Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[NH2:43][CH2:44][CH:45]([OH:52])[CH2:46][N:47]([CH2:50][CH3:51])[CH2:48][CH3:49]>CN(C=O)C>[CH2:48]([N:47]([CH2:50][CH3:51])[CH2:46][CH:45]([OH:52])[CH2:44][NH:43][C:11]([C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:14])[C:4]=2[NH:3][C:2]=1[CH3:1])=[O:13])[CH3:49]
Reactant: CCN(CC)CC(O)CN
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CC(O)CNC(=O)c1c(C)[nH]c2c1CCCC2=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.9 %

Procedure:
A mixture of 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol), HOBt 0.16 g (1.2 mmol), EDCI 0.24 g (1.2 mmol) and triethylamine 0.2 g (2.0 mmol) in 10 ml DMF was stirred at room temperature for 20 min, then 1-amino-3-(diethylamino)propan-2-ol 0.31 g (2.1 mmol) was added. After stirred at room temperature for 24 hours, the mixture was poured into the ice water and extracted with CH2Cl2. The organic layer separated was washed with water and saturated sodium chloride solution, then dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column, eluted with CH2Cl2/MeOH (3:1), to give 0.26 g (81%) of the titled compound as a white solid.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:29])/[CH:12]=[CH:13]/[CH:14]=[C:15](\[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)/[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=CC=1)([O-])=O.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][CH2:37][CH2:38][CH2:39][NH2:40])[CH:31]=1>O1CCCC1>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21](/[C:15](/[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:14]\[CH:13]=[CH:12]\[C:11]([NH:40][CH2:39][CH2:38][CH2:37][CH2:36][C:32]2[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=2)=[O:29])=[CH:26][CH:25]=1
Reactant: CCCCC/C(=C/C=C/C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC)cc1
Reactant: NCCCCc1cccnc1
Solvent: C1CCOC1
Product: CCCCC/C(=C/C=C/C(=O)NCCCCc1cccnc1)c1ccc(OC)cc1
Yield: 70.5 %

Procedure:
As in Example 134, a solution of (2E,4Z)-5-(4-methoxypenyl)-2,4-decadienoic acid 4-nitrophenyl ester (2 g) and 3-pyridinebutanamine (0.9 g) in tetrahydrofuran (20 mL) was stirred overnight at room temperature. After the usual work up, the crude product was purified by HPLC (ethyl acetate) and the resulting solid was triturated with ether to give 1.45 g of (2E,4Z)-5-(4-methoxyphenyl)-N-[4-(3-pyridinyl)butyl]-2,4-decadienamide. A portion was recrystallized from ethyl acetatehexane to furnish the analytical sample, mp 81.5°-82.5° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)=[O:10].[H-].[Na+].CO.C(Cl)Cl>CN(C)C(=O)C>[CH:13]1[N:12]2[C:4]3[C:3]([NH:8][C:9](=[O:10])[C:11]2=[N:15][CH:14]=1)=[CH:2][CH:7]=[CH:6][CH:5]=3
Reactant: O=C(Nc1ccccc1F)c1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Solvent: CO
Product: O=c1[nH]c2ccccc2n2ccnc12
Yield: 78.6 %

Procedure:
10 (2 g, 9.75 mmol) is solubilized in N,N-dimethylacetamide (DMA) (80 ml) before adding sodium hydride (NaH 60% by weight) (1.5 g, 62 mmol). The mixture thus obtained is carried at reflux for 15 h. The reaction is monitored by TLC, eluent: MeOH/CH2Cl2 (10/90). This not being complete, 2 equivalents of NaH are added. The mixture is left at reflux for 30 h. Once the reaction is complete, the mixture is concentrated under vacuum, then to the dry residue are added water and a saturated ammonium chloride aqueous solution. A brown precipitate is formed, which is collected by filtration, washed with water and dried under vacuum. A beige solid (1.42 g, 79%) is obtained. Analysis calculated for C10H7N3O: C, 64.86; H, 3.81; N, 22.69. Experimental: C, 64.44; H, 4.03; N, 22.98.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:14]([C:18]1[CH:37]=[CH:36][C:21]([CH2:22][NH:23][CH2:24][CH2:25][N:26]([CH2:34][CH3:35])[C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:14]([C:18]1[CH:37]=[CH:36][C:21]([CH2:22][N:23]([CH2:24][CH2:25][N:26]([CH2:34][CH3:35])[C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:17]
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Reactant: CCN(CCNCc1ccc(C(C)(C)C)cc1)c1cccc(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCN(CCN(Cc1ccc(C(C)(C)C)cc1)C(=O)c1cc(Cl)cc2cc[nH]c12)c1cccc(C)c1
Temperature: 25 °C
Yield: 59.8 %

Procedure:
97 mg (0.50 mol) of 5-chloro-1H-indole-7-carboxylic acid, 162 mg (0.5 mmol) of N′-(4-tert-butyl-benzyl)-N-ethyl-N-m-tolyl-ethane-1,2-diamine and 108 mg (0.55 mmol) of EDC.HCl were dissolved in 5 ml DCM. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue was dissolved in diethyl ether. The organic layer was washed with 1N aqueous HCl solution, once with 1N aqueous NaOH solution and once with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated to leave 150 mg (60%) product as a colorless oil. MS (ISP) 502.3 (M+H)+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:11][CH2:12][CH2:13][CH2:14][C:15]([Cl:17])=[O:16].Cl>>[Br:11][CH2:12][CH2:13][CH2:14][C:15]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:16].[Br:11][CH2:12][CH2:13][CH2:14][C:15]([Cl:17])=[O:16]
Reactant: c1ccccc1
Agent: Cl
Agent: O=C(Cl)CCCBr
Agent: [Al+3]
Product: O=C(CCCBr)c1ccccc1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A suspension solution of 3.9 g of benzene (50 mmol) and 1.33 g of aluminum chloride (10 mmol) was cooled to 10°C., and 1.95 g of 4-bromobutyryl chloride (purity: 95%, 10 mmol) was dropwise added to the above solution at the same temperature. After raising the temperature to 20 C. and stirring the mixture for two hours, the solution was added into a 10% aqueous solution of hydrochloric acid that had been cooled to 10° C. Then, after the aqueous phase was extracted with benzene and the organic phase was washed with diluted hydrochloric acid and brine, the solvent was removed by distillation under reduced pressure to give 4-bromobutyrophenone in a 84.7% yield from 4-bromobutyryl chloride.
Reaction SMILES: [C:1]([O:13]C)(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.[CH:15]([OH:20])([OH:19])[CH2:16][CH2:17][CH3:18]>>[C:1]([OH:13])(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH:15]([OH:20])([OH:19])[CH2:16][CH2:17][CH3:18]
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: *CCCC*
Agent: *CC*
Agent: CCCC(O)O
Product: O=C(O)c1ccc(C(=O)O)cc1
Temperature: 180 °C

Procedure:
A polyethylene glycol terephtalate/polybutylene terephthalate copolymer may be synthesized from a mixture of dimethyl terephthalate, butanediol (in excess), polyethylene glycol, an antioxidant and a catalyst. The mixture is placed in a reaction vessel and heated to about 180° C., and methanol is distilled as transesterification proceeds. During the transesterification, the ester bond with methyl is replaced with an ester bond with butylene and/or the polyethyene glycol. After transesterification, the temperature is raised slowly to about 245° C., and a vacuum (finally less than 0.1 mbar) is achieved. The excess butanediol is distilled off and a prepolymer of butanediol terephthalate condenses with the polyethylene glycol to form a polyethylene/polybutylene terephthalate copolymer. A terephthalate moiety connects the polyethylene glycol units to the polybutylene terephthalate units of the copolymer and thus such a copolymer also is sometimes referred to as a polyethylene glycol terephthalate/polybutylene terephthalate copolymer (PEGT/PBT copolymer).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32]C)=[O:31])=[CH:25][CH:24]=2)[CH:18]=[N:19][CH:20]=1.O1CCCC1.[OH-].[Na+].Cl>CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:27][CH:28]=2)[CH:18]=[N:19][CH:20]=1
Reactant: COC(=O)Cc1ccc(OCc2cncc(OCc3nc(-c4ccccc4)oc3C)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1cncc(COc2ccc(CC(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
To a mixture of methyl 2-[4-[5-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridylmethoxy]phenyl]acetate (1.50 g), tetrahydrofuran (6 mL) and methanol (6 mL) was added a 1N aqueous sodium hydroxide solution (6 mL) and the mixture was stirred at room temperature for 2 hrs. Dilute hydrochloric acid was added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (1.36 g, 94%) of 2-[4-[5-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridylmethoxy]phenyl]acetic acid. Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 141-142° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[C:20]([C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[S:21][C:14]=12>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][C:13]1[CH:18]=[CH:17][N:16]=[C:15]3[CH:19]=[C:20]([C:22]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:23])[S:21][C:14]=13)=[CH:6][CH:5]=2
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCOCC1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CCOCC5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-chloro-thieno[3,2-b]pyridin-2-yl-morpholin-4-yl-methanone by a procedure analogous to Example 1C. MS: 393 (MH+), HPLC Rf: 3.90 min.; HPLC purity 96%.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[CH2:4]([N:15]([CH2:20][C:21]([OH:23])=[O:22])[CH2:16][C:17]([OH:19])=O)[CH2:5][N:6]([CH2:11][C:12]([OH:14])=[O:13])[CH2:7][C:8]([OH:10])=O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[O:22]=[C:21]1[O:23][C:17](=[O:19])[CH2:16][N:15]([CH2:4][CH2:5][N:6]2[CH2:7][C:8](=[O:10])[O:14][C:12](=[O:13])[CH2:11]2)[CH2:20]1
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: O=C1CN(CCN2CC(=O)OC(=O)C2)CC(=O)O1

Procedure:
To a 250 ml round bottomed flask fitted with a magnetic stirrer, condenser, and a drying tube (calcium chloride), was added pyridine (dried by distillation from potassium hydroxide) (80 ml). Ethylenediaminetetraacetic acid (29.12 g) was added followed by acetic anhydride (37.6 ml). The suspension was stirred and heated at 65°-80° C. for 7 hr. The mixture was cooled overnight and the white solid filtered off. The solid was washed once with pyridine (dry 20 ml) and four times with ether (dry 4×40 ml). The white solid was dried on a manifold and stored in a desiccator.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:11]([C:10](=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:9]=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=Cc1ccccc1
Reactant: CCCCCCCC=O
Product: CCCCCCC(C=O)=Cc1ccccc1

Procedure:
The method of claim 1 or 2, wherein α-hexylcinnamaldehyde is prepared via aldol condensation of benzaldehyde and n-octanal.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:11]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[C:7]#[N:8])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Br)ccc1OCc1ccccc1

Procedure:
5-Bromo-2-hydroxybenzonitrile, benzyl bromide and potassium carbonate were reacted in DMF at room temperature to obtain 2-(benzyloxy)-5-bromobenzonitrile. EI: 287, 289.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:9]1[CH:22]=[C:21]2[C:23]3=[C:24]4[C:14]([CH:15]=[CH:16][CH:17]=[C:18]4[CH:19]=[CH:20]2)=[CH:13][CH:12]=[C:11]3[CH:10]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:2]1([NH:1][C:16]2[CH:15]=[C:14]3[C:24]4=[C:23]5[C:21]([CH:22]=[CH:9][CH:10]=[C:11]5[CH:12]=[CH:13]3)=[CH:20][CH:19]=[C:18]4[CH:17]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cc2ccc3cccc4ccc(c1)c2c34
Reactant: Nc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: c1ccc(Nc2cc3ccc4cccc5ccc(c2)c3c45)cc1

Procedure:
In a three-neck-round floor flask of 250 ml, after 127.5 m mole of aniline, 102 m mole of 2-bromopyrene, 1.53 m mole of tris(dibenzyllidene acetone)dipalladium, 3.06 m mol of BINAP (2,2′-bis(disphenylphosphino)-1,1′-binaphthyl, and 132.6 m mole of sodium-tert-butoxide were melted in 100 mL of toluene and they were mixed for 24 hours in a bath of 1000, when a reaction was terminated, toluene was removed from a reaction mixture and then the reaction mixture was extracted using dichloromethane and water and distilled under a reduced pressure, a solvent of a solution passing through a silica gel column was distilled under a reduced pressure, and thus 5.5 g of an N-phenylpyrene-2-amine liquid was obtained.
Reaction SMILES: C(CC1C=CC([NH:10][C:11]([C:13]2[CH2:14][CH2:15][O:16][C:17]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=4)=[CH:20][C:18]=3[CH:19]=2)=[O:12])=CC=1)#N.Cl.C(O)C.O1CCOCC1>>[CH3:30][C:27]1[CH:26]=[CH:25][C:24]([C:21]2[CH:22]=[CH:23][C:17]3[O:16][CH2:15][CH2:14][C:13]([C:11]([NH2:10])=[O:12])=[CH:19][C:18]=3[CH:20]=2)=[CH:29][CH:28]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CC#N)cc2)CCO3)cc1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(N)=O)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
To N-(4-cyanomethylphenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (200 mg) was added a solution of a 28% hydrogen chloride/ethanol/dioxane (2 ml). The resulting mixture was kept overnight in a refrigerator and then was concentrated, and ethanol (4 ml) and piperidine (1 ml) were added to the residue. After being stirred at room temperature for one hour, the reaction mixture was concentrated and was mixed with an aqueous solution of sodium bicarbonate. The mixture was extracted with ethyl acetate/methanol. The extract was dried (magnesium sulfate) and was then concentrated. To the residue was added 4 N hydrochloric acid/ethyl acetate, and the precipitate was collected by filtration and was washed with ethyl acetate to obtain N-[4-(1-piperidino)carbonimidoylmethyl]phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (compound 46) (103 mg) as a white powder.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:20]=[C:19]3[C:14]([C:15]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:16][C:17]([CH3:21])=[N:18]3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[NH:73]1[CH2:77][CH2:76][CH2:75][CH2:74]1>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:21][C:17]1[CH:16]=[C:15]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:14]2[C:19](=[CH:20][C:11]([O:10][CH2:9][C:6]3[CH:7]=[N:8][C:3]([N:73]4[CH2:77][CH2:76][CH2:75][CH2:74]4)=[CH:4][CH:5]=3)=[CH:12][CH:13]=2)[N:18]=1
Reactant: C1CCNC1
Reactant: Cc1cc(N2CCCC2)c2ccc(OCc3ccc(Cl)nc3)cc2n1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1cc(N2CCCC2)c2ccc(OCc3ccc(N4CCCC4)nc3)cc2n1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
A suspension of 98.5 mg (0.25 mmol) of 7-(6-chloro-pyridin-3-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinoline hydrochloride, product of example 56, 16 mg (0.03 mmol) of BINAP, 2.8 mg (0.01 mmol) of Pd(II) acetate, and 99 mg (1 mmol) of sodium tert-butylate in toluene (4.5 ml) was treated at RT with 36 mg (0.5 mmol) of pyrrolidine and then heated at reflux under an argon atmosphere for 4 h. The reaction mixture was cooled to RT, diluted with methylene chloride (10 ml), and then filtered. The filtrate was concentrated in vacuo, the residue triturated with ether, filtered off by suction and dried in a high vacuum to give 88 mg (84%) of the 2-methyl-4-pyrrolidin-1-yl-7-(6-pyrrolidin-1-yl-pyridin-3-ylmethoxy)-quinoline as a white solid. ISP mass spectrum, m/e: 389.3 (M+1 calculated for C24H28N4O: 389).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[BH3-]C#N.[Na+].O>CC(O)=O>[OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2
Reactant: Oc1cccc2[nH]ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Oc1cccc2c1CCN2
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
A solution of 4-hydroxyindole (0.16 g; 1.2 mmol) in AcOH (6 ml) was treated with NaBH3CN (0.23 g; 3.6 mmol), at rate keeping the temperature below 15° C. The mixture was then stirred for 1 h at room temperature and H2O (0.4 ml) was added and solvents removed in vacuo. The residue was diluted to 15 ml with EtOAc, washed with 5% NaHCO3, brine, dried over anhydrous MgSO4, filtered and filtrate evaporated under reduced pressure to give the title compound (0.16 g; 99%) as creamy solid. 1H-NMR (CDCl3) 2.93 (tr, 2H, J=8.4 Hz); 3.58 (tr, 2H, J=8.4 Hz); 3.74 (broad s, 2H); 6.17 (d, 1H, J=8 Hz); 6.26 (d, 1H, J=7.72 Hz); 6.88 (tr, 1H, J=7.85 Hz).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:15]([CH2:23][CH3:24])=[N:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=23)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>CO>[ClH:25].[CH2:23]([C:15]1[C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[C:18]2[CH2:19][CH2:20][CH2:21][CH2:22][N:17]2[N:16]=1)[CH3:24]
Reactant: CCc1nn2c(c1C1CCN(C(=O)OC(C)(C)C)CC1)CCCC2
Agent: Cl
Solvent: CO
Product: CCc1nn2c(c1C1CCNCC1)CCCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(tert-Butoxycarbonyl)-4-(2-ethyl-4,5,6,7 tetrahydropyrazolo[1,5-a]pyridin-3-yl)-piperidine (1.41 g, from Step F) in MeOH (15 mL) was added a saturated HCl solution in MeOH (15 mL) at 0° C. After stirring at rt for 3 h, the reaction mixture was concentrated to give the title compound as a foamy solid, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:28]([F:29])=[CH:27][C:5]2[N:6]([C@@H:9]3[O:26][CH2:25][C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]3[O:11][C:12](=[O:14])[CH3:13])[CH:7]=[N:8][C:4]=2[CH:3]=1.[Br:30]N1C(=O)CCC1=O>O1CCCC1>[Br:30][C:7]1[N:6]([C@@H:9]2[O:26][CH2:25][C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[C:5]2[CH:27]=[C:28]([F:29])[C:2]([F:1])=[CH:3][C:4]=2[N:8]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1cnc2cc(F)c(F)cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1c(Br)nc2cc(F)c(F)cc21
Yield: 77 %

Procedure:
The title compound was prepared according to General Procedure IV using 5,6-difluoro-1-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole (1.1 g, 2.6 mmol), 60 ml tetrahydrofuran (Aldrich Sure Seal, Milwaukee), and a total of 2,8 g (16 mmol) of N-bromosuccinimide that was added in 3 ca. equivalent portions. The product from work-up by General Procedure IV was purified on a silica gel column (2.5×20 cm, 230-400 mesh) with hexanes and an increasing gradient from 5% to 20% ethyl acetate to give 1.0 g (2.0 mmol, 77% yield); MS (ES+): m/z (rel. intensity) 514 (1.0, M+23 (Na)); 1H NMR (DMSO-d6) δ8.26-8.21 (m, 1H), 7.73-7.69 (m, 1H), 5.93-5.91 (d, 1H, J=9.0 Hz), 5.69-5.62 (m, 3H), 4.11-3.90 (m, 2H), 2.20 (s, 3H), 1.98 (s,3H), 1.73 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9](O)=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[BH4-].[Na+].C1COCC1.[CH2:29]([N:31](CC)CC)C.C([N+](CCCC)(CCCC)CCCC)CCC.[C-]#N.[Na+]>C1(C)C=CC=CC=1.O.CC(C)=O.CN(C=O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH2:9][C:29]#[N:31])=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccccc1Cc1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [BH4-]
Agent: [C-]#N
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: N#CCc1ccccc1Cc1ccc(F)cc1
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 94 %

Procedure:
2-(4-fluoro-benzyl)-benzoic acid is dissolved in toluene (1.5 L/mol) and DMF (1 ml/mol) is added. The reaction mixture is heated up to 40° C. and thionyl chloride (1.1 eq.) is added. During the addition the reaction mixture is further heated up to 50° C. The reaction mixture is stirred at 50° C. during 2.5 hours, then evaporated at 50° C. under vacuum. THF (0.3 L/mol) is added and that solution is dropped into a 2 M NaBH4 solution in THF (1.5 eq.). The temperature rises to reflux (67° C.) and the reaction mixture is stirred at reflux during 2 hours. The reaction mixture is cooled down to room temperature. Acetone (350 ml/mol) is added (temperature rises to 40° C.), the reaction mixture is stirred during 30 minutes, followed by toluene (1 L/mol) and water (1.5 L/mol). The reaction mixture is heated up to 50° C. and the organic layer is evaporated at 50° C. under vacuum. CH2Cl2 (3 L/mol) is added, followed by triethylamine (1.1 eq.). SOCl2 (1.1 eq.) is added dropwise, the temperature rises to reflux. The reaction mixture is stirred during 45 min to room temperature. Water (1 L/mol) is added and the reaction mixture is stirred vigorously during 15 min. The organic layer is washed a second time with water (1 L/mol) and evaporated (40° C., vac.). The product is dissolved in toluene (2.5 L/mol), tetrabutylammonium hydrogenosulfate (phase-transfer catalyst) (0.1 eq.) is added at 70° C. and sodium cyanide 6 M (1.6 eq.) is added at 70° C. under vigorous stirring. The reaction mixture is then heated up to reflux and stirred during 3 hours. After cooling down to room temperature, water (0.5 L/mol) is added and the reaction mixture is stirred during 30 minutes. After washing a second time with water (0.5 L/mol), drying on magnesium sulphate and evaporating the solvent, [2-(4-fluoro-benzyl)-phenyl]-acetonitrile is obtained. Active yield: 94%. N.B. The product can be purified with e.g. thin-film distillation.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]([CH3:20])=O.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C1COCC1>[CH:18]([NH:10][CH2:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([CH3:20])[CH3:17]
Reactant: CC(C)=O
Reactant: NCCC(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)NCCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90.8 %

Procedure:
To a solution of 3,3-diphenylpropan-1-amine 1 (4.22 g, 20.0 mmol) in DCE (100 mL) at room temperature was added acetone (1.19 g, 20.5 mmol, 1.50 mL), acetic acid (1.21 g, 20.1 mmol, 1.15 mL), and NaBH(OAc)3 (5.98 g, 28.2 mmol). The reaction mixture was stirred at room temperature for 5 min, a significant amount of precipitate formed, THF (40 mL) was added, and stirring was continued at room temperature for 3 h. The reaction mixture was quenched with 5 M NaOH, partially concentrated, and diluted with EtOAc. The aqueous phase was extracted with EtOAc (2×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 2% to 8% MeOH (2 M NH3) in DCM) gave N-isopropyl-3,3-diphenylpropan-1-amine 2 (4.60 g, 90.9% yield) as a colorless oil.