Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C#C.[Na].[CH2:4]([C:7]([CH2:9][CH2:10][CH3:11])=[O:8])[CH2:5][CH3:6].[CH3:12][CH2:13]OCC>N>[CH2:4]([C:7]([CH2:9][CH2:10][CH3:11])([OH:8])[C:12]#[CH:13])[CH2:5][CH3:6]
Reactant: CCCC(=O)CCC
Reactant: CCOCC
Agent: C#C
Agent: N
Agent: [Na]
Product: C#CC(O)(CCC)CCC
Reaction time: 12 h

Procedure:
To the acetylene solution in ammonia were added 23 g of finely divided sodium. The bubbling of acetylene was maintained for 1 hour after the introduction of the sodium. After that, 114 g (1 mol) of di-n-propyl ketone were added and the acetylene flow was maintained for 1 hour after which 500 ml of ether were added and the mixture was allowed to stand for 12 hours at room-temperature. It was then hydrolysed by adding damp ether followed by crushed ice. After acidification with 10% sulphuric acid, the ethereal phase was separated out, dried over magnesium sulphate and concentrated under reduced pressure.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18](S(C)(=O)=O)[N:17]=3)[CH:9]=[C:10]3[C:14]=2[NH:13][N:12]=[CH:11]3)=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2.[NH2:30][NH2:31]>>[S:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:30][NH2:31])[N:17]=3)[CH:9]=[C:10]3[C:14]=2[NH:13][N:12]=[CH:11]3)=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2
Reactant: NN
Reactant: CS(=O)(=O)c1nccc(Nc2cc(-c3cc4ccccc4s3)c3[nH]ncc3c2)n1
Product: NNc1nccc(Nc2cc(-c3cc4ccccc4s3)c3[nH]ncc3c2)n1
Yield: 22.3 %

Procedure:
(7-Benzo[b]thiophen-2-yl-1H-indazol-5-yl)-(2-methanesulfonyl-pyrimidin-4-yl)-amine (Preparation #8, 20 mg, 0.048 mmol) was treated with hydrazine (0.4 mL, 12.2 mmol) at ambient temperature for about 5 hours. A solid was filtered off and was further purified by trituration in dichloromethane followed by filtration to yield (7-benzo[b]thiophen-2-yl-1H-indazol-5-yl)-(2-hydrazino-pyrimidin-4-yl)-amine (4 mg, 23% yield); LC/MS (method f) Rt 6.0 min; m/z (ESI−): (M−H)+ 371.7.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.C[O:16][B:17](OC)[O:18]C>>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([B:17]([OH:18])[OH:16])=[CH:3][CH:4]=1
Reactant: COB(OC)OC
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Product: COc1ccc(B(O)O)cn1
Temperature: -75.0999984741211 °C
Yield: 88 %

Procedure:
5-Bromo-2-methoxypyridine (152 g) was dissolved in tetrahydrofuran anhydride (1520 mL) under stirring in nitrogen atmosphere, followed by cooling to −75.1° C. as bulk temperature. Under cooling and stirring, 380 mL of a 2.46 mol/L butyl lithium solution was added dropwise thereinto, followed by the dropwise addition of 192 mL of trimethoxyborane. The cooling bath was removed 30 minutes after completion of the dropwise addition, and the mixture was stirred at room temperature overnight. On the next day, 1.5 L of a 2 mol/L aqueous solution of hydrochloric acid was added thereto, followed by stirring for 1.5 hours. Then, it was neutralized with 460 mL of a 5 mol/L aqueous solution of sodium hydroxide. It was then extracted with 1 L of ethyl acetate, and the resulting aqueous layer was extracted again with 1 L of ethyl acetate. The combined organic layer was washed twice with 1 L of 10% saline water, dried over anhydrous magnesium sulfate, and then evaporated, to give 105 g (88%) of the title compound as a slightly yellowish white solid.
Reaction SMILES: C([Li:5])(CC)C.O=O.[C:8]1([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:22]1CC[CH2:25][CH2:24][CH2:23]1>>[C:8]1([C:14]([Li:5])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:15][CH2:22][CH2:23][CH2:24][CH3:25])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [Li]C(C)CC
Reactant: C1CCCCC1
Reactant: C=C(c1ccccc1)c1ccccc1
Agent: O=O
Product: [Li]C(CCCCC)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An initiator slurry was prepared by mixing 780 ml of 1.3 M sec-butyl lithium in cyclohexane with 8000 g of oxygen-free cyclohexane and stirred at room temperature for about 30 minutes. To this solution was added 197 g of 1,1-diphenylethylene, which resulted in the formation of a red colored solution of 1,1-diphenylhexyl lithium. A 1 wt % solution of 1,6-hexanediol dimethacrylate (HDDMA) was made by pre-dissolving 40 g of HDDMA in 4000 g of purified cyclohexane. The initiator solution was introduced by peristaltic pump at a rate of 24 ml/min into zone 1 of the 3.3 Liter STR along with a 1.0 M solution of triisobutyl aluminum (pressure fed at 4.5 g/min). Purified 2-ethylhexyl methacrylate (EHMA), t-butyl methacrylate (t-BMA) and HDDMA streams were delivered via a reciprocating piston pump at various rates and to various locations of the STR, depending upon the targeted architecture (see Table 3).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C:51]4([C:56]([O:58][CH3:59])=[O:57])[CH2:55][CH2:54][CH2:53][CH2:52]4)[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[C:60]([C:64]1[CH:72]=[CH:71][C:67]([C:68](Cl)=[O:69])=[CH:66][CH:65]=1)([CH3:63])([CH3:62])[CH3:61]>>[C:60]([C:64]1[CH:65]=[CH:66][C:67]([C:68]([NH:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3[CH:49]=[C:48]4[C:44]([CH2:45][N:46]([C:51]5([C:56]([O:58][CH3:59])=[O:57])[CH2:55][CH2:54][CH2:53][CH2:52]5)[C:47]4=[O:50])=[CH:43][CH:42]=3)=[CH:39][CH:40]=2)=[O:69])=[CH:71][CH:72]=1)([CH3:63])([CH3:61])[CH3:62]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COC(=O)C1(N2Cc3ccc(-c4ccc(N)cc4)cc3C2=O)CCCC1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)C1(N2Cc3ccc(-c4ccc(NC(=O)c5ccc(C(C)(C)C)cc5)cc4)cc3C2=O)CCCC1
Yield: 79 %

Procedure:
The compound of example 530 was prepared analogous to compound of example 97 by reaction of compound of example 527 with 4-(t-butyl)benzoyl chloride.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:18]=[C:17]([N:19]([CH3:27])[CH2:20][C:21]2[O:22][C:23]([CH3:26])=[N:24][N:25]=2)[C:16]2[C:11](=[CH:12][C:13]([CH3:28])=[CH:14][CH:15]=2)[N:10]=1.[H-].[Na+].COC1C=CC=CC=1C1N=C(NCC2OC(C)=NN=2)C2C(=CC(C)=CC=2)N=1.CI>CN(C=O)C>[CH3:28][C:13]1[CH:12]=[C:11]2[C:16]([C:17]([N:19]([CH3:27])[CH2:20][C:21]3[O:22][C:23]([CH3:26])=[N:24][N:25]=3)=[N:18][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[OH:2])=[N:10]2)=[CH:15][CH:14]=1
Reactant: COc1ccccc1-c1nc(N(C)Cc2nnc(C)o2)c2ccc(C)cc2n1
Agent: COc1ccccc1-c1nc(NCc2nnc(C)o2)c2ccc(C)cc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1ccc2c(N(C)Cc3nnc(C)o3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
[2-(2-Methoxy-phenyl)-7-methyl-quinazolin-4-yl]-methyl-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amine To a stirring suspension of freshly washed sodium hydride (42 mg, 1.04 mmol) in dry DMF at 0° C. under a nitrogen atmosphere was added the [2-(2-Methoxy-phenyl)-7-methyl-quinazolin-4-yl]-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amine (180 mg, 0.518 mmol, in 5 ml DMF). After 30 minutes at 0° C., MeI (74 μl, 1.19 mmol) was added and the reaction was allowed to warm to room temperature. After one hour the reaction was quenched with water and extracted 3 times with EtOAc. Organics were combined, dried over MgSO4, filtered and concentrated to a yellow oil. Purified by flash chromatography 50/50 EtOAc/hexanes to afford the desired product as a clear oil. 128 mg, 66% yield. LC/MS (10-99%) M/Z 376.1, retention time 2.06 minutes.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16]C(C)(C)C)=O)[CH2:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.F[C:22](F)(F)C(O)=O.C(OC(=O)C)(=O)C>C(Cl)Cl>[F:1][C:2]1[C:7]([C:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:22])[CH2:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccnc2F)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CC=C(c2cccnc2F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 4-(2-fluoropyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.69 g, 9.67 mmol) in CH2Cl2 (8 mL) was added trifluoroacetic acid (7.45 mL, 97 mmol) and stirred at RT for 2 h. The reaction was concentrated in vacuo, and the residue was partitioned between CH2Cl2 and aqueous saturated NaHCO3 solution. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo to give a golden yellow oil. A solution of the crude golden yellow oil in CH2Cl2 (10 mL) was cooled to 0° C. and added acetic anhydride (4.5 mL, 48.3 mmol). The reaction was gradually allowed to warm to RT and stirred for 16 h. The reaction was diluted with CH2Cl2 and washed with aqueous saturated NaHCO3 solution; the aqueous layer was back-extracted with CH2Cl2 (1×). The organic extracts were combined, dried (MgSO4), and concentrated in vacuo. Flash column chromatography (20% to 80% EtOAc/Hexanes) afforded 1-(4-(2-fluoropyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone as a colorless oil. [M+1]=221.1.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:8]([CH2:10][CH2:11][CH2:12][CH3:13])[CH3:9].[I:14][C:15]1[C:23]([I:24])=[C:22]([C:25]([O-:27])=[O:26])[C:21]([I:28])=[C:20]([I:29])[C:16]=1[C:17]([O-:19])=[O:18]>CN(C=O)C>[I:14][C:15]1[C:23]([I:24])=[C:22]([C:25]([O:27][CH:8]([CH2:10][CH2:11][CH2:12][CH3:13])[CH3:9])=[O:26])[C:21]([I:28])=[C:20]([I:29])[C:16]=1[C:17]([O:19][CH:8]([CH2:10][CH2:11][CH2:12][CH3:13])[CH3:9])=[O:18]
Reactant: O=C([O-])c1c(I)c(I)c(C(=O)[O-])c(I)c1I
Reactant: CCCCC(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCC(C)OC(=O)c1c(I)c(I)c(C(=O)OC(C)CCCC)c(I)c1I
Temperature: 76 °C
Reaction time: 22 h
Yield: 31 %

Procedure:
Cesium carbonate (1.63 g, 5.0 mmol) and 2-bromohexane (2.0 ml, 16 mmol) were added to a flask containing a stirred mixture of 2,3,5,6-tetraiodoterephthalate acid (1.4 g, 2.0 mmol) and dry DMF (20 ml). The reaction flask was immersed in an oil bath which was warmed to 76° C. over a period of 0.5 hr. After stirring under an atmosphere of N2 for 22 hrs, the reaction was allowed to cool, diluted with DMF, filtered through a pad of celite and evaporated in vacuo. The resulting residue was taken up into EtOAc (200 ml), washed with saturated aqueous sodium bicarbonate (2×50 ml), water (50 ml) and brine (50 ml), dried (Na2SO4), filtered and evaporated in vacuo. Flash column chromatography (silica, 1:19; Et2O: hexanes) provided bis(2-hexyl) 2,3,5,6-tetraiodoterephthalate (0.52 g, 44%) as a light yellow solid. Mp 114°-115° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([OH:16])=[O:15])([O-:3])=[O:2].OS(O)(=O)=O.[CH3:22][CH2:23]O>>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([O:16][CH2:22][CH3:23])=[O:15])([O-:3])=[O:2]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
A mixture of 2,4-dinitrophenylacetic acid (10 g) and H2SO4 (0.1 eq) in EtOH (300 ml) was refluxed overnight. The solvent was evaporated, and EtOAc (150 ml) and H2O (200 ml) were added. The solution was extracted three times with EtOAc and washed with H2O followed by brine, dried over Na2SO4 and evaporated to give ethyl 2-(2,4-dinitrophenyl)acetate for next step without further purification. The above compound (5 g) was mixed with Pd—C (10%, 500 mg) in EtOH (200 ml) and hydrogenated under H2 atmosphere overnight. The reaction was filtered through Celite and evaporated. The residue was washed with EtOAc and filtered to give 6-aminoindolin-2-one.
Reaction SMILES: CCO[CH2:4][CH3:5].[Mg].[CH3:7][Si:8]([Cl:11])([Cl:10])[Cl:9].[C:12]1(Cl)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[CH3:7][Si:8]([Cl:11])([Cl:10])[Cl:9].[Si:8]([Cl:11])([C:5]1[CH:4]=[CH:14][CH:13]=[CH:12][CH:17]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:7]
Reactant: CCOCC
Reactant: Clc1ccccc1
Agent: C[Si](Cl)(Cl)Cl
Agent: [Mg]
Solvent: O
Product: C[Si](Cl)(c1ccccc1)c1ccccc1

Procedure:
The ether and phenylCl are fed in a ratio of 4:1 and the magnesium is fed at a rate to sustain the reaction as monitored by the reactor temperature profile, jacket water temperature rise, and agitator motor amps. The MeSiCl3 feed is varied to obtain a coupling ratio between 0.25 and 0.90 moles of PhCl/mole of MeSiCl3 depending on the ratio of Ph2SiMeCl/PhMeSiCl2 desired. Toluene is fed in at a 3:1 ratio to the PhenylCl in ether.
Reaction SMILES: [N:1]([CH2:10][C:11]([OH:13])=[O:12])([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].[Fe:14].C(N(CC(O)=O)CCO)CN(CC(O)=O)CC(O)=O.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O>O>[CH2:10]([N:1]([CH2:2][C:3]([O-:5])=[O:4])[CH2:6][C:7]([O-:9])=[O:8])[C:11]([O-:13])=[O:12].[Fe+3:14]
Reactant: O=C(O)CN(CC(=O)O)CC(=O)O
Reactant: [Fe]
Agent: O=C(O)CN(CCO)CCN(CC(=O)O)CC(=O)O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: O
Product: O=C([O-])CN(CC(=O)[O-])CC(=O)[O-]
Product: [Fe+3]

Procedure:
The experiment of Example I was repeated except that 10 mM of the ferric chelate of nitrilotriacetic acid (Fe-NTA) solution was used, rather than Fe-HEDTA. The Fe-NTA solution was prepared by dissolving 0.191 g of NTA in 100 mL of distilled water and adding FeCl3.6H2O, as described in Example I. The composition so produced formed a blue color, as in Example I, in the presence of 0.139 milligram of hemoglobin per deciliter and 50 μM ascorbate.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([NH:14][O:15][CH3:16])=[O:13])=[C:10]([Cl:17])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:18](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CN(C)C=O>[Cl:1][C:2]1[C:11]([C:12](=[N:14][O:15][CH3:16])[O:13][CH3:18])=[C:10]([Cl:17])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CONC(=O)c1c(Cl)ccc(C(=O)OC)c1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: CON=C(OC)c1c(Cl)ccc(C(=O)OC)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.8 %

Procedure:
A mixture of 16.0 g (0.058 mol) of methyl 2,4-dichloro-3-methoxyaminocarbonylbenzoate and 10.1 g (0.073 mol) of potassium carbonate in 300 ml of dimethylformamide was stirred for 30 minutes at room temperature. 11.0 g (0.087 mol) of dimethyl sulfate were subsequently added dropwise, the mixture was stirred for 12 hours at room temperature, and another 11.0 g of dimethyl sulfate were added. After the mixture had been heated for 6 hours at 60° C., it was cooled and stirred into 2 l of ice-water. Then, the aqueous phase was extracted with ethyl acetate, the combined organic phases were dried and the solvent was distilled off in vacuo. After chromatography of the residue on silica gel (eluant:toluene/ethyl acetate=9/1), 2.0 g of methyl 2,4-dichloro-3-(1'-methoxyimino-1'-(methoxy)methyl)benzoate were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH2:18][CH2:19]Cl)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=[O:23])C.[K+].O.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH2:18][CH2:19][OH:23])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)CCCCl)CC1
Reactant: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)CCCO)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In N,N-dimethylformamide (10 ml), 4-tert-butoxycarbonyl-1-[(3-chloro-1-propyl)sulfonyl]piperazine (1.18 g) was dissolved, followed by the addition of potassium acetate (1.06 g). After stirring at room temperature for 2 hours, the reaction mixture was stirred under heat at 100° C. for 3 hours. The reaction mixture was diluted with ethyl acetate, followed by the addition of water and a saturated aqueous solution of sodium bicarbonate. After stirring, the organic layer so separated was washed with a 5% aqueous citric acid solution, water and saturated saline. After drying over anhydrous sodium sulfate, the residue obtained by distilling off the solvent under reduced pressure was dissolved in tetrahydrofuran (20 ml). To the resulting solution, water and lithium hydroxide monohydrate (221 mg) were added, followed by stirring at room temperature for 18 hours. Ethyl acetate and saturated saline were added to the reaction mixture to separated an organic layer. From the water layer, another organic layer was extracted with ethyl acetate. The organic layers were combined together, washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate an hexane, whereby the title compound (944 mg, 84%) was obtained.
Reaction SMILES: [C:1]([C:3]1([OH:13])[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1)#[CH:2].C([Li])CCC.CON(C)[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[N:25][CH:24]=1.[Cl-].[NH4+]>O1CCCC1>[OH:13][C:3]1([C:1]#[C:2][C:22]([C:23]2[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=2)=[O:30])[CH2:12][CH2:11][C:6]2([O:7][CH2:8][CH2:9][O:10]2)[CH2:5][CH2:4]1
Reactant: C#CC1(O)CCC2(CC1)OCCO2
Reactant: CON(C)C(=O)c1ccc(C)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)C#CC2(O)CCC3(CC2)OCCO3)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution of 8-ethynyl-1,4-dioxaspiro[4.5]decan-8-ol (Reference Example 1) (592 mg, 3.25 mmol) in tetrahydrofuran (6 mL), 2.63 M n-butyllithium (solution in n-hexane, 2.6 mL, 6.82 mmol) was added dropwise at −78° C. for 5 minutes, and the obtained solution was stirred at the same temperature for 30 minutes. Thereafter, a solution of N-methoxy-N-methyl-6-methyl-nicotinamide (614.5 mg, 3.41 mmol) in tetrahydrofuran (5 ml) was added dropwise at −78° C. for 20 minutes, and the obtained solution was stirred at the same temperature for 30 minutes. The reaction solution was allowed to warm to room temperature and poured into saturated aqueous ammonium chloride solution. The reaction solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (626.3 mg, 2.08 mmol, 65%) as a pale yellow solid.
Reaction SMILES: C(N(CC)CC)C.[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:14][CH2:15][CH2:16][C:17]1[CH:25]=[CH:24][C:20]([CH2:21][CH2:22][OH:23])=[CH:19][CH:18]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>C(Cl)Cl>[CH3:26][S:27]([O:23][CH2:22][CH2:21][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][O:14][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][O:8]2)=[CH:25][CH:24]=1)(=[O:29])=[O:28]
Reactant: OCCc1ccc(CCOC2CCCCO2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCCc1ccc(CCOC2CCCCO2)cc1
Yield: 99.9 %

Procedure:
Triethylamine (3.22 g, 31.82 mmol) was added to a solution of 4-(2-(tetrahydropyran-2-yloxy)ethyl)phenethyl alcohol (4.00 g, 15.97 mmol) in methylene chloride (40 ml). The mixture was stirred under ice-cooling, and methanesulfonyl chloride (2.19 g, 19.11 mmol) was added dropwise to the mixture. After the addition, the resulting mixture was stirred under ice-cooling for 10 minutes. Then, water (40 ml) was added. The mixture was extracted with methylene chloride and dried over magnesium sulfate. Evaporation of the solvent gave the desired 4-(2-(tetrahydropyran-2-yloxy)ethyl)phenethyl methanesulfonate (5.24 g, 99%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)[CH3:2].[C:13]1([CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:34]2[CH2:33][CH2:32][N:31]([C:28]3[CH:29]=[CH:30][C:25]([N:22]4[CH2:21][CH2:20][CH:19]([C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=5)[CH2:24][CH2:23]4)=[CH:26][CH:27]=3)[CH2:36][CH2:35]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: c1ccc(C2CCN(c3ccc(N4CCNCC4)cc3)CC2)cc1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CCN(c3ccc(N4CCC(c5ccccc5)CC4)cc3)CC2)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 46 %

Procedure:
A mixture of 4-fluorobenzoic acid ethyl ester (1.25 g), 1-[4-(4-phenylpiperidin-1-yl)phenyl]piperazine (1.19 g) and potassium carbonate (1.53 g) in dimethylsulfoxide (18 ml) was stirred for 12 hours at 150° C. The reaction mixture was pulverized with water. The mixture was extracted with dichloromethane. The organic layer was separated, washed with brine, dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography over silica using dichloromethane/methyl alcohol (200:1) as the elution. The powder was recrystallized from toluene (60 ml). The crystal was collected by filtration, and dried under reduced pressure to give 4-[4-[4-(4-phenylpiperidin-1-yl)phenyl]piperazin-1-yl]benzoic acid ethyl ester (0.80 g).
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[C:11]([OH:23])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[C:35](Cl)(=[O:40])[CH2:36][CH:37]([CH3:39])[CH3:38]>>[C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[C:11]([O:23][C:35](=[O:40])[CH2:36][CH:37]([CH3:39])[CH3:38])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CC(=O)Cl
Reactant: Cc1ccc(Oc2ccc(C(=O)CNC(C)(C)C)cc2O)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: Cc1ccc(Oc2ccc(C(=O)CNC(C)(C)C)cc2OC(=O)CC(C)C)cc1

Procedure:
Following a procedure similar to that described in Example 2A above, when 3-hydroxy-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone is interacted with oen equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with isovaleryl chloride there is obtained 3-(isovaleryl oxy)-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 2B, there is obtained 3-(isovaleryloxy)-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl) benzyl alcohol hydrochloride.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH3:18][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[CH:24]=[CH2:25]>CN1C(=O)CCC1.O>[CH3:1][N:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:25][CH2:24][C:20]3[S:21][CH:22]=[CH:23][C:19]=3[CH3:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1sccc1C
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2sccc2C)C=CN(C)C1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (250 mg, 1.25 mmol) in NMP (1 mL) were added powdered KOH (490 mg, 8.75 mmol) and 3-methyl-2-vinyl-thiophene (310 mg, 2.25 mmol), and the reaction mixture stirred at 90° C. for 5 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layer was washed with water (5×25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to yield 2,8-dimethyl-5-[2-(3-methyl-thiophen-2-yl)-ethyl]-2,5-dihydro-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.25 (d, 1H), 7.22 (s, 1H), 7.1 (d, 1H), 7.02 (d, 1H), 6.7 (d, 1H), 4.41 (s, 2H), 4.3 (t, 2H), 2.42 (bs, 2H), 3.2 (t, 2H), 3.0 (s, 3H), 2.61 (bs, 2H), 2.4 (s, 3H), 1.6 (s, 3H).