in 20 ml of CHCl3 and added to a solution of 0.975 g (0.0097 mol) of (3R)-1-methylpyrrolidin-3-ol (Intermediate I-19) in 15 ml of CHCl3 cooled at 0–5° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated and the residue was dissolved in toluene and extracted with HCl 2N. The aqueous layer was basified with K2CO3 and extracted with CHCl3. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness to yield 2.53 g (93%) of the title product as an oil.