Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[CH:15]1([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[CH:15]1([N:21]2[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=[CH:7]3)[CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: ClCCCCn1cnc2ccccc21
Reactant: C1CCC(N2CCNCC2)CC1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2c(c1)ncn2CCCCN1CCN(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.7 %

Procedure:
1-(4-chlorobutyl)-1H-benzimidazole (7.51 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(1-cyclohexyl) piperazine (5.1 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, eluted with dichloromethane/methanol mixture to produce 6.4 g compound (I-15) with a yield of 62.9%. ESI-MS [M+H]+: m/z 341.3.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][C:3]=1[C:20](=[O:22])[CH3:21].I[CH2:24][CH3:25]>>[CH2:24]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:7][C:8]([CH3:12])([CH3:13])[O:9]2)=[CH:4][C:3]=1[C:20](=[O:22])[CH3:21])[CH3:25]
Reactant: CC(=O)c1cc2c(cc1O)OC(C)(C)C=C2c1ccccc1
Reactant: CCI
Product: CCOc1cc2c(cc1C(C)=O)C(c1ccccc1)=CC(C)(C)O2

Procedure:
Following General Procedure A, 1-(7-hydroxy-2,2-dimethyl-4-phenyl-2H-chromen-6-yl)-ethanone (Compound 61, 992 mg, 3.08 nmol) and 1-iodoethane (1.67 mL, 15.4 mmol) were reacted to produce the title compound as a white solid
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N+:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][C:21](OCC)=[O:22])([O-:9])=[O:8]>C1COCC1>[OH:22][CH2:21][CH2:20][CH2:19][C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=2)[NH:15][CH:14]=1
Reactant: CCOC(=O)CCc1c[nH]c2ccc([N+](=O)[O-])cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2[nH]cc(CCCO)c2c1
Reaction time: 0.33 h
Yield: 69.7 %

Procedure:
To a suspension of 95% LiAlH4 (2.20 g, 0.058 mol) in 60 mL of dry THF was added a solution of ethyl 5-nitro-3-indolepropionate (7.30 g, 0.028 mol) in 100 mL of dry THF, at 0° C. under Ar. After stirring for 20 min, the mixture was quenched by the cautious addition of 3 mL of H2O. The resulting suspension was stirred for 10 min and then it was filtered and the filtercake was washed with additional THF. The filtrate was evaporated and the residue was taken up in ether, dried (Na2SO4) and evaporated, and the resulting solid was triturated with hexane to give the title compound (4.30 g, 70%) as a yellow solid, mp 107°-110° C.: IR (KBr) 3480, 3180, 1625 cm-1 ; 1H NMR (CDCl3, 200 MHz) δ8.60 (d, J=2.1 Hz, 1H), 8.35 (br s, 1H), 8.11 (dd, J=9.0, 2.2 Hz, 1H), 7.38 (d, J=8.9 Hz, 1H), 7.16 (m, 1H), 3.75 (t, J=6.2 Hz, 2H), 2.91 (t, J=7.2 Hz, 2H), 2.07-1.93 (m, 2H), 1.37 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][CH:8]([C:13]([O:15]C)=[O:14])[C:9](OC)=[O:10])=[C:5]([N+:19]([O-])=O)[CH:4]=1>[C].[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([CH2:7][CH:8]([C:13]([OH:15])=[O:14])[C:9](=[O:10])[NH:19]2)=[CH:17][CH:18]=1
Reactant: COC(=O)C(Cc1ccc(OC)cc1[N+](=O)[O-])C(=O)OC
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1)NC(=O)C(C(=O)O)C2
Temperature: 80 °C
Reaction time: 24 h
Yield: 82.7 %

Procedure:
10% Palladium- carbon (2.0 g) was added to an ethanol (200 ml) solution of dimethyl (4-methoxy-2-nitrobenzyl)malonate (19 g), and catalytic hydrogenation was conducted at room temperature under an atmospheric pressure for 24 hours. The reaction mixture was further stirred at 80° C. for 24 hours. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was dissolved in a mixed solvent of THF (250 ml) and methanol (250 ml), to which was added dropwise 1N aqueous sodium hydroxide solution (126 ml) under ice-cooling. The reaction mixture was stirred at room temperature for 72 hours and concentrated. 1N Hydrochloric acid was added to the residue to make acidic, and the precipitated crystals were collected by filtration. The obtained crude crystals were washed with acetone to give the entitled compound (11.7 g).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]\[CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:19][CH:18]=1)=O)(C)(C)C>C(Cl)Cl>[CH:25]1(/[CH:24]=[CH:23]\[C:20]2[CH:19]=[CH:18][C:17]([CH2:16][NH2:15])=[CH:22][CH:21]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(/C=C\C2CCCCC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccc(/C=C\C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
Add trifluoroacetic acid (1 mL) to a solution of (Z)—N-(tert-butoxycarbonyl)-4-(2-cyclohexylvinyl)-benzylamine (0.49 g, 1.5 mmol) in DCM (10 mL). Stir the mixture at room temperature for 2 h, concentrate in vacuo and purify the residue by SCX chromatography to obtain the title compound (0.3 g, 87%, estimate 10% of alkane present). Use this material in the next step without additional purification. MS (ES+) m/z: 199.3 (M-NH3+H)+.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29]/[CH:30]=[CH:31]/[CH2:32][C:33]([CH2:44][CH3:45])([O:36][Si](CC)(CC)CC)[CH2:34][CH3:35])[CH2:12][C@@H:11]([O:46][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH2:34]([C:33]([OH:36])([CH2:44][CH3:45])[CH2:32]/[CH:31]=[CH:30]/[O:29][CH2:28][C:20]1[C@:21]2([CH2:23][CH2:24][C@H:25]3[C:16](=[CH:15][CH:14]=[C:13]4[C@:26]3([CH3:27])[C@@H:9]([OH:8])[CH2:10][C@H:11]([OH:46])[CH2:12]4)[C@@H:17]2[CH2:18][CH:19]=1)[CH3:22])[CH3:35]
Reactant: CCC(CC)(C/C=C/OCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)O[Si](CC)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(O)(CC)C/C=C/OCC1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 73 %

Procedure:
The mixture (540 mg) containing the 1α,3β-bis(tert-butyldimethylsilyloxy)-17-{4-ethyl-4-triethylsilyloxy-(2E)-hexenyloxymethyl}androsta-5,7,16-triene obtained in Example 10(1) and a 1M tetra-n-butylammonium fluoride tetrahydrofuran solution (7 ml) were subjected to reaction using a procedure similar to that of Example 5(2) (3 hours), worked up and purified by column chromatography (dichloromethane:ethyl acetate=1:4) to give the titled compound (222 mg, 73%) as a white foam.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:28][C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=2)[N:22]=1>>[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:28][C:29]2[CH:37]=[CH:36][C:32]([C:33]([NH:19][C:3]3[CH:4]=[CH:5][C:6]([N:8]4[CH2:12][CH2:11][CH:10]([N:13]5[CH2:17][CH2:16][CH2:15][CH:14]5[CH3:18])[CH2:9]4)=[CH:7][C:2]=3[CH3:1])=[O:34])=[CH:31][CH:30]=2)[N:22]=1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: Cc1cc(C)nc(Nc2ccc(C(=O)O)cc2)n1
Product: Cc1cc(C)nc(Nc2ccc(C(=O)Nc3ccc(N4CCC(N5CCCC5C)C4)cc3C)cc2)n1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-(4,6-dimethyl-pyrimidin-2-ylamino)benzoic acid. MS: 485.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[C:10]([OH:14])(=[O:13])[CH:11]=[CH2:12]>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:12][CH2:11][C:10]([OH:14])=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: C=CC(=O)O
Reactant: COc1cccc(S)c1
Solvent: CCOCC
Product: COc1cccc(SCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 113.8 h
Yield: 36.4 %

Procedure:
3-Methoxythiophenol (5.70 g, 41 mmol) was placed in a flask with acrylic acid (2.36 g, 33 mmol) and stirred at room temperature for 113.8 hours. The reaction mixture was dissolved in ether and extracted with 10% Na2CO3. The aqueous layer was acidified with concentrated HCl, extracted with ether, dried over MgSO4, and concentrated in vacuo to give the 3-(3-methoxyphenylthio)propanoic acid (2.55 g, 37%) as a white solid: mp 39°-42° C.; 1H NMR (CDCl3) 300 MHz 7.21 (m, 1H) 6.91 (m, 2H) 6.77 (d, J=8.3 Hz, 1H) 3.79 (s, 3H) 3.16 (t, J=7.5 Hz, 2H) 2.68 (t, J=7.3 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:66])[C@H:10]([CH2:62][CH:63]([CH3:65])[CH3:64])[NH:11][C:12](=[O:61])[C@H:13]([C:57]([CH3:60])([CH3:59])[CH3:58])[NH:14][C:15](=[O:56])[C@H:16]([CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[CH3:55])[NH:17][C:18](=[O:47])[C@H:19]([CH2:38][CH2:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[NH:20]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N1CCCCC1.ClCCl>[CH2:1]([O:8][C:9](=[O:66])[C@H:10]([CH2:62][CH:63]([CH3:64])[CH3:65])[NH:11][C:12](=[O:61])[C@H:13]([C:57]([CH3:59])([CH3:58])[CH3:60])[NH:14][C:15](=[O:56])[C@H:16]([CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[CH3:55])[NH:17][C:18](=[O:47])[C@H:19]([CH2:38][CH2:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[NH2:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1)C(C)(C)C
Solvent: C1CCNCC1
Solvent: ClCCl
Product: Cc1ccccc1C[C@H](NC(=O)[C@@H](N)CCC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1)C(C)(C)C

Procedure:
A solution of 10.89 g (12.07 mmol) of N-[N-[N-[N-[(9-fluorenyl)methoxycarbonyl]-O-tert-butyl-L-a-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester in 30 ml of piperidine and 120 ml of dichloromethane was stirred for 30 minutes at room temperature. The solvent was removed by evaporation and the residue was chromatographed on silica gel using firstly 20% ethyl acetate in hexane and then 10% methanol in dichloromethane for the elution. Evaporation gave N-[N-[N-[O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester in the form of an oil which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH:17]([CH3:23])[C:18]([O:20]CC)=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].O.[OH-].[Li+].O.Cl>C(O)C>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([S:16][CH:17]([CH3:23])[C:18]([OH:20])=[O:19])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: CCOC(=O)C(C)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)O
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-[[3,5-bis(1,1-dimethylethyl)-4hydroxyphenyl]thio]propanoate (1.16 g, 3.4 mmole) from Example 5 in absolute ethanol (20ml) was added lithium hydroxide hydrate (0.2g, 4.8 mmole). Water was added until the solution became cloudy and the mixture was then stirred for 20 hours Additional lithium hydroxide hydrate (0.75 g, 17.9 mmole) was added and the mixture was stirred for another two hours. The mixture was poured into 0.5 N hydrochloric acid (75 ml) and extracted with diethyl ether (100 ml in two portions). The ether extract was dried over magnesium sulfate, filtered, and concentrated in vacuo to a solid. Recrystallization from hexane gave the title compound, m.p. 110°-113°.
Reaction SMILES: FC(F)(F)C(O)=O.C1N2CN3CN(C2)CN1C3.[CH2:18]([C:29]1[CH:34]=[C:33]([CH2:35][OH:36])[C:32]([OH:37])=[C:31]([CH3:38])[CH:30]=1)[C:19]1[CH:24]=[C:23]([CH2:25][OH:26])[C:22]([OH:27])=[C:21]([CH3:28])[CH:20]=1>C1(C)C=CC=CC=1.C(C(C)=O)C(C)C.CO>[CH2:18]([C:19]1[CH:24]=[C:23]([CH:25]=[O:26])[C:22]([OH:27])=[C:21]([CH3:28])[CH:20]=1)[C:29]1[CH:34]=[C:33]([CH:35]=[O:36])[C:32]([OH:37])=[C:31]([CH3:38])[CH:30]=1
Reactant: Cc1cc(Cc2cc(C)c(O)c(CO)c2)cc(CO)c1O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: CC(=O)CC(C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cc(Cc2cc(C)c(O)c(C=O)c2)cc(C=O)c1O
Temperature: 85 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
1140.0 g (10.0 mols) of trifluoroacetic acid was put in a four-way flask with a capacity of 5 liters and the reaction container was substituted by nitrogen, after which 315.0 g (2.25 mols) of hexamethylene tetramine was added at a temperature of approx. 30° C., and then 288.0 g of 4,4′-methylene bis(2-methyl-6-hydroxymethylphenol) (1.0 mol; purity 93% based on high-speed liquid chromatograph (HPLC)) was added under agitation over 3 hours at a temperature of 40° C. to cause reaction. After the entire amount of the material had been added, the temperature was raised to 85° C., and then the mixture was further agitated for 3 hours as a post-reaction. After the reaction, the obtained liquid was partially collected and hydrolyzed, and then analyzed based on HPLC. As a result, the main component that appeared to be the target substance had a composition ratio of 70%. Next, 800.0 g of water was added to the liquid obtained from the reaction to implement hydrolysis reaction for 1 hour at a temperature of 60° C. Crystal precipitated during this reaction. After the reaction, 1471.0 g of 16% aqueous sodium hydroxide solution was added to neutralize the obtained mixture liquid, and then 50 g of methyl isobutyl ketone and 50 g of methanol were added further, after which the mixture was cooled and precipitated crystal was filtered out to obtain 302.3 g of a composition. The obtained composition was put in a four-way flask with a capacity of 2 liters, and 369.2 g of methyl isobutyl ketone and 255.6 g of toluene were added, and then the mixture was maintained at a temperature of 70° C. and agitated for 30 minutes in a slurry state. The mixture was cooled and precipitated crystal was filtered out and dried to obtain 196.8 g of yellow powder crystal having a purity of 95.8% based on HPLC. The yield with respect to 4,4′-methylene bis(2-methyl-6-hydroxymethylphenol) was 69.3%. Based on the results of NMR and mass spectrometry, the obtained crystal was confirmed to be the target substance.
Reaction SMILES: [OH-:1].[K+].[CH2:3]([N:5]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:6]1=[O:7])[CH3:4]>CO>[CH2:3]([N:5]1[C:15]2[C:10](=[C:11]([O:16][CH2:10][CH:11]([OH:16])[CH2:12][OH:1])[CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:6]1=[O:7])[CH3:4]
Reactant: CCN1C(=O)CCc2c(O)cccc21
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Product: CCN1C(=O)CCc2c(OCC(O)CO)cccc21
Yield: 52.7 %

Procedure:
2.0 g of potassium hydroxide was dissolved in 80 ml of methanol, and 5.2 g of 1-ethyl-5-hydroxy-3,4-dihydrocarbostyril and 5.0 g of glycerol α-bromohydrin were added to the resulting solution followed by refluxing the mixture for 4 hours. The mixture was then worked up in the same manner as described in Example 1 to obtain a residue after removal of the chloroform by distillation. The residue thus obtained was recrystallized from ethyl acetate to give 1.9 g of 1-ethyl-5-(2,3-dihydroxy)propoxy-3,4-dihydrocarbostyril as a colorless amorphous solid having a melting point of 105° - 107° C.
Reaction SMILES: S(OC1CCC(C)=CC1)([C:4]1[CH:10]=C[C:7](C)=[CH:6][CH:5]=1)(=O)=O.Cl.O1[CH2:24][CH2:23][CH2:22][CH2:21]1>[Cl-].[Zn+2].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:21][C:22]1[CH2:7][CH2:6][CH:5]([C:4]#[CH:10])[CH2:24][CH:23]=1
Reactant: CC1=CCC(OS(=O)(=O)c2ccc(C)cc2)CC1
Reactant: C1CCOC1
Agent: [Pd]
Agent: Cl
Agent: [Cl-]
Product: C#CC1CC=C(C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of lithium acetylide ethylenediamine complex (4.53 g) in dry tetrahydrofuran (38 mL), stirred and cooled to 0° C., is slowly added a 0.5M solution of zinc chloride in dry tetrahydrofuran (100 mL). The mixture is stirred at 10° C. for 30 minutes, then cooled to 0° C. again. A solution of tosylate 4D (R=methyl) (5 g) in dry tetrahydrofuran (11 mL) is then added dropwise, followed by addition of palladium tetrakis(triphenylphosphine) (650 mg). The reaction mixture is stirred overnight at room temperature. The mixture is poured into 10% HCl and extracted into ether. The combined organic layers are sequentially washed with a dilute sodium carbonate solution and brine, then dried over magnesium sulfate. The solvent is removed in vacuo.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C#N)CC=CCC=1C#N.CCCC[N+](CCCC)(CCCC)CCCC.[N-:47]=[N+:48]=[N-:49].[F:50][C:51]1[N:56]=[CH:55][C:54]([CH:57](O)[CH3:58])=[CH:53][CH:52]=1>ClCCl>[N:47]([CH:57]([C:54]1[CH:53]=[CH:52][C:51]([F:50])=[N:56][CH:55]=1)[CH3:58])=[N+:48]=[N-:49]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(O)c1ccc(F)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#CC1=C(C#N)CC=CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(N=[N+]=[N-])c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To a 1-L flask kept cold in a ice bath, add triphenylphosphine (27.9 g, 106.3 mmol), 1,4-cyclohexadiene-1,2-dicarbonitrile, 4,5-dichloro-3,6-dioxo-(24.12 g, 106.3 mmol). Add dichloromethane slowly with stirring (150 mL). To the dark solution add tetra-N-butylammonium azide (30.23 g, 106.3 mmol) slowly, followed by 1-(6-fluoro-pyridin-3-yl)-ethanol (10 g, 70.85 mmol) dissolved in dichloromethane (10 mL). Remove the flask from the ice bath and stir at room temperature for 1 hour. Remove the solvent on a rotovap and purify by normal phase chromatography 5% to 20% ethyl acetate in hexanes to obtain the product as colorless oil (7.75 g). GCMS (EI) m/z 166 M+.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](Br)=[CH:4][C:3]=1[CH3:10].C([Li])CCC.Cl[Si:17]([CH3:20])([CH3:19])[CH3:18]>C(OCC)C.O1CCCC1.CCCCCC>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:4][C:3]=1[CH3:10]
Reactant: C[Si](C)(C)Cl
Reactant: Cc1cc(Br)cc(C)c1Br
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc([Si](C)(C)C)cc(C)c1Br
Reaction time: 1 h

Procedure:
A solution of 2,5-dibromo-1,3-dimethylbenzene (500 mg) in diethylether (3 mL) and tetrahydrofuran (2.5 mL) is cooled to −78° C. and treated dropwise with n-butyllithium (200 μL of a 10 M solution in n-hexane). The mixture is stirred for 1 hour and treated dropwise with chloro-trimethyl-silane (275 μL). After stirring for 2 hours the reaction is quenched by addition of saturated aqueous NH4Cl solution. The mixture is extracted with diethylether. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→90:10) to give the title compound. Yield: 260 mg; Mass spectrum (ESI+): m/z=279 [M+Na]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[CH:11]=[C:10]([CH3:14])[N:9]1[CH3:15].FC1C=CC=CC=1[N:23]1C(=O)C=C(C)N1.IC.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[NH2:23][C:11]1[C:12](=[O:13])[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:9]([CH3:15])[C:10]=1[CH3:14]
Reactant: Cc1cc(=O)n(-c2ccccc2F)[nH]1
Reactant: Cc1cc(=O)n(-c2ccccc2F)n1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(N)c(=O)n(-c2ccccc2F)n1C
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
2-(2-Fluorophenyl)-1,5-dimethyl-1H-pyrazol-3(2H)-one To a solution of 2-(2-fluorophenyl)-5-methyl-1H-pyrazol-3(2H)-one (500 g, 2602 mmol) in THF (2500 ml) heated to 58° C. was added iodomethane (163 ml) dropwise over 15 mins and the mixture was stirred at 65° C. for 30 mins. K2CO3 (198 g) was added over 20 mins and stirred for 16 hrs. Further iodomethane (16.3 ml) was added and stirring continued for 1 hr. The resulting mixture was cooled to 0° C., filtered and washed with THF (50 ml). The filtrate was evaporated to dryness and purified by column chromatography, eluting with EtOAc/Heptane to give the title compound as a red solid.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH:12]=O)=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]1([C@H:24]([NH2:26])[CH3:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[C:14]1([C@H:24]([NH:26][CH2:12][C:11]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[CH:9][CH:10]=2)[CH3:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccnn1-c1ccccc1
Reactant: C[C@@H](N)c1cccc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C[C@@H](NCc1ccnn1-c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-phenyl-1H-pyrazole-5-carbaldehyde 38 (0.517 g, 3 mmol) in DCE (10 mL) at room temperature was added (R)-1-(naphthalen-1-yl)ethanamine 39 (0.625 g, 4 mmol), acetic acid (0.208 g, 3 mmol), and NaBH(OAc)3 (0.946 g, 4 mmol). The reaction mixture was stirred at room temperature for 18 h, quenched with saturated NaHCO3, diluted with EtOAc, washed with saturated NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 20% to 70% EtOAc in hexanes) gave (1R)-1-(1-naphthalenyl)-N-((1-phenyl-1H-pyrazol-5-yl)methyl)ethanamine 40. Mass spectrum: calculated for C22H21N3 327.2; found 328.2 (M++1).
Reaction SMILES: [CH3:1][Si:2]([CH3:21])([CH3:20])[CH2:3][CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]([O:17]CC)=O)[CH2:9]1)=[O:7].Cl.[C:23]([NH2:29])(=[NH:28])[CH2:24][CH2:25][CH2:26][CH3:27].C[O-].[Na+].CCOCC>C(O)C.CO.O>[CH3:21][Si:2]([CH3:1])([CH3:20])[CH2:3][CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:28]=[C:23]([CH2:24][CH2:25][CH2:26][CH3:27])[NH:29][C:15](=[O:17])[C:10]=2[CH2:9]1)=[O:7]
Reactant: CCOC(=O)C1CN(C(=O)OCC[Si](C)(C)C)CCC1=O
Reactant: CCCCC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: CCCCc1nc2c(c(=O)[nH]1)CN(C(=O)OCC[Si](C)(C)C)CC2
Yield: 32.6 %

Procedure:
To a mixture of 2.2 g of 4-oxo-1,3-piperidinedicarboxylic acid 3-ethyl 1-[2-(trimethylsilyl)ethyl]ester and 1.2 g of valeramidine hydrochloride in 15 ml of dry ethyl alcohol is added 7 ml of 1M sodium methoxide in methanol. The resulting mixture is stirred and heated under reflux for 25 minutes. The reaction mixture is allowed to cool, filtered and the solid washed with ethyl alcohol. The combined filtrates are evaporated in vacuo without heat to give an oily solid. Ether and water are added to the residue followed by refrigeration. The resulting crystalline solid is collected, washed with ether and air dried to give 0.8 g of the desired product as a crystalline solid, m.p. 152°-155° C.