Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH:25]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[NH:24][C:23]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=3[O:41][CH3:42])=[N:22]2)=[CH:17][CH:16]=1>C(Cl)Cl>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]2[CH:25]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)[N:24]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[C:23]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=3[O:41][CH3:42])=[N:22]2)=[CH:19][CH:20]=1
Reactant: CC(C)C(=O)Cl
Reactant: COc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2)c(OC)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)C(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Isobutyryl chloride (19 μL, 0.18 mmol) was added to a solution of triethylamine (25 μL, 0.18 mmol) and 4,5-bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-1H-imidazole (70 mg, 0.164 mmol). The reaction mixture was stirred at room temperature for 2 h. It was diluted with methylene chloride and washed with water and brine, and dried over sodium sulfate. The solvents were removed under reduced pressure and chromatography of the residue over silica gel using 0.5-1% methanol in methylene chloride gave 1-[4,5-bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-imidazole-1-yl]-2-methyl-propan-1-one. HR-MS (EI, m/z) calculated for C27H26N2O3Cl2 (M+) 496.1320, observed 496.1319.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34]#[N:35])[CH:29]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([C:34]#[N:35])[CH:29]=3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Nc2ccnc(Cl)c2)n1
Reactant: N#Cc1cc(Br)ccn1
Product: Cc1cc(-c2ccnc(C#N)c2)cc(C(=O)Nc2ccnc(Cl)c2)n1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (2-chloro-pyridin-4-yl)-amide in accordance with the general method of example 131, step 2 using 4-Bromo-2-cyanopyridine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a white solid, MS (ISP): m/e=350.2, 352.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH3:14][S:15]SC>>[CH3:14][S:15][C:10]1[CH:11]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: CSSC
Product: CSc1cc(C(F)(F)F)ccc1C(=O)O

Procedure:
The title compound, white solid, MS: m/e=235.0 [(M−H)−], was prepared in accordance with the general method of intermediate E from 4-(trifluoromethyl)benzoic acid and dimethyl disulfide.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]1[N:16]=[C:15]([NH:17][C:18]2[C:19]([O:24][CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=2)[C:14]([N+:26]([O-:28])=[O:27])=[CH:13][CH:12]=1.Cl.[F:30][C:31]1[CH:32]=[CH:33][C:34]([C@@H:37]([NH2:39])[CH3:38])=[N:35][CH:36]=1>C(O)CCC.C(OCC)(=O)C>[F:30][C:31]1[CH:32]=[CH:33][C:34]([C@@H:37]([NH:39][C:11]2[N:16]=[C:15]([NH:17][C:18]3[C:19]([O:24][CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=3)[C:14]([N+:26]([O-:28])=[O:27])=[CH:13][CH:12]=2)[CH3:38])=[N:35][CH:36]=1
Reactant: COc1ncccc1Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: C[C@H](N)c1ccc(F)cn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1ncccc1Nc1nc(N[C@@H](C)c2ccc(F)cn2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
Diisopropylethylamine (0.49 mL, 2.81 mmol) was added to a solution of 6-chloro-N-(2-methoxypyridin-3-yl)-3-nitropyridin-2-amine (Preparation 22a, 0.26 g, 0.69 mmol) and (S)-1-(5-fluoropyridin-2-yl)ethanamine hydrochloride (prepared according to the method described in WO2006/82392A1, 0.13 g, 0.74 mmol) in butanol (5 mL) and the resulting mixture was stirred at 80° C. overnight. Subsequently, the reaction was cooled down, diluted with ethyl acetate and washed with brine (×3). The organic phase was separated, dried over anhydrous magnesium sulphate and the solvent removed under reduced pressure. The residue was purified by flash chromatography (hexanes 100% to 1:1 hexanes/ethyl acetate) to give the title compound (253 mg, 94%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].[OH-].[Na+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>CC(C)=O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:14][CH3:15])=[CH:9][CH:8]=2)(=[O:11])=[O:12])=[O:27])=[CH:21][CH:20]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCN(CC)c1ccc(S(N)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCN(CC)c1ccc(S(=O)(=O)NC(=O)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
This benzenesulfonamide (0.99 g, 4.3 mmoles) was dissolved in acetone (4.3 ml) to which was then added 1.0N sodium hydroxide (4.4 ml). To this mixture was added 4-chlorophenylisocyanate (0.68 g, 4.4 mmoles), dissolved in 4.3 ml of acetone. This mixture was allowed to stir at room temperature for about 15 minutes. A solid was then removed from the reaction mixture by filtration. To the filtrate was added 1.0N hydrochloric acid (4.4 ml), causing separation of a brown oil. Water (5 ml) was then added and the mixture stirred until the oil had converted to a solid. The solid was collected and washed three times with water.
Reaction SMILES: [CH:1]([Si:4]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[O:5][CH2:6][CH2:7][NH:8][C:9]1[C:14]([C:15]#[N:16])=[CH:13][N:12]=[CH:11][CH:10]=1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:26][C:27]([O:29][CH3:30])=[O:28].[Cl-].[NH4+]>CN(C=O)C>[CH3:30][O:29][C:27]([C:26]1[N:8]([CH2:7][CH2:6][O:5][Si:4]([CH:1]([CH3:2])[CH3:3])([CH:17]([CH3:19])[CH3:18])[CH:20]([CH3:22])[CH3:21])[C:9]2[CH:10]=[CH:11][N:12]=[CH:13][C:14]=2[C:15]=1[NH2:16])=[O:28]
Reactant: COC(=O)CBr
Reactant: CC(C)[Si](OCCNc1ccncc1C#N)(C(C)C)C(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(N)c2cnccc2n1CCO[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 0.25 h
Yield: 15.2 %

Procedure:
To a solution of 4-(2-triisopropylsilanyloxy-ethylamino)-nicotinonitrile (6.4 g, 20 mmol) in DMF at 0° C. under an inert atmosphere was added sodium hydride (60% dispersion in mineral oil, 880 mg, 22 mmol) in a stepwise manner over a 45 min period. The temperature was kept below 110° C. and the reaction mixture was stirred for 15 minutes. Methyl bromoacetate (2.0 mL, 22 mmol) was added to the reaction mixture which was allowed to reach room temperature and was stirred for 18 hours. Aqueous ammonium chloride (1M sltn. ca 100 mL) was added to the reaction mixture which extracted into ethyl acetate. The organic layer was separated, washed with water then brine, dried (Na2SO4), filtered and concentrated to give residue. The residue was purified by flash chromatography (Si-PPC, EtOAc:MeOH, gradient 100:0 to 90:10) to provide the title compound as a brown solid (1.19 g, 15%). LCMS (method B): RT=2.79 min, M+H+=392.
Reaction SMILES: [CH2:1]([CH:8]1[NH:13][C:12](=O)[CH2:11][NH:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CNC(=O)C(Cc2ccccc2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: c1ccc(CC2CNCCN2)cc1
Temperature: 0 °C

Procedure:
To a suspension of 3-benzyl-piperazine-2,5-dione (14.98 g, 73 mmol, prepared following generally the procedure of Halpern and Westley, J. Org. Chem. 1968, 33, 864) in dry diethyl ether (500 mL) is added dropwise to a solution of lithium aluminum hydride (400 mL of a 1 M solution in diethyl ether, 400 mmol, 5.4 eq). The suspension is heated at reflux for 23 hours and then cooled to 0° C. Water (70 mL) is then cautiously added and the resulting suspension is warmed to room temperature. After 3 hours the suspension is filtered and the solid washed with diethyl ether (1 L). The filtrate is concentrated under vacuum to provide crude title compound (11.40 g, 88%) as a yellow, crystalline solid. A sample (2 g) is recrystallized from cyclohexane and then from toluene to provide the purified title compound (0.83 g) as a fine, white crystals: mp 80-81° C.
Reaction SMILES: C[N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][N:8]([CH2:34][C:35]1[CH:65]=[CH:64][C:38]([CH2:39][N:40]([CH2:52][C:53]2[N:57](C3CCCCO3)[N:56]=[N:55][N:54]=2)[CH2:41][CH2:42][CH2:43][CH2:44][N:45]([CH2:49][CH2:50][CH3:51])[CH2:46][CH2:47][CH3:48])=[CH:37][CH:36]=1)[CH2:9][C:10]1[N:11]([C:15](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:12]=[CH:13][N:14]=1.Cl.CO>CO>[NH:4]1[CH:5]=[CH:6][N:2]=[C:3]1[CH2:7][N:8]([CH2:34][C:35]1[CH:65]=[CH:64][C:38]([CH2:39][N:40]([CH2:52][C:53]2[NH:57][N:56]=[N:55][N:54]=2)[CH2:41][CH2:42][CH2:43][CH2:44][N:45]([CH2:49][CH2:50][CH3:51])[CH2:46][CH2:47][CH3:48])=[CH:37][CH:36]=1)[CH2:9][C:10]1[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=1
Reactant: CCCN(CCC)CCCCN(Cc1ccc(CN(Cc2nccn2C)Cc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)Cc1nnnn1C1CCCCO1
Agent: Cl
Solvent: CO
Product: CCCN(CCC)CCCCN(Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1)Cc1nnn[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.1 %

Procedure:
The compound (35.6 mg) obtained in Example 91-4 was dissolved in methanol (0.80 ml) and added with a 10% hydrogen chloride/methanol solution (0.80 ml) and the whole was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was added with ethyl acetate and water, and the aqueous layer was washed with ethylacetate. The aqueous layer was concentrated and evaporated to dryness under reduced pressure, thereby obtaining a hydrochloride (23.9 mg) of the subject compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:19]2[NH:28][C:22]3=[N:23][CH:24]=[C:25](Br)[CH:26]=[C:21]3[N:20]=2)[CH:12]=[C:13]([O:15][CH:16]([CH3:18])[CH3:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:19]2[NH:28][C:22]3=[N:23][CH:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:26]=[C:21]3[N:20]=2)[CH:12]=[C:13]([O:15][CH:16]([CH3:18])[CH3:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Oc1cc(OCc2ccccc2)cc(-c2nc3cc(Br)cnc3[nH]2)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: CC(C)Oc1cc(OCc2ccccc2)cc(-c2nc3cc(-c4ccccc4)cnc3[nH]2)c1
Temperature: 150 °C
Reaction time: 0.07 h
Yield: 100.6 %

Procedure:
To a mixture of 2-(3-(benzyloxy)-5-isopropoxyphenyl)-6-bromo-3H-imidazo[4,5-b]pyridine (0.11 g), phenylboronic acid (0.05 g) and tetrakis(triphenylphosphine)palladium(0) (0.01 g) in a mixed solvent of dimethoxyethane (3.0 ml) and ethanol (1 ml) was 0.5M aqueous sodium carbonate solution (1 ml), and the mixture was subjected to microwave irradiation in a sealed reaction container and stirred at 150° C. for 4 min. After completion of the reaction, water (2 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 ml). The extract was washed successively with water and saturated brine and dried over magnesium sulfate. The solvent was concentrated under reduced pressure, and the obtained crystals were collected by filtration, washed with isopropyl ether and dried to give the title compound (0.11 g). 1H NMR (CDCl3) δ ppm 1.33 (6 H, d, J=6.03 Hz), 4.59-4.71 (1 H, m), 5.19 (2 H, s), 6.70 (1 H, t, J=1.88 Hz), 7.35-7.50 (9 H, m), 7.58 (1 H, s), 7.70 (2 H, d, J=6.97 Hz), 8.37 (1 H, d, J=1.70 Hz), 8.86 (1 H, d, J=1.70 Hz), 14.11 (1 H, s).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:22])[CH:4]=[C:5]([CH2:10][NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])(=[O:14])=[O:13])[O:6][C:7]=1[CH2:8][OH:9].[CH2:23](OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1CO)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:1][C:2]1[C:3](=[O:22])[CH:4]=[C:5]([CH2:10][NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])(=[O:14])=[O:13])[O:6][C:7]=1[CH2:8][OH:9])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=c1cc(CNS(=O)(=O)c2ccccc2)oc(CO)c1OCc1ccccc1
Reactant: Cc1ccccc1S(=O)(=O)NCc1cc(=O)c(O)c(CO)o1
Product: Cc1ccccc1S(=O)(=O)NCc1cc(=O)c(OCc2ccccc2)c(CO)o1
Yield: 40.85 %

Procedure:
N-(5-Benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-2-methyl-benzenesulfonamide (10-02) (4.7 g, 40.85%) was synthesized as a white solid from N-(5-hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-2-methyl-benzenesulfonamide (9-02) (9.0 g, 27.69 mmol) following the procedure described for N-(5-benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (10-01).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4][CH2:3]1.[F:19][C:20]([Si](C)(C)C)([F:22])[F:21]>[F-].[Cs+]>[OH:1][C:2]1([C:20]([F:22])([F:21])[F:19])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:4][CH2:3]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C1CCCN(C(=O)OCc2ccccc2)CC1
Agent: [Cs+]
Agent: [F-]
Product: O=C(OCc1ccccc1)N1CCCC(O)(C(F)(F)F)CC1
Yield: 57.7 %

Procedure:
To a solution of benzyl 4-oxoazepane-1-carboxylate (2.0 g, 8.08 mmol) in trifluoromethyltrimethylsilane (1.42 mL, 9.70 mmol) was added caesium fluoride (70.4 mg, 0.40 mmol). The reaction mixture was stirred at room temperature until complete consumption of trifluoromethyltrimethylsilane was observed by 19F NMR and quenched with a 1 M HCl solution (50 mL). The mixture was extracted with EtOAc (3×50 mL) and the combined organic layers were washed with brine (50 mL), separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave benzyl 4-hydroxy-4-(trifluoromethyl)azepane-1-carboxylate as a yellow oil (1.48 g). To a solution of this oil (1.3 g, 4.1 mmol) in ethanol (20 mL) was added methylcyclohexadiene (4.6 mL) and 10% palladium on carbon (0.13 g). The reaction mixture was heated at reflux for 30 min before being cooled down to room temperature, filtered through Celite®, washed with MeOH and concentrated under reduced pressure. The residue was dissolved in DMSO (10 mL) and 5-chloro-1-methyl-4-nitro-1H-pyrazole (637 mg, 3.94 mmol) and potassium fluoride (916 mg, 15.76 mmol) were added. The reaction mixture was heated at 70° C. for 16 hr, quenched with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)-4-(trifluoromethyl)azepan-4-ol as a yellow solid (1.06 g, 40% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 3.78 (s, 3H), 3.71 (ddd, J=14.7, 10.5, 2.0 Hz, 1H), 3.31 (dt, J=11.8, 4.4 Hz, 1H), 3.14 (td, J=11.3, 4.6 Hz, 1H), 3.06 (ddd, J=14.7, 5.7, 2.9 Hz, 1H), 2.31-2.13 (m, 1H), 2.14-1.94 (m, 5H), 1.92-1.83 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH:12]=O)=[CH:8][CH:7]=1)[CH2:3][CH3:4].N1C=CC=CC=1.Cl.[CH2:23]([O:25][NH2:26])[CH3:24].O>O1CCOCC1>[CH2:23]([O:25][N:26]=[CH:12][CH2:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH:2]([CH3:1])[CH2:3][CH3:4])=[CH:15][CH:14]=1)[CH3:24]
Reactant: CCC(C)Oc1ccc(OCC=O)cc1
Reactant: CCON
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: C1COCCO1
Product: CCON=CCOc1ccc(OC(C)CC)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of 4-(1-methylpropoxy)phenoxyacetaldehyde (0.68 g, 3.3 mmol) and pyridine (0.50 g, 6.3 mmol) in 5 ml of p-dioxane is added a solution of ethoxyamine hydrochloride (0.60 g, 6.2 mmol) in a minimum amount of water. The reaction mixture is stirred at RT for 6 hours, after which the dioxane is removed in vacuo. The residue is taken up in ether and the organic layer is washed with water. The aqueous phase is extracted with ether, and the combined organic phases are dried, the solvent is removed in vacuo and the product is purified by column chromatography to give 4-(1-methylpropoxy)phenoxyacetaldehyde O-ethyloxime as a mixture of syn and anti stereo isomers. MS m/e 251 (M+).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([NH:11][C:12]2[C:13]([Cl:19])=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=1.[OH-].[Na+].O.O.O.O.O.O.[Cl-].[Sr+2:29].[Cl-]>O.C(O)C.O>[Sr:29].[CH:1]1[CH:2]=[CH:3][C:4]([NH:11][C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=1
Reactant: [Sr+2]
Agent: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: [Sr]
Reaction time: 0.33 h

Procedure:
Diclofenac (0.35 g, 1.18 mmol) was dissolved in water/ethanol (30 ml, 50:50 (volume)) containing sodium hydroxide (24 mg, 0.59 mmol). A solution of strontium chloride hexahydrate (0.16 g, 0.59 mmol) in water (3 ml) was added. The mixture was stirred for 20 minutes, and the title compound was isolated by filtration and dried. Yield 0.122 g (15%).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[OH-].[Li+:24].O1CCCC1>O.C(#N)C>[Li+:24].[F:20][C:18]([F:19])([F:21])[C:15]1[CH:16]=[CH:17][C:12]([N:9]2[CH2:10][CH2:11][CH:6]([CH2:5][CH2:4][C:3]([O-:22])=[O:2])[CH2:7][CH2:8]2)=[CH:13][CH:14]=1
Reactant: COC(=O)CCC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])CCC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 77.6 %

Procedure:
To 3-[1-(4-trifluoromethyl-phenyl)-piperidin-4-yl]-propionic acid methyl ester (480 mg; 1.52 mmol, prepared in accordance with Example 139) is added lithium hydroxide (72 mg; 3.00 mmol) dissolved in water (6.5 mL). After dilution with tetrahydrofuran (10 mL) the reaction mixture is stirred for 2-4 hours. The mixture is then diluted with acetonitrile until a precipitate is formed. The solid is collected by filtration and dried under high vacuum to deliver the desired compound (364 mg; 1.18 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C.[CH2:19]([CH:21]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:22]Br)[CH3:20]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:22][CH:21]([CH2:19][CH3:20])[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5][CH:4]=1
Reactant: CCCCC(CC)CBr
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCC(CC)COc1ccc(OC)cc1
Yield: 80.4 %

Procedure:
A mixture of 4-methoxyphenol (100.0 g, 0.8 mol), dry potassium carbonate (166.7 g, 1.2 mol), acetonitrile (800 mL), and 2-ethylhexyl bromide (173.8 g, 0.9 mol) was stirred mechanically and heated at reflux for 4 days. After cooling, the mixture was diluted with water (1.5 L), and then the organic phase was separated. The aqueous layer was extracted with hexane, and the combined organic layers were washed two times with 1.0 M NaOH and water. After drying over MgSO4, the solvent was removed under reduced pressure to give an orange oil. The crude product was distilled under reduced pressure to give 152 g (80%) of a clear oil. (bp 135-138° C. at 0.4 mmHg).
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[NH2:10][C@H:11]1[CH:16]2[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]2)[CH2:12]1.[CH2:19]([C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)[CH2:20][CH2:21][CH3:22].[I-].ClC1C=CC=C[N+]=1C>O.C(#N)C>[CH2:19]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([NH:10][C@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:28])=[CH:30][CH:31]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCc1ccc(C(=O)O)cc1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CCCCc1ccc(C(=O)N[C@@H]2CN3CCC2CC3)cc1
Reaction time: 8 h
Yield: 95 %

Procedure:
1.5 ml of Acetonitrile and Triethylamine (700 uL, 5.0 mmol) was added to a flask charged with (S)-(−)-3-Aminoquinuclidine dihydrochloride (199 mg, 1.0 mmol) and 4-Butylbenzoic acid (196 mg, 1.1 mmol), followed by addition of 2-Chloro-1-methylpyridinium iodide (383 mg, 1.5 mmol) at room temperature. After stirring overnight, about 2 ml of water was added to reaction mixture to resolve a clear solution that was subsequently injected into a Preparative HPLC instrument for purification. Desired fractions were combined and concentrated under vacuum. (S)-4-butyl-N-(quinuclidin-3-yl)benzamide (272 mg, 95% yield) was isolated as an oil. 1H NMR (400 MHz, Methanol-D4) δ (ppm): 8.24 (d, J=8.2 Hz, 2H), 8.41 (d, J=8.4 Hz, 2H), 4.42 (m, 1H), 3.84 (ddd, J=11.7, 9.9, 2.6 Hz, 1H), 3.35 (m, 4H), 2.69 (t, J=7.7 Hz, 2H), 2.36 (q, J=3.1 Hz, 1H), 2.24 (m, 1H), 2.10 (m, 2H), 1.94 (m, 1H), 1.62 (q, J=7.6 Hz, 2H), 1.37 (q, J=7.4 Hz, 2H), 0.95 (t, J=7.4 Hz, 3H). LCMS (ESI): m/z 287.1 (M+H [C18H26N2O]=287.20).
Reaction SMILES: N[C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:11][B-](F)(F)F.[H+].N(OCCC(C)C)=O>C(O)C>[F:11][C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccnc1[N+](=O)[O-]
Reactant: F[B-](F)(F)F
Agent: CC(C)CCON=O
Agent: [H+]
Solvent: CCO
Product: O=[N+]([O-])c1ncccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
To a stirred solution of 3-Amino 2-nitro pyridine (2.5 g, 17.97 mmol) in dry ethanol (20 ml) was added 10 ml of tetrafluoroboric acid (48% in water). The reaction mixture was cooled to 0° C. and isoamyl nitrite (2.6 g, 22.4 mmol) was added dropwise at 0° C. and stirred at 0° C. for 1 hour. The reaction mixture was filtered, and the solid obtained was washed with diethyl ether. The filtered solid was added to preheated (150 mL) toluene with stirring and reaction mixture was refluxed for 24 hours. The solvent was evaporated and the residue taken in ethyl acetate (200 ml) and washed with water followed by brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to get the crude 3-fluoro-2-nitropyridine. This was purified by column over silica gel using 10% ethyl acetate in pet ether as eluant to get 1 g (39%) of the title compound as a yellow solid.