Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [PH4+].[C:2]([O:6][C:7]([C@@H:9]([N:12]1[C:16](=[O:17])[CH2:15][CH:14]([CH:18]=[O:19])[CH2:13]1)[CH2:10][CH3:11])=[O:8])([CH3:5])([CH3:4])[CH3:3].[Li]CCCC.C1C=CC([P:31](C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)Br>C1COCC1>[C:2]([O:6][C:7]([C@@H:9]([N:12]1[C:16](=[O:17])[CH2:15][CH:14]([CH:18]=[O:19])[CH2:13]1)[CH2:10][CH3:11])=[O:8])([CH3:5])([CH3:3])[CH3:4].[PH3:31]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: BrC(Br)(Br)Br
Agent: CC[C@@H](C(=O)OC(C)(C)C)N1CC(C=O)CC1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: P

Procedure:
Reduction of the Ester 397 to the Alcohol 398 It is done using the method described in §7.0.2.a using 397 either as a single enantiomer, a mixture of two diastereoisomers or a 1/1/1/1 mixture of 4 stereoisomers. For a 1/1 diastereoisomeric mixture of tert-butyl (2S)-2-[4-(hydroxymethyl)-2-oxo-1-pyrrolidinyl]butanoate 398: GC/MS: 257 M+ Oxydation to the Aldehyde 396 In a three necked flask, under argon, a solution of tert-butyl (2S)-2-[4-(hydroxymethyl)-2-oxo-1-pyrrolidinyl]butanoate 398 (4.0 g, 0.016 mol.) in CH2Cl2 (8 ml) is added to a suspension of CrO3 (6.2 g, 0.062 mol.) in pyridine (11.3 ml)/CH2Cl2 (80 ml) stirred at room temperature. The temperature increases to 30° C. and the suspension is stirred for 0.2 h. The suspension is filtered through celite and the filtrate is washed successively with HCl 1N, brine, dried over magnesium sulfate and concentrated in vacuo to afford the crude aldehyde which is purified by column chromatography on silicagel (hexane/acetone 70/30 (v/v)) to afford 2.03 g of 1-[(1S)-1-(tertbutoxycarbonyl)propyl]-5-oxo-3-pyrrolidinecarboxaldehyde 396 (41%). Alternatively, the reaction can also be conducted with racemic ester to afford the racemic aldehyde with a similar yield. Analysis of a 1/1 mixture of 1-[(1S)-1-(tertbutoxycarbonyl)propyl]-5-oxo-3-pyrrolidinecarboxaldehyde 396: 1H NMR (250 MHz, (CDCl3): 0.91 (t, 3H), 1.44 (s, 9H), 1.55-1.77 (m, 1H), 1.90-2.15 (m, 1H), 2.63-2.82 (m, 2H), 3.47-3.61 (m, 1H), 3.65-3.79 (m, 1H), 3.83-3.94 (m, 1H of one of the diastereoisomers), 4.48-4.62 (m, 1H), 9.74 (s (broad), 1H). 6.2. Olefination of 1-[(1S)-1-(tertbutoxycarbonyl)propyl]-5-oxo-3-pyrrolidinecarboxaldehyde 396 6.2.1. Synthesis of Ethylenic Derivatives. Alternatively to §6.2.3., ethylenic derivatives can be obtained by Wittig olefination of the 1-[(1S)-1-(tertbutoxycarbonyl)propyl]-5-oxo-3-pyrrolidinecarboxaldehyde 396 and a phosphonium salt in the presence of a strong base. For example, (2S)-2-(2-oxo-4-vinyl-1-pyrrolidinyl)butanoic acid 2,2dimethyl)ethyl ester is obtained by reaction of the aldehyde 396 with Ph3PCH3Br and n-BuLi in THF. 6.2.2. By Olefination with Ph3P/CBr4 Alternatively to §6.2.3., halovinyl derivatives can be obtained by Wittig olefination of the 1-[(1S)-1-(tertbutoxycarbonyl)propyl]-5-oxo-3-pyrrolidinecarboxaldehyde 396 in the presence of a phosphine and an halogenomethane. For example, (2S)-2-(2-oxo-4-(2,2-dibromovinyl)-1-pyrrolidinyl)butanoic acid 2,2-(dimethyl)ethyl ester is obtained from aldehyde 396 and CBr4 in the presence of triphenylphosphine. 6.2.3. By olefination with (Me2N)3P/CF2Br2
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]3[C:15]=2[CH2:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[C:18]1([C:9]2[NH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:15]3[C:10]=2[CH2:11][CH:12]([CH3:17])[CH:13]([CH3:16])[CH2:14]3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC1=C(C)Cc2c(-c3ccccc3)[nH]c(-c3ccccc3)c2C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC1Cc2c(-c3ccccc3)[nH]c(-c3ccccc3)c2CC1C

Procedure:
1 g of the product obtained in Example 6, 1.2 g of ammonium formate and 0.2 g of 10% Pd/C in 70 ml of ethanol are heated at reflux for 3 hours, then filtered and concentrated. The expected product is isolated by chromatography on silica gel (eluant: cyclohexane/ethyl acetate: 90/10).
Reaction SMILES: [C:1]([NH:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].O.[N+:15](C)([O-:17])=[O:16]>>[C:1]([NH:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: C[N+](=O)[O-]
Reactant: CC(=O)NC1CCc2ccccc21
Solvent: O
Product: CC(=O)NC1CCc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled suspension of (rac)-N-acetyl-1-aminoindan (Ex. 17, 17.5 g, 0.1 mole) in nitromethane (165 ml), was added dropwise a nitrating mixture (H2SO4HNO3, H2O ) while the temperature was kept between 8° C. and 2° C. stirring was continued for 1.5 hours in the ice-bath and the mixture was then poured on to a mechanically stirred mixture of ice (500 g) and water (1300 ml) stirring being continued for 1 hour. The suspension was filtered, the white solid washed with water and dried (14.05 g, 63.9%). It is sufficiently pure for hydrogenation (Ex. 59).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[C:5]([CH3:12])=[CH:4][C:3]=1[NH:13][C@H:14]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:15]1=[O:25].[Cl:26][C:27]1[CH:32]=[N:31][C:30](Cl)=[CH:29][N:28]=1.C(N(C(C)C)C(C)C)C.O>CS(C)=O>[Cl:26][C:27]1[N:28]=[CH:29][C:30]([N:22]2[CH2:21][CH2:20][CH:19]([N:16]3[CH2:17][CH2:18][C@H:14]([NH:13][C:3]4[CH:4]=[C:5]([CH3:12])[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=4[F:1])[C:15]3=[O:25])[CH2:24][CH2:23]2)=[N:31][CH:32]=1
Reactant: Cc1cc(N[C@H]2CCN(C3CCNCC3)C2=O)c(F)cc1S(C)(=O)=O
Reactant: Clc1cnc(Cl)cn1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc(N[C@H]2CCN(C3CCN(c4cnc(Cl)cn4)CC3)C2=O)c(F)cc1S(C)(=O)=O
Temperature: 110 °C
Yield: 60.1 %

Procedure:
(S)-3-(2-Fluoro-5-methyl-4-(methylsulfonyl)phenylamino)-1-(piperidin-4-yl)pyrrolidin-2-one (420 mg, 1.14 mmol) was dissolved in DMSO (10 mL) and 2,5-dichloropyrazine (203 mg, 1.36 mmol) and N-ethyl-N-isopropylpropan-2-amine (297 μL, 1.71 mmol) were added and the reaction heated to 110° C. overnight. The reaction was cooled to ambient temperature, water (60 mL) was added and the solids filtered. The solids were dissolved in CH2Cl2, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (70 to 100% EtOAc in hexanes) to afford (S)-1-(1-(5-chloropyrazin-2-yl)piperidin-4-yl)-3-(2-fluoro-5-methyl-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one (330 mg, 0.685 mmol, 60.2% yield) as a pale yellow solid. Mass spectrum (apci) m/z=482.2 (M+H).
Reaction SMILES: C[O:2][C:3]1[CH:10]=[N:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH:5]=[O:6].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[OH:2][C:3]1[CH:10]=[N:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH:5]=[O:6]
Reactant: COc1cncc(OC)c1C=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cncc(O)c1C=O
Temperature: 25 °C
Yield: 17 %

Procedure:
To a solution of 3,5-dimethoxyisonicotinaldehyde (2.7 g, 16.16 mmol, 1 eq.) in DCM (100 mL) was added AlCl3 (4.31 g, 32.32 mmol, 2.0 eq.) at rt. The mixture was reflux O/N, cooled to rt, and added into ice (200 g). The aqueous layer was extracted with DCM three times. The combined organic layers were dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3-hydroxy-5-methoxyisonicotinaldehyde (420 mg, 17%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 10.96 (s, 1H), 10.26 (s, 1H), 7.96 (s, 1H), 7.80 (s, 1H), 3.84 (s, 3H). LRMS (M+H+) m/z 154.1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH2:12][CH2:13][CH2:14][OH:15])[CH:9]=[CH:10][CH:11]=2)=[CH:2]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH2:12][CH2:13][CH:14]=[O:15])[CH:9]=[CH:10][CH:11]=2)=[CH:2]1
Reactant: OCCCc1cccc(-c2ccsc2)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: O=CCCc1cccc(-c2ccsc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
150 mg of the resulting alcohol compound was dissolved in 5 ml of chloroform, and 222 mg of pyridinium chlorochromate was added. The mixture was stirred overnight at room temperature, and then the s precipitate was removed by filtration. The filtrate was Worked up in a customary manner, and the product was purified by silica gel column chromatography [hexane/ethyl acetate=5/1] to give 115 mg Of the captioned compound as a colorless oil.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[C:10]=1[C:17]#[N:18])(=O)C.[OH-].[Na+]>C1COCC1.CO>[NH2:18][CH2:17][C:10]1[C:11]([Cl:16])=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=1[CH2:8][O:7][CH2:6][CH2:5][OH:4]
Reactant: CC(=O)OCCOCc1cc(Cl)cc(Cl)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: NCc1c(Cl)cc(Cl)cc1COCCO
Temperature: 60 °C

Procedure:
A solution of BH3 (1.46 mL, 1M in THF) was added to a solution of 2-((3,5-dichloro-2-cyanobenzyl)oxy)ethyl acetate (0.36 mmol) in 1.5 mL MeOH. The reaction mixture was heated to 60° C. for 3 h. At 0° C., 1.5 mL MeOH was dropwise added and the mixture was stirred until gaz evolution was finished. An aq. solution of 10% NaOH was added still under cooling. The solvent was removed under vacuo, the residue was diluted with water and extracted 3 times with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired product as yellow solid.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][CH:9]=1.[C:19](=[O:21])=[O:20].CC(C)=O>CCOCC>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[S:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][CH:18]=2)=[CH:12][CH:13]=1
Reactant: O=C=O
Reactant: COc1ccc(-c2cccs2)cc1
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: CCOCC
Product: COc1ccc(-c2ccc(C(=O)O)s2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
To a solution of 6.3 mL of n-butyllithium (2.5 M solution in hexane) in 50 mL of dry ether is added a solution of 3.0 g (15.8 mmol) of 2-(4-methoxyphenyl)thiophene in 20 mL of dry ether under N2 atmosphere. The mixture is stirred at room temperature for 3 hours and then heated at reflux for 30 minutes. After the reaction mixture is cooled to -78° C. with dry ice and acetone bath, dry CO2 gas is bubbled through the reaction mixture for 3 hours and the resulting solution is stirred at room temperature overnight. The reaction mixture is diluted with 200 mL of chloroform, washed with 1% HCl solution (200 mL) and with water (2×200 mL). The separated organic layer is dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 1.8 g (50%) of 5-(4-methoxyphenyl)-2-thienoic acid.
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].[N:49]1([CH2:55][CH2:56][CH2:57][NH-:58])[CH2:53][CH2:52][CH2:51][C:50]1=[O:54].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:37])[CH3:38])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:49]1([CH2:55][CH2:56][CH2:57][NH-:58])[CH2:53][CH2:52][CH2:51][C:50]1=[O:54]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)N[C@H](C(=O)O)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [NH-]CCCN1CCCC1=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)C

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 221 mg of Z-Phe-His-OH, 150 mg of H-Leu-Val-3-(2-pyrrolidinon-1-yl)-propyl amide, 77 mg of HOBt and 122 mg of DCCI, the title compound is obtained after flash chromatography (65 g of silica gel 60, 40-63 μm, eluant system B7). Rf (B7)=0.26, Rf (N12)=0.34.
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH:8]([CH2:10][C:11]([OH:13])=[O:12])[CH2:9][C:4]=2[N:3]=[CH:2]1.S(Cl)(Cl)=O.[CH2:18](O)[CH3:19]>>[CH2:18]([O:12][C:11](=[O:13])[CH2:10][CH:8]1[CH2:7][CH2:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH2:9]1)[CH3:19]
Reactant: O=C(O)CC1CCc2[nH]cnc2C1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CC1CCc2[nH]cnc2C1
Reaction time: 0.5 h

Procedure:
A mixture of 4,5,6,7-tetrahydro-1H-benzimidazole-5-acetic acid (2.2 g, 10 mmol) and ethanol (40 ml) was placed on an ice-bath and thionylchloride (1.78 g, 15 mmol) was added dropwise. When addition was complete, the mixture was stirred for 30 minutes and then heated at reflux for 5 hours. The solvent was evaporated and the residue was re-evaporated with acetonitrile and then stirred with acetonitrile (40 ml) and triethylamine (1.5 ml). The resulting mixture was filtered and the solid was discarded. From the filtrate the solvent was evaporated to give crude 4,5,6,7-tetrahydro-1H-benzimidazole-5-acetic acid ethyl ester. This ester was dissolved in acetonitrile (40 ml) and triethylamine (1.5 ml, 11 mmol) was added followed by portionwise addition of triphenylmethylchloride (2.8 g, 10 mmol). When addition was complete the mixture was stirred overnight at ambient temperature. The mixture was filtered and from the filtrate the solvent was evaporated. The residue was dissolved in ethyl acetate (25 ml) and left for crystallisation. The solid formed was isolated and discarded and from the filtrate the solvent was evaporated. The residue was dissolved in THF (40 ml) and the mixture was placed under an atmosphere of nitrogen. 1 N Lithiumaluminium hydride in THF (6 ml, 6 mmol) was added dropwise. When addition was complete the mixture was stirred at ambient temperature for 3 hours. The mixture was quenched with small amounts of water and 4 N Sodium hydroxide and ethyl acetate was added (50 ml). The solid was removed by filtration and the filtrate was dried (magnesium sulphate). The solvent was evaporated to give a residue that was crystallised from ethyl acetatete (20 ml). This afforded 1.3 g (32%) of 2-(1(3)-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazol-5-yl)ethanol.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)[CH3:10].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:1]1([C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccccc1
Reactant: Br[Mg]c1ccccc1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: C=C(c1ccccc1)c1ccccc1

Procedure:
Crude DPE (Aldrich or from reaction of phenylmagnesium bromide with acetophenone, acetylation with acetic anhydride and thermal elimination of acetic acid) is distilled through a column having at least 50 theoretical plates (spinning-band column; a Sulzer packed column for larger amounts) to a purity of 99.8%. The usually slightly yellow distillate is filtered through a 20 cm Alox column (Woelm alumina for chromatography, anhydrous), titrated with 1.5N sec-butyllithium to a deep red color and distilled off over a simple still head under reduced pressure (1 mbar). The resulting product is completely colorless and can be used directly in the anionic polymerization.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11](O)[CH2:10][CH2:9]1)=[O:7].[CH2:24]([N:31]1[CH2:36][CH2:35][C:34]2([C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[NH:38][CH2:37]2)[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]1[CH2:36][CH2:35][C:34]2([C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]([CH:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:8]([C:6](=[O:7])[C:5]4[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH2:9][CH2:10]3)[CH2:37]2)[CH2:33][CH2:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1ccc(C(=O)N2CCC(O)c3ccccc32)cc1OC
Reactant: c1ccc(CN2CCC3(CC2)CNc2ccccc23)cc1
Product: COc1ccc(C(=O)N2CCC(N3CC4(CCN(Cc5ccccc5)CC4)c4ccccc43)c3ccccc32)cc1OC
Yield: 48.4 %

Procedure:
Starting with 1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-4-quinolinol (250 mg, 0.76 mmol) prepared in Reference Example 2 and 1′-benzylspiro[indoline-3,4′-piperidine] (532 mg, 1.91 mmol), the same procedure as shown in Example 1 was repeated to give the product of interest, i.e., 4-(1′-benzylspiro[indoline-3,4′-piperidin]-1-yl)-1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydroquinoline (211 mg, yield: 48%) as a white crystal.
Reaction SMILES: [C:1]1([S:7][CH:8]([CH:16]([S:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:17]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)O)[CH:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.O>O1CCOCC1>[C:25]1([S:24][CH:16]2[CH:8]([S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[O:10][CH:17]2[C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: OC(c1cccs1)C(Sc1ccccc1)C(Sc1ccccc1)C(O)c1cccs1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(SC2C(c3cccs3)OC(c3cccs3)C2Sc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a suspension of 2,3-bis(phenylthio)-1,4-di(2-thienyl)-1,4-butanediol (54.0 g, 114.9 mmol) in 350 ml dioxane there is added 8.70 g conc. sulfuric acid in 4 almost equal portions with a 45 minutes interval between each addition. The rather thick suspension is stirred mechanically for 4 days at room temperature whereby a clear solution is obtained. The solution is poured into 500 ml water and the product is extracted with 2×300 ml toluene. The organic layer is washed with 2×250 ml water, then dried and rotary evaporated. A quantity of 50 ml ether, followed by 200 ml methanol as well as some seed crystals are stirred into the residue. The crystallized product is filtered off and washed with methanol. It weighs 21.83 g. The filtrate is rotary evaporated and the residue is chromatographed on an aluminum oxide column (16×3 cm) using a 1/1 mixture of toluene and hexane as the eluent, thus obtaining a fraction with an additional amount of the product. This fraction is rotary evaporated and the residue is dissolved in some ether. Methanol is added while stirring, whereupon 3,4-bis (phenylthio)-2,5-di(2-thienyl)-tetrahydrofuran crystallizes. It is isolated in the usual way and weighs 7.04 g. The total yield is 28.87 g (63.9 mmol, 56%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:10]([C:13]1[C:14]([CH:19]=O)=[N:15][CH:16]=[CH:17][CH:18]=1)([CH3:12])[CH3:11].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH:10]([C:13]1[C:14]([CH2:19][NH:9][CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[N:15][CH:16]=[CH:17][CH:18]=1)([CH3:12])[CH3:11]
Reactant: Cc1cccnc1CN
Reactant: CC(C)c1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CNCc1ncccc1C(C)C

Procedure:
Using General Procedure B: Reaction of C-(3-methyl-pyridin-2-yl)-methylamine and 3-isopropyl-pyridine-2-carboxaldehyde with NaBH(OAc)3 in CH2Cl2 gave (3-isopropyl-pyridin-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amine as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([OH:21])=[N:14][C:15]=1[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18].[CH:22]1([CH:25]([C:32]2[CH:37]=[C:36]([CH2:38]O)[N:35]=[CH:34][N:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1COCC1>[CH:22]1([CH:25]([C:32]2[CH:37]=[C:36]([CH2:38][O:21][C:13]3[CH:12]=[CH:11][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:15]([CH2:16][C:17]([CH3:18])([CH3:20])[CH3:19])[N:14]=3)[N:35]=[CH:34][N:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1
Reactant: CCOC(=O)CC(c1cc(CO)ncn1)C1CC1
Reactant: COc1ccc(F)c(-c2ccc(O)nc2CC(C)(C)C)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1cc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)ncn1)C1CC1
Reaction time: 4 h
Yield: 64.6 %

Procedure:
Under a nitrogen atmosphere, to a solution of 5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-ol (200 mg) and ethyl 3-cyclopropyl-3-(6-(hydroxymethyl)pyrimidin-4-yl)propanoate (173 mg) in THF (5.0 mL) were added 1,1′-(azodicarbonyl)dipiperidine (279 mg) and tributylphosphine (273 μL) at room temperature, and the mixture was stirred for 4 hr. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (233 mg) as a colorless oil.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12](C)[CH:11]([CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10]1)=O)(C)(C)C>O1CCOCC1.C(O)C>[ClH:1].[ClH:1].[CH:16]([CH:11]1[CH2:10][NH:9][CH2:14][CH2:13][NH:12]1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN1CCN(C(=O)OC(C)(C)C)CC1C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: c1ccc(C(c2ccccc2)C2CNCCN2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4N Hydrogen chloride in 1,4-dioxane (44 ml) was added to a solution of 4-tert-butoxycarbonyl-2-benzhydryl-1-methylpiperazine (6.5 g) in ethanol (33 ml) under ice-cooling over 30 minutes. The mixture was stirred at room temperature for 4 hours and evaporated under reduced pressure. The residue was triturated with diisopropyl ether and the resulting solid was collected by filtration to give 2-benzhydrylpiperazine dihydrochloride (6.02 g) as a powder.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:6][C:7]([CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][CH2:10]1)=[O:8]>>[CH3:15][C:13]1([CH3:16])[CH2:12][CH2:11][CH2:10][CH:9]([C:7]([OH:8])([CH2:2][CH2:3][CH2:4][CH3:5])[CH3:6])[CH2:14]1
Reactant: CCCCBr
Reactant: CC(=O)C1CCCC(C)(C)C1
Product: CCCCC(C)(O)C1CCCC(C)(C)C1

Procedure:
The protocol of example 1 is carried out again with 1-bromobutane replacing bromoethane and herbac replacing dehydroherbac.
Reaction SMILES: N1C2C(=CC(N)=CC=2)N=[CH:3][CH:2]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([NH2:22])[CH:16]=1)([O-:14])=[O:13].C(C=O)=O>C(#N)C>[N+:12]([C:15]1[CH:16]=[C:17]2[C:18](=[CH:19][CH:20]=1)[N:21]=[CH:3][CH:2]=[N:22]2)([O-:14])=[O:13]
Reactant: Nc1ccc2nccnc2c1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Agent: O=CC=O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc2nccnc2c1

Procedure:
Quinoxaline-6-ylamine. To a round-bottomed flask equipped with magnetic stirring was added 4-nitro-1,2-phenylenediamine (1.0 g, 6.5 mmol, Aldrich), acetonitrile (10 mL) and glyoxal (2.2 mL, 19 mmol, 40 wt. % in water, Aldrich). The reaction mixture was allowed to stir at 50° C. for 12 h, then concentrated in vacuo to yield 1.1 g crude 6-nitro-quinoxaline. The crude product was dissolved in methanol, treated with 10% Pd/C (10 mg, Aldrich) and stirred under H2 (1 atm) at 25° C. overnight. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo to provide the title product. MS (ESI, pos. ion) m/z: 146 (M+1).