Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:18]=1)(=[O:16])=[O:15].I[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>O1CCCC1.CN1CCCN(C)C1=O>[CH:29]1([CH2:28][CH:23]([C:20]2[CH:19]=[CH:18][C:17]([S:14]([CH3:13])(=[O:15])=[O:16])=[CH:22][CH:21]=2)[C:24]([OH:26])=[O:25])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Reactant: ICC1CCCC1
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
A solution of diisopropylamine (3.3 mL, 23.5 mmol) in dry tetrahydrofuran (50 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 mL) was cooled to −78° C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (2.35 mL, 23.5 mmol). The yellow reaction mixture was stirred at −78° C. for 30 min and then treated dropwise with a solution of 4-methylsulfonylphenylacetic acid (2.40 g, 11.2 mmol) in a small amount of dry tetrahydrofuran. After approximately one-half of the 4-methylsulfonylphenylacetic acid in dry tetrahydrofuran was added, a precipitate formed. Upon further addition of the remaining 4-methylsulfonylphenylacetic acid in dry tetrahydrofuran, the reaction mixture became thick in nature. After complete addition of the 4-methylsulfonylphenylacetic acid in dry tetrahydrofuran, the reaction mixture was very thick and became difficult to stir. An additional amount of dry tetrahydrofuran (20 mL) was added to the thick reaction mixture, and the reaction mixture was stirred at −78° C. for 45 min, at which time, a solution of iodomethylcyclopentane (2.35 g, 11.2 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25° C. where it was stirred for 15 h. The reaction mixture was quenched with water (100 mL), and the resulting yellow reaction mixture was concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was acidified to pH=2 using concentrated hydrochloric acid. The aqueous layer was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/3 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid (1.80 g, 52%) as a white solid: mp 152-154° C.; EI-HRMS m/e calcd for C15H20O4S (M+) 296.1082, found 296.1080.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[Br:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].C([O-])(O)=O.[Na+]>C(O)C>[Br:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:17]#[N:18])[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1cccc(Br)c1
Reactant: CCOc1cc2c(Cl)c(C#N)cnc2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc2c(Nc3cccc(Br)c3)c(C#N)cnc2cc1OC
Yield: 86.1 %

Procedure:
A mixture of 1.00 g (3.82 mmol) of 4-chloro-6-ethoxy-7-methoxyquinoline-3-carbonitrile and 0.788 g (4.58 mmol) of 3-bromoaniline in 20 mL of ethanol was refluxed under N2 for 7 h. Saturated NaHCO3 was added, volatile material was removed and the residue was azeotroped with ethanol. The crude product was slurried with hexane, filtered, washed with water and dried. Recrystallization from ethanol gave 1.31 g of 4-(3-bromophenylamino)-6-ethoxy-7-methoxyquinoline-3-carbonitrile as tan crystals: mass spectrum (electrospray, m/e): M+H 397.9, 399.8.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][C@@H:6]([C:28]1[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)[N:7]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][NH:18][C:17]=3[N:16]=2)[C:8]1=[N:25][C:26]#[N:27])C.[Li+].[OH-].Cl>C1COCC1.O>[CH3:35][O:34][C:31]1[N:30]=[CH:29][C:28]([C@@H:6]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]3[CH:24]=[CH:23][C:22]4[CH2:21][CH2:20][CH2:19][NH:18][C:17]=4[N:16]=3)[C:8]2=[N:25][C:26]#[N:27])[CH2:5][C:4]([OH:36])=[O:3])=[CH:33][CH:32]=1
Reactant: CCOC(=O)C[C@@H](c1ccc(OC)nc1)N1CCN(CCCc2ccc3c(n2)NCCC3)C1=NC#N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc([C@H](CC(=O)O)N2CCN(CCCc3ccc4c(n3)NCCC4)C2=NC#N)cn1
Reaction time: 16 h

Procedure:
To a solution of the ester 1-3 (180 mg, 0.37 mmol) in THF (20 mL) and water (20 mL) at room temperature was added 1N LiOH solution (5 mL, 5 mmol) and the mixture stirred for 16 hr. The mixture was neutralized with 1N HCl and the solvent removed. Column chromatography of the residue (silica gel; CHCl3/EtOAc/MeOH 8:1:1) gave 1-4 as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])[CH3:9].CC(C)(C(=O)CC(=O)C(C)(C)C)C.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[OH-].[NH4+]>[Cu]Cl.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[CH3:9]
Reactant: Brc1cccnc1
Reactant: CCOc1ccccc1O
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOc1ccccc1Oc1cccnc1
Temperature: 119 °C
Reaction time: 20 h
Yield: 76.2 %

Procedure:
3-Bromopyridine (224 g, 1.42 mol) and 2-ethoxyphenol (275 g, 1.99 mol) were added to a jacketed reactor vessel containing toluene (2.2 L) at 20° C., and the resulting mixture was stirred until all solids were dissolved. 2,2,6,6-Tetramethylheptane-3,5-dione (118 g, 0.640 mol), copper(I) chloride (71.8 g, 0.71 mol), and cesium carbonate (749 g, 2.27 mol) were added sequentially, and the jacket temperature was raised to 119° C. The mixture became thick, and stirring resumed as the temperature increased. After 20 hours, the mixture was cooled to 30° C. The organic layer was washed sequentially with water (0.75 L) and with aqueous 15% ammonium hydroxide solution (0.70 L), and then was extracted with aqueous 3M hydrochloric acid solution (1.18 L, 3.55 mol). Ethyl acetate (1.8 L) and aqueous 15% ammonium hydroxide solution (0.500 L, 3.60 mol) were then added sequentially to the acidic aqueous phase. The blue aqueous layer was separated, and the resulting organic layer was washed sequentially with aqueous 15% ammonium hydroxide solution (0.50 L) and with 2:1 water:brine solution (0.30 L). The organic layer and Darco G60 activated charcoal (60 g) were stirred at 45° C. for 1 hour, and then were filtered through a pad of Celite, rinsing with ethyl acetate (0.35 L). The filtrate was concentrated under vacuum and the resulting residue was re-concentrated from methanol (0.30 L) to afford 3-(2-ethoxyphenoxy)pyridine (233 g) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 2H), 7.34 (dd, 1H), 7.18 (m, 4H), 6.99 (t, 1H), 4.01 (q, 2H), 1.11 (t, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[CH2:3][C:2]1=O.[OH-].[Na+].P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1Cc2ncccc2O1
Agent: [Na+]
Agent: [OH-]
Product: Clc1cc2ncccc2o1

Procedure:
Furopyridone (6, 3.26 g, 24.15 mmol) is treated with phosphorus oxychloride (10 ml) at refluxing temperature for 3 hours. After cooling, the dark solution is poured into ice and basified with aqueous sodium hydroxide to pH ˜9. The mixture is extracted with chloroform. After evaporation of the chloroform, the brown oil is applied to flash column chromatography on silica gel to give chlorofuropyridine as yellow crystalline solid (7).
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:5]=1.[OH-].[Na+]>CO.O1CCOCC1>[CH2:26]([O:25][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:3]([OH:40])=[O:2])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1OCCCCCCCCCCCCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1OCCCCCCCCCCCCCC
Yield: 73.1 %

Procedure:
A solution of 3,4-bis(tetradecyloxy)benzoic acid methyl ester (1.1 g, 2.0 mmol) and 1.6 ml (9.6 mmol) of 6N NaOH in 40 ml of methanol and 20 ml of dioxane was stirred at reflux for 17 hours. The solvents were removed at reduced pressure, the residue was acidified and the solid was filtered and recrystallized from methanol-THF-water to give 0.8 g (73% yield, mp 112°-113°) of 3,4-bis(tetradecyloxy)benzoic acid.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:34])[NH2:33])=[CH:28][CH:27]=3)[CH:24]=2)[NH:19][CH:18]=1)=O)C1C=CC=CC=1>C(O)C>[C:32]([C:29]1[CH:30]=[CH:31][C:26]([C:23]2[CH:24]=[C:25]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH:18]=[C:17]3[CH2:16][C@H:12]2[CH2:13][CH2:14][CH2:15][NH:11]2)=[CH:27][CH:28]=1)(=[O:34])[NH2:33]
Reactant: NC(=O)c1ccc(-c2ccc3[nH]cc(C[C@H]4CCCN4C(=O)OCc4ccccc4)c3c2)cc1
Solvent: CCO
Product: NC(=O)c1ccc(-c2ccc3[nH]cc(C[C@H]4CCCN4)c3c2)cc1
Yield: 83.9 %

Procedure:
3-(1-Benzyloxycarbonylpyrrolidin-2(R)-ylmethyl)-5-(4-carbamoylphenyl)-1H-indole (355 mg, 0.784 mmol) (see Preparation 41) in ethanol was reduced using catalytic hydrogenation, as described in Example 35. This gave the title compound as a white foam (210 mg). Found: C,72.33; H,6.80; N,12.35; C20H21N3O.3/4H2O requires: C,72.16; H,6.81; N,12.62%.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:13][C:14]#[N:15]>>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([CH2:13][C:14]#[N:15])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N#CCBr
Reactant: C1CCC(N2CCNCC2)C1
Product: N#CCN1CCN(C2CCCC2)CC1

Procedure:
The title compound is synthesized by coupling of 1-Cyclopentyl-piperazine (commercially available from CHESS GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=194.2: 1HNMR(DMSO-d6) 3.65 (s, 2H), 2.45-2.20 (m, 9H), 1.80-1.20 (m, 8H).
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH3:13])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]1.[CH3:15][C:16](=O)[CH2:17][CH2:18][C:19](=O)[CH3:20]>CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:20][C:19]1[N:12]([C:9]2[CH:10]=[CH:11][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:14])([CH3:13])[CH3:1])[N:8]=2)[C:16]([CH3:15])=[CH:17][CH:18]=1
Reactant: C[Si](C)(C)CCOCn1ccc(N)n1
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccn(COCC[Si](C)(C)C)n1
Yield: 87.8 %

Procedure:
Into a 2 L round-bottom flask under nitrogen was placed 1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-3-amine (110 g, 515.58 mmol, 1.00 equiv.), toluene (1.2 L), hexane-2,5-dione (60.0 g, 525.66 mmol, 1.00 equiv.), and 4-methylbenzene-1-sulfonic acid (1.0 g, 5.81 mmol, 0.10 equiv.). The resulting solution was heated to reflux for 2 h, cooled and concentrated under vacuum. The residue was purified by SiO2 chromatography eluting with EtOAc/petroleum ether (1:50) to afford 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole (132 g, 83%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[S:14][CH:15]=[CH:16][C:17]=2[NH2:18])=[O:12])=[CH:6][CH:5]=1.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH:31]=O)=[CH:23][CH:22]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O.ClCCl>[F:20][C:2]([F:19])([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:13]2[S:14][CH:15]=[CH:16][C:17]=2[NH:18][CH2:31][C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:21]=[CH:22][CH:23]=2)=[O:12])=[CH:8][CH:9]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: Nc1ccsc1C(=O)Nc1ccc(OC(F)(F)F)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1sccc1NCc1ccnc2ccccc12
Temperature: 25 °C

Procedure:
A solution of N-(4-trifluoromethoxyphenyl) 3-aminothiophene-2-carboxamide (1 g, 3.31 mmol) and quinoline-4-carboxaldehyde (347 mg, 2.21 mmol) in trifluoroacetic acid:dichloromethane (1:1, 30 mL) was heated at reflux for 2 h under nitrogen. The reaction was cooled to RT and triethylsilane (0.71 mL, 4.42 mmol) was added. The resulting solution was then stirred at reflux for 16 h under nitrogen. After cooling to RT, the reaction mixture was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (3×100 mL) and saturated sodium bicarbonate solution (50 mL). The organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (20-30% ethyl acetate in hexane) to give EXAMPLE 1 as a light yellow solid, mp: 168-170° C. 1H-NMR (400 MHz/CDCl3):δ=5.01 (d, J=6.2 Hz, 2H), 6.56 (d, J=5.4 Hz, 1H), 7.12 (s, 1H), 7.22 (d, J=8.7 Hz, 2H), 7.25 (s, 1H), 7.44 (d, J=4.3 Hz, 1H), 7.58 (d, J=9.0 Hz, 2H), 7.62 (t, J=8.2 Hz, 1H), 7.76 (t, J=8.3 Hz, 1H), 8.02 (d, J=7.5 Hz, 2H), 8.17 (d, J=8.3 Hz, 1H), 8.86 (d, J=4.5 Hz, 1H). MS (ES+): 444 [MH+]. 13C-NMR (400 MHz/CDCl3): δ=45.9, 101.4, 117.9, 118.9, 119.5, 121.9, 122.0, 122.6, 126.5, 127.2, 129.1, 129.7, 130.6, 136.8, 144.5, 145.4, 148.3, 150.7, 155.9, 163.8. Anal. Calcd for C22H16F3N3O2S: C, 59.59; H, 3.64; N, 9.48; F, 12.85; S, 7.23. Found: C, 59.59; H, 3.67; N, 9.46; F, 13.01; S, 7.23.
Reaction SMILES: [CH3:1][N:2]1[CH2:26][CH2:25][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=3)(O)[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.S(=O)(=O)(O)O.[OH-].[K+]>>[CH3:1][N:2]1[CH2:26][CH2:25][C:5]2[N:6](/[CH:14]=[C:15](/[C:18]3[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=3)\[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccc(C)nc2)CCN(C)C1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(C)nc1
Temperature: 0 °C

Procedure:
1-(1,2,3,4-Tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(6-methylpyridin-3-yl)propan-2-ol (1 g, 2.86 mmol, 1 equiv.) was refluxed with 25% sulfuric acid (7 mL) for 2 h. The reaction mixture was cooled to 5° C. in ice-water bath. KOH (15% aqueous solution) was added dropwise to the reaction mixture until pH 9-10 was achieved. The reaction mixture was extracted with EtOAc (3×10 mL). The combined organic layer was washed with water (10 mL) followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product was purified by silica gel chromatography (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%), followed by further purification by HPLC.
Reaction SMILES: NC1C(F)=CC(Cl)=C(O[C:9](=O)[O:10][C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([F:18])=[CH:13][C:12]=2[Cl:19])C=1.[CH:23]1(Br)[CH2:27]C[CH2:25][CH2:24]1.[OH-].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:19][C:12]1[C:11]([O:10][CH:9]2[CH2:25][CH2:24][CH2:23][CH2:27]2)=[CH:16][C:15]([NH2:17])=[C:14]([F:18])[CH:13]=1
Reactant: Nc1cc(OC(=O)Oc2cc(N)c(F)cc2Cl)c(Cl)cc1F
Reactant: BrC1CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1cc(OC2CCCC2)c(Cl)cc1F
Temperature: 80 °C
Yield: 192.7 %

Procedure:
A round-bottomed flask (50 cc) was charged with bis(5-amino-2-chloro-4-fluorophenyl)carbonate (1.52 g, 4.36 mmol), cyclopentyl bromide (1.39 g, 9.29 mmol) and tetrabutylammonium bromide (74 mg, 0.23 mmol) to prepare a solution in toluene (12 mL). Subsequently, 48% sodium hydroxide in aqueous solution (6 mL) was added slowly and the mixture was stirred under heating at 80° C. for 1 h. After completion of the reaction, the reaction mixture was cooled to room temperature and water (15 mL) was added, followed by extraction with toluene (10 mL×2). The organic layers were combined and washed with water (10 mL×2). The solvent was distilled off under vacuum from the resulting toluene solution, thereby giving 4-chloro-5-cyclopentyloxy-2-fluoroaniline (1.93 g, 8.40 mmol; yield=96.3% ).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]([CH2:8][OH:9])[CH2:4][C@H:3]1[CH2:10][O:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[H-].[Na+].[CH3:20]I.[I-]>C1COCC1>[CH3:20][O:9][CH2:8][CH:5]1[C:6](=[O:7])[N:2]([CH3:1])[C@H:3]([CH2:10][O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:4]1
Reactant: CI
Reactant: CN1C(=O)C(CO)C[C@H]1COc1cccnc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1C[C@@H](COc2cccnc2)N(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 327 mg (139 mmmol) sample of 3-(1-methyl-4hydroxymethyl-5-oxo-2(S)-pyrrolidinylmethoxy)pyridine, prepared as in Example 48a above, was dissolved in 13 mL of anhydrous THF, 111 mg (2.77 mmol) of NaH was added, and the mixture was stirred for 30 minutes at room temperature. To this solution was added 258 mL (4.17 mmol) of methyl iodide and 256 mg of tetrabutylammomnum iodide, and the reaction was stirred at room temperature for 2 hours. The reaction was quenched by the addition of water, and the mixture was extracted with chloroform. The extract was dried over MgSO4, filtered and concentrated. The solvent was removed, and the residue was purified by column chromatography on silica gel, eluting with 10: 1 chloroform:methanol to give 314 mg of the title compound. MS (DCI/NH3) m/e: 251 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.37-8.25 (m, 2H), 7.35-7.25 (m, 2H), 4.18-4.0 (m, 2H), 3.99-3.84 (m, 1H), 3.73-3.58 (m, 2H), 3.37 (s, 2H), 3.36 (s, 1H), 3.05 (s, 1H), 2.95 (s, 1H), 2.94 (s, 1H), 2.90-2.63 (m, 1H), 2.49-2.24 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1OCC[O:15]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].C(O)(=O)C.O1CCCC1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][CH:2]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[O:15])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: CC(C)CCCC(C)OCCCCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)CCCC(C)OCCCCC=O
Yield: 26 %

Procedure:
{4-[(1,5-dimethylhexyl)oxy]butyl}-1,3-dioxolane (1.4 g, 43% pure by GC RPA, 3.9 mmol), acetic acid (10 mL), tetrahydrofuran (16 mL) and water (20 mL) were added to a 100 mL three-necked flask fitted with thermocouple, magnetic stirrer and condenser. The reaction mixture was refluxed for 2 hrs, cooled and saturated sodium carbonate (150 mL) added. The crude reaction mixture was extracted with hexane (4×100 mL), the combined organic phase dried over magnesium sulphate, filtered and the solvent removed in vacuo. The crude product was chromatographed over silica gel (hexane/methyltert-butyl ether) to yield pure 5-[(1,5-dimethylhexyl)oxy]pentanal as a colourless oil (0.22 g, 1.02 mmol, chemical yield 26%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[OH:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:20]=1.C(O)C.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.ClCCl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[O:18][CH2:19][CH3:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2c(O)cccc2C1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CO
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1cccc2c1CCN(C(=O)OC(C)(C)C)C2

Procedure:
2.1 g (8.43 mmol) of 2-t-butoxycarbonyl-5-hydroxy-1,2,3,4-tetrahydroisoquinoline (Example 7), 2.77 g (10.5 mmol) triphenylphosphine and 0.75 mL (12.6 mmol) ethanol were dissolved in dry tetrahydrofuran and 1.63 mL (10.5 mmol) diethylazodicarboxylate was added dropwise. After completion of the reaction (tlc, 1% MeOH), the mixture was diluted with dichloromethane, washed with aqueous sodium bicarbonate and with aqueous sodium chloride, evaporated to dryness and purified by silicagel chromathography (System B). Yield 1.55 g, 66%. 1H NMR (CDCl3): 7.12 (1H, t, 8.1 Hz), 6.69 (2H, t, 8.1 Hz), 4.55 (2H, s), 4.02 (2H, q, 6.8 Hz), 3.63 (2H, t, 5.6 Hz), 2.76 (2H, t, 5.9 Hz), 1.48 (9H, s), 1.41 (3H, t, 7.1 Hz).
Reaction SMILES: C[N:2](C)/[CH:3]=[C:4](\[CH2:24][CH3:25])/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[C:27]1([NH:33]N)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.C(O)(=O)C>[CH2:24]([C:4]1[CH:3]=[N:2][N:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:5]=1[C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)[CH3:25]
Reactant: CC/C(=C\N(C)C)C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Reactant: NNc1ccccc1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCc1cnn(-c2ccccc2)c1-c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O

Procedure:
3-{2-[1-Dimethylamino-meth-(E)-ylidene]-butyryl}-1-(3-methanesulfonyl-phenyl)-1H-pyridazin-4-one and phenyl hydrazine (1.5 eq) were dissolved in a sealed tube in DMF with 2 drops acetic acid and irradiated in MW at 120° C. for 15 min. The solvent of the reaction mixture was removed and the crude product was purified by preparative HPLC yielding the desired product. MS: M=421.2 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[N:4]([CH3:6])[CH3:5].[N+]([O-])(O)=[O:13].C(=O)([O-])[O-].[Na+].[Na+].[N+](C1C(C)=C(C(C)=CC=1)N(C)C)([O-])=O>S(=O)(=O)(O)O.O>[OH:13][C:10]1[C:2]([CH3:1])=[C:3]([C:7]([CH3:11])=[CH:8][CH:9]=1)[N:4]([CH3:5])[CH3:6]
Reactant: Cc1cccc(C)c1N(C)C
Reactant: O=[N+]([O-])O
Agent: Cc1ccc([N+](=O)[O-])c(C)c1N(C)C
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1ccc(O)c(C)c1N(C)C

Procedure:
40 ml of 2,6-dimethyl-N,N-dimethylaniline was dissolved in 88 ml of concentrated sulfuric acid at a temperature below 15° C., followed by dropwise addition of 35 ml of concentrated nitric acid by maintaining the temperature below 15° C. Thereafter, the mixture was reacted for one hour, poured into cold water and then neutralized with sodium carbonate, whereby 3-nitro-2,6-dimethyl-N,N-dimethylaniline was precipitated in the form of crystals. The produced nitro compound was reduced, diazotized and then pyrolyzed to obtain 3-hydroxy-2,6-dimethyl-N,N-dimethylaniline. This phenol compound was dissolved in an alkaline solution and treated with excess dimethyl sulfate at 40°-45° C. The resulting 3-methoxy-2,6-dimethyl-N,N-dimethylaniline was dissolved in hydrochloric acid and then admixed with double molar amount of zinc chloride to precipitate a double salt. It was recrystallized from dilute hydrochloric acid to obtain the salt of formula V. M.p.: 162°-165° C., amount of zinc: 11.8% (calculated: 11.4%); infrared absorption spectra: 3100 cm-1, 1450 cm-1, 1260 cm-1, 1070 cm-1, 820 cm-1, 1600 cm-1 ; NMR (chemical shift): 3.4 ppm, 3.9 ppm, 2.4 ppm, 2.5 ppm, 7.1 ppm, 7.2 ppm, 7.0 ppm, 7.3 ppm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:15]3[O:14][CH:13]([CH2:16][NH:17]C(=O)OCC4C=CC=CC=4)[CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:2]=1.C[Si](I)(C)C>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:15]3[O:14][CH:13]([CH2:16][NH2:17])[CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:2]=1
Reactant: O=C(NCC1Cc2cccc(-c3cccnc3)c2O1)OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: CO
Product: NCC1Cc2cccc(-c3cccnc3)c2O1

Procedure:
The title compound was prepared (0.17 g, 78%) following the general procedure of Example 129 as a yellow solid, hydrochloride salt from (+)-benzyl {[7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (0.30 g, 0.832 mmol) and trimethylsilyl iodide (0.66 g, 3.33 mmol). [α]D25=+27.2 (c 10.0 in methanol); mp 168-171° C.