Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH2:10]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].N1CCCCC1.C(OCC)(=O)C>O>[CH2:10]([C:18]1[CH:25]=[CH:24][C:21](/[CH:22]=[C:2](/[C:3](=[O:4])[CH3:5])\[C:1]([O:7][CH2:8][CH3:9])=[O:6])=[CH:20][CH:19]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCc1ccc(C=O)cc1
Reactant: CCOC(=O)CC(C)=O
Solvent: O
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: CCCCCCCCc1ccc(/C=C(/C(C)=O)C(=O)OCC)cc1

Procedure:
Ethyl acetoacetate (11.8g, 0.092 moles), paraoctylbenzaldehyde (10.0 g, 0.046 moles) and piperidine (1.5ml) were stirred for 48 hrs. at room temperature. Ethyl acetate (50ml) was added and the solution was added to water (100ml). The layers were separated and the organic layer dried over anhydrous sodium sulfate, filtered and concentrated to an oily solid. The title products were separated and purified by silica gel chromatography. The structure assignments were supported by NMR, infrared spectra and elemental analysis (330.5)
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([Cl:18])=[CH:11][N:12]2[CH:15]2[CH2:17][CH2:16]2)=[C:8]([O:19][CH3:20])[CH:7]=1)=[O:5])C>CO.C1COCC1>[Cl:18][C:10]1[C:9]2[C:13](=[CH:14][C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]=2[O:19][CH3:20])[N:12]([CH:15]2[CH2:17][CH2:16]2)[CH:11]=1
Reactant: CCOC(=O)c1cc(OC)c2c(Cl)cn(C3CC3)c2c1
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)O)cc2c1c(Cl)cn2C1CC1
Temperature: 60 °C
Reaction time: 9 h
Yield: 85.7 %

Procedure:
To a stirred solution of 1.03 g of ethyl-3-chloro-1-cyclopropyl-4-(methyloxy)-1H-indole-6-carboxylate in 15 ml of MeOH and 10 ml of THF was added 2 ml of 5N NaOHaq and the mixture was stirred at 60° C. for 9 hrs. After evaporation of MeOH and THF, the mixture was diluted with water and 2 ml of 5N HClaq was added thereto. The precipitate was collected by filtration and dried in vacuo to give 798 mg of 3-chloro-1-cyclopropyl-4-(methyloxy)-1H-indole-6-carboxylic acid as a colorless solid.
Reaction SMILES: [CH2:1]([Sn:5]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([OH:15])([CH3:14])[CH3:13])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH3:26]I>C1COCC1.CCOC(C)=O>[CH3:26][O:15][C:12]([C:8]1[CH:7]=[C:6]([Sn:5]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:20][CH2:21][CH2:22][CH3:23])[CH:11]=[CH:10][N:9]=1)([CH3:13])[CH3:14]
Reactant: CI
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(C(C)(C)O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)c1ccnc(C(C)(C)OC)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 2-(4-tributylstannanyl-pyridin-2-yl)-propan-2-ol 12AO (0.12 g, 0.27 mmol) in THF (2 ml) was added in a dry NaH (0.02 g, 0.54 mmol). Reaction mixture was stirred for 20 min at r.t. It was cooled to 0° C. and CH3I (0.02 ml, 0.32 mmol) was added drop wise. After 30 mins at 0° C., reaction mixture was warmed up to r.t. It was diluted with EtOAc (15 ml) after 2 hr and washed with water (2×3 ml) and brine (5 ml). Organic extracts were dried over MgSO4, filtered and concentrated. The residue was purified on silica gel eluting with 1/4 EtOAc/Hexane to give the desired product 2-(1-methoxy-1-methyl-ethyl)-4-tributylstannanyl-pyridine 13AO (0.1 g, 88%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[S:7]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]1.Cl.[Br:17][C:18]1[CH:19]=[C:20]([NH:24][NH2:25])[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>ClCCl.CN(C=O)C>[Br:17][C:18]1[CH:19]=[C:20]([NH:24][NH:25][C:13]([CH:10]2[CH2:9][CH2:8][S:7][CH2:12][CH2:11]2)=[O:15])[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)C1CCSCC1
Reactant: NNc1cccc(Br)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NNc1cccc(Br)c1)C1CCSCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.5 %

Procedure:
Oxalyl chloride (1.20 mL, 14.2 mmol) was added dropwise to a stirred solution of tetrahydro-2H-thiopyran-4-carboxylic acid (WO2007006732, 2.00 g, 13.7 mmol) in dichloromethane (25 mL). Then, two drops of N,N′-dimethylformamide were added and stirring was continued. After 1.5 hours, the resultant solution was added dropwise over 30 minutes to a stirred, cooled (ice-bath) solution of (3-bromophenyl)hydrazine hydrochloride (3.05 g, 13.7 mmol) and triethylamine (4.20 mL, 30.1 mmol) in dichloromethane (40 mL). After the addition, the mixture was warmed to room temperature and stirred for two hours. The mixture was then concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with 4% aqueous sodium hydrogen carbonate solution, dried (MgSO4) and evaporated. The residue was triturated with diethyl ether and the solid was filtered and dried to give the title compound (2.57 g, 60%) as an off-white solid.
Reaction SMILES: [I:1][CH2:2][CH2:3][OH:4].N1C=CN=C1.[CH3:10][C:11]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])[CH3:12]>ClCCl>[I:1][CH2:2][CH2:3][O:4][Si:14]([C:11]([CH3:13])([CH3:12])[CH3:10])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCI
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCI
Temperature: 25 °C
Reaction time: 12 h
Yield: 115.1 %

Procedure:
To a solution of 2-iodoethanol (3 g, 17 mmol) and imidazole (1.74 g, 25 mmol) in 20 mL anhydrous dichloromethane was added TBSCl (2.82 g, 18.7 mmol). The mixture was stirred at room temperature overnight (12 hours). The reaction mixture was washed with water (2×10 mL), brine (10 mL) and dried over Na2SO4. Removal of the solvent afforded pure product I(CH2)2OTBS (1) (5.6 g, 98% yield, MW: 286.02).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([O:27]CC)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.C(O)CCC.CC([O-])(C)C.[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([OH:27])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc12
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)O
Temperature: 100 °C
Yield: 92.3 %

Procedure:
Ethyl 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example D.a19; 52.73 g; 131.4 mmol) is dissolved in tert. BuOH (500.0 mL) and water (5.0 mL). After addition of commercially available KOtBu (73.70 g; 656.8 mmol) the reaction mixture is stirred at 100° C. over night and cooled to ambient temperature. Water (1500 mL) is added and pH is adjusted to 6.0 by careful addition of 2M aqueous citric acid. The precipitated product is filtered washed with several portions of water and dried under reduced pressure to yield 45.3 g of the title compound as off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]([CH:38]=[CH:39][CH:40]=1)[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[CH:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]2=[O:37])[CH2:17][CH2:16]1)=[O:10])C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH3:1][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH:38]=[CH:39][CH:40]=1)[CH2:14][N:15]1[CH2:16][CH2:17][CH:18]([N:21]2[CH:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]2=[O:37])[CH2:19][CH2:20]1)=[O:10]
Reactant: O=C(OCc1ccccc1)c1cccc(CN2CCC(N3C(=O)Nc4ccccc4C3c3ccccc3)CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cccc(CN2CCC(N3C(=O)Nc4ccccc4C3c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.6 %

Procedure:
To a solution of 300 mg (0.56 mmol) of 3-[1-(3-benzyloxycarbonylbenzyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone in 20 mL of methanol was added 8 mg (0.06 mmol) of potassium carbonate and the mixture was stirred for 12 hours at ambient temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer separated was washed with brine, dried on sodium sulfate and concentrated in vacuo. The residue was purified by means of column chromatography (silica gel, 1:9 methanol:chloroform) to give 179 mg (0.39 mmol) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24].[C:25](OC(=O)C)(=[O:27])[CH3:26].O.Cl>N1C=CC=CC=1.C(OCC)(=O)C>[O:23]=[C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:24])[N:14]1[CH2:13][CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][NH:1][C:25](=[O:27])[CH3:26])[CH:4]=2)[NH:8][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)NCc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
An ice-cold suspension of 2-[2-[5-(aminomethyl)-1H-indol-3-yl]ethyl]-1H-isoindole-1,3(2H)-dione, hemisulphate, hydrate (1.01 g) in pyridine (40 ml) was treated dropwise with acetic anhydride (0.6 ml). The mixture was stirred at room temperature for 1 h, water (15 ml) was added, and after a further 15 min the solution was acidified with hydrochloric acid (2N) and extracted into ethyl acetate (3×150 ml). The combined extract was washed with sodium carbonate (2N; 300 ml), dried (MgSO4) and evaporated to dryness, affording a yellow foam. On trituration with ethyl acetate (ca. 10 ml) this afforded the title amide as a pale yellow crystalline solid (0.79 g) m.p. 180°-2°.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([O:14][CH3:15])=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:28][S:29]([O:13][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][C:3]2[C:16]([CH3:20])=[CH:17][CH:18]=[CH:19][C:2]=2[CH3:1])[C:7]=1[O:14][CH3:15])(=[O:31])=[O:30]
Reactant: COc1c(CO)cccc1OCc1c(C)cccc1C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(COS(C)(=O)=O)cccc1OCc1c(C)cccc1C
Temperature: 25 °C

Procedure:
To a solution of (3-(2,6-dimethylbenzyloxy)-2-methoxyphenyl)methanol (Step B, 9.5 g, 32.7 mmol) and triethylamine (5.80 g, 57.4 mmol) in dry CH2Cl2 (100 ml) was added drop wise methanesulfonyl chloride (3.5 ml, 45 mmol) at 0° C. under argon. The reaction mixture was warmed to room temperature for 6 hours or until all the starting material is consumed, neutralized with cooled 10% Na2CO3 and extracted with CH2Cl2. The organic layer was concentrated, and purified by flash chromatography on a silica gel column (hex:methylene chloride 2:1) to give the title compound as light yellow oil
Reaction SMILES: [N+:1]([C:4]1[S:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1)([O-:3])=[O:2].[F:11][C:12]([F:26])([F:25])[C:13]1[CH:14]=[C:15]([S:19]([CH2:22][C:23]#[N:24])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>>[N+:1]([C:4]1[S:5][C:6](/[CH:9]=[C:22](/[S:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([F:26])([F:11])[F:25])[CH:14]=2)(=[O:21])=[O:20])\[C:23]#[N:24])=[CH:7][CH:8]=1)([O-:3])=[O:2]
Reactant: N#CCS(=O)(=O)c1cccc(C(F)(F)F)c1
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Product: N#C/C(=C\c1ccc([N+](=O)[O-])s1)S(=O)(=O)c1cccc(C(F)(F)F)c1

Procedure:
Reaction of 2-nitrothiophen-5-carboxaldehyde and 3-trifluoromethylphenylsulfonylacetonitrile as in Example 1 gave (E)-3-(2-nitrothien-5-yl)-2-[3-(trifluoromethyl)phenylsulfonyl]acrylonitrile
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[N:6]=[CH:5]2.[CH3:17][C@H:18]([NH2:27])[C@H:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(#N)CCC.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]I>[CH3:17][CH:18]([NH2:27])[CH:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[O:26][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[N:6]=[CH:5]2
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Reactant: Ic1ccc2c(cnn2-c2ccccn2)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCC#N
Product: CC(N)C(Oc1ccc2c(cnn2-c2ccccn2)c1)c1ccccc1
Temperature: 125 °C
Reaction time: 2 h
Yield: 16.3 %

Procedure:
5-Iodo-1-pyridin-2-yl-1H-indazole (118b, 81 mg, 0.25 mmol), (1R,2S)-(−)-norephedrine (119 mg, 0.79 mmol) and butyronitrile (3 ml) were charged in a 7 ml vial. Copper(I) iodide (5.8 mg, 0.1 mol %) and cesium carbonate (261 mg, 0.8 mmol) were added, the vial was sealed and the solution was stirred (magnetic bar) at 125° C. for 2 h. Inorganic material was filtered off, and washed with ethyl acetate. The ethyl acetate phase was collected and concentrated and purified on silica with methanol:ethyl acetate 0:100 to 30:70 over 45 min. Pure fractions were pooled and concentrated to give 14 mg (16%) of 1-methyl-2-phenyl-2-(1-pyridin-2-yl-1H-indazol-5-yloxy)-ethylamine.
Reaction SMILES: [CH2:1]([CH:7]1[S:12]CCCS1)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.C(=O)C1OC=CC=1.[CH2:20](S)[CH2:21][CH2:22][SH:23].C[Si](Cl)(C)C>C(Cl)(Cl)Cl>[CH2:1]([CH:7]1[CH2:20][CH2:21][CH2:22][S:23][S:12]1)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1coc(CC2SCCCS2)c1
Reactant: SCCCS
Agent: C[Si](C)(C)Cl
Solvent: ClC(Cl)Cl
Solvent: O=Cc1ccco1
Product: c1coc(CC2CCCSS2)c1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
Preparation of 2-furfuryl-1,3-dithiane—Furfural (40 mL, 0.4825 mol) was dissolved in CHCl3 (400 mL) and cooled to 0° C. (ice bath) with 1,3-propanedithiol (48.5 mL, 0.482 mol, 1 eq) and a catalytic amount of TMSCl (3 pipets full). The reaction mixture was allowed to warm gradually to room temperature overnight and then partitioned with aqueous 5% NaOH (200 mL) and separated. The aqueous layer was extracted with Et2O and the combined organics were dried (Na2SO4), filtered, and evaporated to afford crude furfuryl dithiane (85 g, 0.457 mol, 94.8% yield), which was taken on to the next step without further purification. 1H NMR: δ 7.38 (m, 1H), 6.40 (m, 1H), 6.35 (m, 1H), 5.23 (s, 1H, —SH), 2.97 (m, 4H), 2.19–2.10 (m, 1H), 2.05–1.94 (m, 1H). 13C NMR: δ 152.2, 142.7, 111.0, 108.3, 42.5, 30.7, 25.7.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH2:16][CH2:17][NH:18][CH2:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH2:16][CH2:17][N:18]([S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])[CH2:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2CCNC3)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2CCN(S(=O)(=O)c2ccccc2)C3)CC1

Procedure:
4-(1,2,3,4-Tetrahydroisoquinolin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester as a viscous oil (150 mg) from Step 3 was reacted with benzenesulfonyl chloride (60 microliters) using the Schotten-Baumann procedure (50 mL diethyl ether (Et2O) and 50 mL aqueous sodium carbonate). The ether layer was separated, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed to provide 1.76 mg of 4-(2-benzenesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O.C(N(CC)C(C)C)(C)C.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH2:56]([O:63][C:64](=[O:72])[CH2:65][C@@H:66]([NH2:71])[CH2:67][N:68]([CH3:70])[CH3:69])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>CN(C)C=O>[CH2:56]([O:63][C:64](=[O:72])[CH2:65][C@@H:66]([NH:71][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]1[CH:17]=[CH:18][C:19]([F:20])=[C:2]([F:1])[CH:3]=1)[CH2:67][N:68]([CH3:69])[CH3:70])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: O=C(O)CCCCCCCOCc1ccc(F)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCOCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.9 %

Procedure:
A solution of 8-(3,4-difluoro-benzyloxy)-octanoic acid (153 mg, 0.53 mmol), N,N-diisopropylethylamine (414 mg, 3.21 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophophate (244 mg, 0.64 mmol) in N,N-dimethylformamide was stirred for 1 h at room temperature, then a solution of (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride (198 mg, 0.64 mmol) in N,N-dimethylformamide (1 mL) was added. The reaction mixture was stirred for 16 h at room temperature, then evaporated. Chromatography (SiO2, dichloromethane-[dichloromethane/methanol/25% aq. ammonia solution 110:10:1] gradient) produced (R)-3-[8-(3,4-difluoro-benzyloxy)-octanoylamino]-4-dimethylamino-butyric acid benzyl ester (136 mg, 50%). Light yellow oil, m/e=505.4 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:19]O>>[CH3:19][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[Cl:1]
Reactant: CO
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C

Procedure:
2-Chloro-5-nitrobenzoic acid (11 g, 54.5 mmol) was dissolved in methanol (100 mL). Conc. H2SO4 (2 mL) was added slowly and the reaction mixture heated to reflux for 4 h. The mixture was concentrated and the residue was allowed to cool to room temperature. It was poured over crushed ice. The organic product was extracted using diethyl ether (2×200 mL). The organic extract was washed with water, 10% aqueous NaHCO3, dried (anhydrous Na2SO4) and concentrated to get the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([NH:36][CH2:37][CH2:38][CH3:39])[CH2:34][CH3:35]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([N:36]([CH2:37][CH2:38][CH3:39])[CH2:33][CH2:34][CH3:35])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2cccc(Br)c2)nc2cccnc21
Reactant: CCCNCCC
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCCN(CCC)C(=O)Cn1c(-c2cccc(Br)c2)nc2cccnc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under nitrogen bubbling, a mixture of 2-(3-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.98 g, 0.015 mole) and 1,1'-carbonyldiimidazole (2.59 g, 0.016 mole) in 120 ml of tetrahydrofruan was stirred at room temperature for 4 hrs. The di-n-propylamine (3.04 g, 0.03 mole) was added and the reaction mixture was heated at reflux for (65° C.) for 8-9 hrs. The reaction mixture was filtered and the filtrate was evaporated to an oil, which was placed under high vacuum for 3 hrs. The solid residue was treated with water, collected by filtration, washed with water, and dried under high vacuum. The solid was recrystallized from isopropyl alcohol-water, collected by filtration, washed with water, and dried under high vacuum to give 3.2 g (52%), mp 125°-27° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[N:12]=[C:11]([NH2:13])[NH:10][N:9]=2)[CH:2]=1.[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.C(Cl)Cl>[C:14]1([NH:20][C:21]([N:10]2[C:11]([NH2:13])=[N:12][C:8]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[N:9]2)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1nc(Nc2cccnc2)n[nH]1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Nc1nc(Nc2cccnc2)nn1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.3 %

Procedure:
To a solution of N3-(3-pyridyl)-1H-[1,2,4]triazole-3,5-diamine (0.43 mmol) in dry THF (3 mL) and dry DCM (3 mL) was added phenylisocyanate (0.43 mmol) dropwise over 1 minute, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography [Merck silica, eluted with EtOAc and Hexanes (4:1)] to afford compound the title compound (22.0 mg, 17%). 1H NMR (400 MHz, DMSO-d6) 7.17 (1H, t), 7.28 (1H, m), 7.39 (4H, m), 7.65 (2H, d), 8.09 (1H, m), 8.23 (1H, m), 8.79 (1H, d), 9.44 (1H, s), 9.64 (1H, s); MS (ES+): m/e=296.3 (100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:24]([N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[C:25]#[CH:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(=O)C([O-])=O>C(N(CC)CC)C>[N:27]1([CH2:24][C:25]#[C:26][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Brc1ccc(-c2ccc(OCCCN3CCCCC3)cc2)cc1
Reactant: C#CCN1CCCCC1
Agent: O=C([O-])C(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C(#Cc1ccc(-c2ccc(OCCCN3CCCCC3)cc2)cc1)CN1CCCCC1
Yield: 21.4 %

Procedure:
Following the procedure described in example 43§C, but starting from 1-{3-[(4′-bromobiphenyl-4-yl)oxy]propyl}piperidine (0.75 g), 1-prop-2-yn-1-ylpiperidine (320 mg), triethylamine (20 mL), cuprous iodide (4.2 mg), triphenylphosphine (20 mg) and bis(triphenylphosphinepalladiumdichloride) affords 179 mg of 1-(3-{[4′-(3-piperidinoprop-1-yn-1-yl)biphenyl-4-yl]oxy}propyl)piperidine which oxalate melts at 195° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[C:5]([CH3:13])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[H][H]>[Rh]>[CH3:1][C:2]1([CH3:14])[CH2:11][CH:10]([CH3:12])[CH:9]2[CH:4]([CH:5]([CH3:13])[CH2:6][CH2:7][CH2:8]2)[NH:3]1
Reactant: [H][H]
Reactant: CC1=CC(C)(C)Nc2c(C)cccc21
Agent: [Rh]
Product: CC1CC(C)(C)NC2C(C)CCCC12
Reaction time: 8 h

Procedure:
2,2,4,8-tetramethyldecahydroquinoline was prepared by reacting 74 grams of 2,2,4,8-tetramethyl-1,2-dihydroquinoline with hydrogen in the presence of 2 grams of rhodium at 5% by weight on charcoal at a temperature of 200° C., a pressure of 1000 psig, and over a period of 8 hours. The desired product was confirmed by NMR spectral analysis and carbon, hydrogen, nitrogen analysis (calculated content for C13H25N is the same as above and analyzed contents were 80.03% carbon, 13.38% hydrogen, and 6.09% nitrogen). The product was 90% pure as determined by vapor pressure chromotography and boiled at 65° C. at 0.6 mm of Hg.
Reaction SMILES: [FH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([F:1])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: FC1(c2ccc(Cl)cc2)CCNCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 52 %

Procedure:
To a cooled (0° C.) solution of hydrogen fluoride (65-70%) in pyridine (4 ml) was added 4-(4-chloro-phenyl)-piperidin-4-ol (500 mg, 2.36 mmol). The resulting solution was stirred at 0° C. for 15 min and then warmed to rt and stirred 1 h. The mixture was slowly poured into a saturated aqueous sodium bicarbonate solution (30 mL) and extracted with methylene chloride (100 ml; ADD SOLVENT AND EXTRACT SLOWLY AND WITH CAUTION). Excess hydrogen fluoride was neutralized with solid sodium carbonate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography, eluting with a methylene chloride to methylene chloride/methanol/ammonium hydroxide (8.5/1/0.5) gradient to give 4-(4-Chloro-phenyl)-4-fluoro-piperidine (260 mg, 52%).