Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C1C=CC=CC=1)(C1C=CC=CC=1)C1CCN(CCCC([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])=[CH:16][CH:15]=2)=O)CC1.[BH4-].[Na+]>CO>[CH3:25][C:20]([C:17]1[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1)([CH3:24])[C:21]([OH:23])=[O:22]
Reactant: CC(C)(C(=O)O)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylacetic acid, prepared in accordance with Example 12, and 300 mg of NaBH4 in 25 mL of CH3OH was stirred overnight at room temperature. The mixture was then concentrated in vacuo. The residue was partitioned between EtOAc and H2O. The aqueous portion was treated with concentrated HCl until pH 6, then extracted with EtOAc. The organics were concentrated in vacuo. The residue was dissolved in EtOAc, filtered, and concentrated in vacuo to an oil. The oil was dissolved in CH3OH and concentrated to a solid. The solid was slurried with EtOAc, filtered, and rinsed with EtOAc to afford 4-[4-[4-hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[CH3:24])[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:13][CH:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[CH3:24])[CH2:15]2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(F)cnc1N1CC(Nc2ccc(F)cc2C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(F)ccc1NC1CN(c2ncc(F)cc2C(=O)O)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a solution of methyl 5-fluoro-2-(3-((4-fluoro-2-methylphenyl)amino)azetidin-1-yl)nicotinate (D90) (150 mg, 0.450 mmol) in 1,4-dioxane/water (3 ml/1 ml), 1M NaOH (0.675 ml, 0.657 mmol) was added and the resulting mixture was stirred 2 h at 60° C. Organic solvent was evaporated. The remaining aqueous were washed with dichloromethane (5 ml) then acidified to pH2 by addition of 2M HCl and extracted with ethylacetate (3×20 ml). Collected organics, after solvent evaporation afforded the title compound (D135) (140 mg).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[C:19]([CH3:24])=[N:20][N:21]([CH3:23])[CH:22]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[C:19]([CH3:24])=[N:20][N:21]([CH3:23])[CH:22]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nn(C)cc1Nc1cnc2c(n1)c(C(=O)NC(C)(C)C)cn2COCC[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn(C)cc1Nc1cnc2[nH]cc(C(=O)NC(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.9 %

Procedure:
To a solution of N-tert-butyl-2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (89 mg, 194 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (443 mg, 300 μL, 3.89 mmol) and the mixture stirred at room temperature for 16 h. The mixture was concentrated then re-dissolved in dichloromethane (3 mL), methanol (1.5 mL) and ammonium hydroxide (0.45 mL) and the mixture stirred at room temperature for 2 h. The reaction mixture was concentrated then purified by chromatography (silica, 5-8% methanol in dichloromethane) to give N-tert-butyl-2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (40 mg, 122 μmol, 63%) as a light brown solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.13 (s, 1H), 8.44 (s, 1H), 7.91 (s, 1H), 7.87 (d, J=3.2, 1 H), 7.82 (s, 1H), 7.81 (s, 1H), 3.71 (s, 3H), 2.09 (s, 3H), 1.35 (s, 9H); MS (EI/CI) m/z: 328.1 [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.[Li]CCCC.[CH2:27]([N:34]([C:42]12[CH2:49][CH2:48][C:45]([CH:50]=[O:51])([CH2:46][CH2:47]1)[CH2:44][CH2:43]2)[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[CH2:27]([N:34]([C:42]12[CH2:47][CH2:46][C:45]([CH:50]([C:3]3[C:2]([Cl:1])=[CH:7][N:6]=[C:5]4[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:4]=34)[OH:51])([CH2:44][CH2:43]1)[CH2:48][CH2:49]2)[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)C12CCC(C=O)(CC1)CC2
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(I)c(Cl)cnc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(O)C34CCC(N(Cc5ccccc5)C(=O)OC(C)(C)C)(CC3)CC4)c(Cl)cnc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 63.6 %

Procedure:
To a solution of 5-chloro-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (1.33 g, 3.06 mmol, Adesis) in THF (25 mL) at about −78° C. was added n-BuLi (1.6 M solution in hexanes, 2.00 mL, 3.20 mmol) at such a rate that the internal temperature did not exceed about −70° C. The reaction mixture was stirred for about 45 min and a solution of tert-butyl benzyl(4-formylbicyclo[2.2.2]octan-1-yl)carbamate (1.05 g, 3.06 mmol) in THF (6 mL) was added dropwise. The reaction mixture was stirred at about −78° C. for about 1 h and was slowly warmed to ambient temperature and stirred for about 1 h. Saturated aqueous NH4Cl and EtOAc (10 mL each) were added and the layers were separated. The aqueous phase was extracted with EtOAc (2×10 mL) and the combined organics were washed with brine (10 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The remaining oil was purified by silica gel chromatography eluting with a gradient of 0-40% EtOAc in heptane to give tert-butyl benzyl(4-((5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)(hydroxy)methyl)bicyclo[2.2.2]octan-1-yl)carbamate (1.27 g, 64%) as a clear colorless oil: LC/MS (Table 1, Method o) Rt=3.78 min; MS m/z: 652 (M+H)+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH3:29])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]2[C:15]3[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:17][C:16]=3[CH:18]=[C:19]([CH3:29])[CH:20]=2)=[CH:23][CH:24]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C)cc(-c4ccc(Cl)cc4)c3O2)cc1
Product: CNCC1Cc2cc(C)cc(-c3ccc(Cl)cc3)c2O1

Procedure:
The title compound was prepared (0.026 g, 21%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(4-chlorophenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.16 g, 0.37 mmol) and methylamine (0.115 g, 3.7 mmol). mp 210-213° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:12]1.C(N(C(C)C)CC)(C)C>>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:12]1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)NCC1CCCNC1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC1CCCN(c2ccncc2[N+](=O)[O-])C1
Yield: 99 %

Procedure:
The method of Example 1 was followed using 1 eq each of 4-chloro-3-nitropyridine, tert-butyl piperidin-3-ylmethylcarbamate and diisopropylethylamine yielding tert-butyl (1-(3-nitropyridin-4-yl)piperidin-3-yl)methylcarbamate (99%). LCMS (m/z): 336.9 (MH+); LC Rt=2.27 min. 1H NMR (CDCl3): δ 8.80 (s, 1H), 8.33 (d, J=6.0 Hz, 1H), 6.85 (d, J=6.3 Hz, 1H), 4.63 (bs, 1H), 3.28-3.46 (m, 2H), 2.89-3.15 (m, 3H), 2.69-2.86 (m, 1H), 1.55-1.99 (m, 5H), 1.45 (s, 9H).
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:11]=2)[C:6]=1[C:27]([NH2:29])=[O:28])(=O)C.[OH-].[Na+].Cl>CO.O>[OH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:11]=2)[C:6]=1[C:27]([NH2:29])=[O:28]
Reactant: CCCCCCCCCCCCc1ccc2c(C(N)=O)c(OC(C)=O)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCc1ccc2c(C(N)=O)c(O)ccc2c1
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
8.0 g of 2-acetoxy-6-n-dodecyl aminocarbonylnaphthalene obtained in Example 1 was suspended in 64 g of 50% methanol-water. To the suspension, 3.4 g of 48% sodium hydroxide aqueous solution was added and allowed to react at 60° C. for 1 hour. The reaction liquid was neutralized with 5% hydrochloric acid and stirred for 30 minutes and then precipitation was filtrated, washed thoroughly with methanol and water, dried to give 6.8 g of 2-hydroxy-6-n-dodecyl aminocarbonylnaphthalene (decomposition point: 329° C.). The infrared absorption spectrum (KBr) of the compound is shown in FIG. 2. The triboelectric charge was measured by blow-off method as described in example 1. The triboelectric charge of the compound was +6.7 μC/g.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][CH:12]=[C:13]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:17][O:18][C:19]=2[CH3:20])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1>>[CH2:1]([O:8][CH2:9][C:10]1[N:11]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[CH:12]=[C:13]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:17][O:18][C:19]=2[CH3:20])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]c(COCc2ccccc2)n1
Reactant: N#Cc1ccc(F)cc1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C#N)cc2)c(COCc2ccccc2)n1
Yield: 82 %

Procedure:
As described for Example 63, 4-(2-benzyloxymethyl-1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (100 mg, 0.29 mmol) using 4-fluorobenzonitrile instead of 4-fluoroacetophenone was converted to the title compound (106 mg, 82%) which was obtained as a white foam. MS: m/e=447.4 [M+H]+.
Reaction SMILES: Cl.Cl.[C:3](=[NH:9])([NH2:8])[CH2:4][C:5](=[NH:7])[NH2:6].C[O-].[Na+].[F:13][C:14]1[CH:34]=[CH:33][CH:32]=[CH:31][C:15]=1[CH2:16][C:17]1[N:18]=[C:19]([C:26](OCC)=O)[N:20]2[CH:25]=[CH:24][CH:23]=[N:22][C:21]=12>CO>[F:13][C:14]1[CH:34]=[CH:33][CH:32]=[CH:31][C:15]=1[CH2:16][C:17]1[N:18]=[C:19]([C:26]2[N:9]=[C:3]([NH2:8])[CH:4]=[C:5]([NH2:6])[N:7]=2)[N:20]2[CH:25]=[CH:24][CH:23]=[N:22][C:21]=12
Reactant: N=C(N)CC(=N)N
Reactant: CCOC(=O)c1nc(Cc2ccccc2F)c2ncccn12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Nc1cc(N)nc(-c2nc(Cc3ccccc3F)c3ncccn23)n1
Temperature: 50 °C

Procedure:
147 mg (0.85 mmol) of 1,3-propanediimidamide dihydrochloride are introduced into 2 ml of methanol, and 0.37 ml (2.00 mmol) of a 30% strength methanolic sodium methanolate solution is added. The mixture is heated at 50° C. for 30 min. It is then allowed to cool to RT, a solution of 150 mg (0.50 mmol) of ethyl 8-(2-fluorobenzyl)imidazo[1,5-a]pyrimidine-6-carboxylate from example 10A in 2.0 ml of methanol is added, and the mixture is heated to reflux for 3 h. Cooling is followed by dilution with water and extraction with ethyl acetate. The organic phase is dried over sodium sulfate, and the solvent is removed in vacuo. The residue is purified by preparative HPLC to result in 36 mg (21% of theory) of the desired product as yellow crystals.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:18])C=1.[OH-].[Na+].C[O-].[Na+].CO>ClCCl.CO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[O:18])=[N:7][CH:8]=1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1ccc(C)nc1
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCc1ccc(C=O)nc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 20 %

Procedure:
In dichloromethane (25.0 ml), 5-ethyl-2-methyl-pyridine (2.31 g) was dissolved. The reaction solution was cooled to 0° C. and added with meta-chloroperbenzoic acid (4.43 g), followed by stirring at room temperature for 2.5 hours. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then subjected to extraction with chloroform. Subsequently, the organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. The drying agent was filtrated out and the solvent was then distilled off, followed by dissolving the resulting residue in dichloromethane (40.0 ml). The reaction solution was added with trifluoroacetic anhydride (5.6 ml) and subjected to thermal reflux for 3.5 hours. After the reaction solution had been cooled to room temperature, the solvent was distilled off. The residue obtained was dissolved in methanol (80.0 ml). After having been cooled to 0° C., the reaction solution was added with a 12.5% sodium methoxide/methanol solution and adjusted to pH 10, followed by stirring at room temperature for 16.5 hours. After the solvent had been distilled off, the residue was added with distilled water and extracted with chloroform. The organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. The drying agent was filtrated out and the solvent was then distilled off, followed by dissolving the resulting residue in chloroform (50.0 ml). The reaction solution was added with manganese dioxide (chemically processed product) (7.44 g) and then stirred at room temperature for 18 hours. The reaction solution was filtrated through Celite. The solvent in the filtrate was distilled off and the residue obtained was then purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (515.6 mg) as a yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[C@H:4]([NH:32]C(OCC1C=CC=CC=1)=O)[CH2:5][N:6]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31])[CH2:7][C:8](=O)[CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1.C(N(CC)CC)C.[Pd]>[CH3:1][O:2][C:3]([C@H:4]1[CH2:5][N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])[CH2:7][CH:8]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:32]1)=[O:43]
Reactant: COC(=O)[C@@H](CN(CC(=O)C(c1ccccc1)c1ccccc1)Cc1ccccc1OC)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CN(Cc2ccccc2OC)CC(C(c2ccccc2)c2ccccc2)N1
Yield: 57.8 %

Procedure:
(2R)-2-Benzyloxycarbonylamino-3-[N-(2-methoxybenzyl)-N-(2-oxo-3,3-diphenylpropyl)amino]propionic acid methyl ester (1.55 g) was dissolved in a mixture of tetrahydrofuran (50 ml) and triethylamine (0.744 ml), and the whole was hydrogenated over 10% palladium-charcoal (50% wet, 0.15 g) at room temperature under atmospheric pressure for 4 hours. After removal of the catalyst by filtration, the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (2:1) as an eluent. The fractions containing the objective compound were collected and evaporated under reduced pressure to give (2R)-6-benzhydryl-4-(2-methoxybenzyl)piperazine-2-carboxylic acid methyl ester (663.8 mg) as a yellow oil.
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3[CH2:12][O:11]3)[CH:7]=[CH:6][C:5]=12.[CH3:13][C:14]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15]1>C(O)C>[CH3:13][C:14]1([NH:19][CH2:12][C@@H:10]([C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[N:2][N:1]=3)[CH:9]=2)[OH:11])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC1(N)CCCC1
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Solvent: CCO
Product: CC1(NC[C@H](O)c2ccc3nnnn3c2)CCCC1
Yield: 62.1 %

Procedure:
A solution of (R)-2-(tetrazolo[1,5-a]pyrid-6-yl)oxirane (375 mg, 2.31 mmol) and (1-methylcyclopentyl)amine (229 mg, 2.31 mmol) in 10 ml of absolute ethanol was heated at reflux for 20 hours. The reaction mixture was concentrated to dryness and the residue (532 mg) purified by preparative Tlc on silica gel (90:10:1 methylene chloride:methanol: NH4OH) to afford 375 mg of product.
Reaction SMILES: [Cl-:1].[Li+].[F:3][C:4]([F:21])([C:17]([F:20])([F:19])[F:18])[CH2:5]OS(C1C=CC(C)=CC=1)(=O)=O>CN1CCCC1=O>[Cl:1][CH2:5][C:4]([F:21])([F:3])[C:17]([F:20])([F:19])[F:18]
Reactant: [Cl-]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)C(F)(F)F)cc1
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: FC(F)(F)C(F)(F)CCl

Procedure:
These solvents are readily prepared from commercially available materials by standard and well-known organic syntheses techniques. For example, to prepare 1,1-dichloro-2,2,3,3,3-pentafluoropropane, 2,2,3,3,3-pentafluoro-1-propanol and p-toluenesulfonate chloride are reacted together to form 2,2,3,3,3-pentafluoropropyl-p-toluenesulfonate. Then, N-methylpyrrolidone, lithium chloride, and the 2,2,3,3,3-pentafluoropropyl-p-toluenesulfonate are reacted together to form 1-chloro-2,2,3,3,3-pentafluoropropane. Chlorine and the 1-chloro-2,2,3,3,3-pentafluoropropane are then reacted together to form 1,1-dichloro-2,2,3,3,3-pentafluoropropane.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[OH:43][CH2:44][C@@H:45]1[C@@H:49]([OH:50])[CH2:48][CH2:47][NH:46]1>CS(C)=O.C(OCC)(=O)C>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:46]3[CH2:47][CH2:48][C@H:49]([OH:50])[C@H:45]3[CH2:44][OH:43])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OC[C@H]1NCC[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CC[C@H](O)[C@H]2CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 130 °C
Reaction time: 68 h
Yield: 67.1 %

Procedure:
A mixture of 11.0 g (20.6 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 14.3 g (103 mmol) potassium carbonate and 12.2 g (75.7 mmol) (2R,3S)-2-(hydroxymethyl)-3-hydroxypyrrolidine in 110 ml dimethyl sulfoxide was stirred at 130° C. for 68 h. The reaction mixture was diluted with 800 ml ethyl acetate and washed with 800 ml saturated sodium carbonate solution, 500 ml water and 750 ml brine. The combined aqueous layers were extracted with two 800-ml portions of ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography gave 8.48 g (67%) of the title compound as a light yellow foam.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[CH:3]=1.[Br:21]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:21][CH2:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: COc1ccc(-c2nc3c(C)cc(OC)cc3s2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(-c2nc3c(CBr)cc(OC)cc3s2)cc1
Temperature: 25 °C
Yield: 69 %

Procedure:
4-Methyl-6-methoxy-2-(4-methoxy-phenyl)-benzothiazole (0.53 g, 1.87 mmol), N-bromosuccinimide (0.33 g, 1.87 mmol) and benzoyl peroxide (9 mg) were suspended in carbon tetrachloride (6 mL) and refluxed for 3.5 h, then cooled to room temperature. Solvent was evaporated and the mixture was purified by chromatography to give 4-bromomethyl-6-methoxy-2-(4-methoxy-phenyl)-benzothiazole (0.47 g, 70% yield) as a white solid. Mass spec: MH+=364.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[NH2:26][C:27]1[C:32]([CH3:33])=[CH:31][C:30](Br)=[CH:29][N:28]=1>>[CH3:33][C:32]1[C:27]([NH2:26])=[N:28][CH:29]=[C:30]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:31]=1
Reactant: Cc1cc(Br)cnc1N
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1cc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cnc1N

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 2-amino-5-bromo-3-methylpyridine (168 mg, 1.0 mmol) according to general procedure II. Obtained as a dark-red solid (140 mg, 30%). MS (ISP) 462.2 [(M+H)+]; mp 233-234° C.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:21])=[C:18](Br)[CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:22]([Sn](CCCC)(CCCC)CCCC)[CH:23]=[CH2:24]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:24]([C:18]1[CH:19]=[C:14]([O:13][CH2:12][C@@H:9]2[CH2:10][CH2:11][N:8]2[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH:15]=[N:16][C:17]=1[Cl:21])[CH:23]=[CH2:22]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(Br)c1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCc1cc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cnc1Cl
Yield: 83.5 %

Procedure:
3-(1-BOC-2-(S)-Azetidinylmethoxy)-5-bromo-6-chloropyridine (1.0 g, 2.65 mmol) in toluene (10 mL) was added tetrakis(triphenylphosphine) palladium (100 mg) and allyltributyltin (0.99 mL, 3.18 mmol). The mixture was stirred and refluxed for two days. Solvent was evaporated and the residue was chromatographed (silica gel; hexane/EtOAc, 5:1 to 1:1) to afford an oil (750 mg, 83%): 1H NMR (CDCl3, 300 MHz) δ 1.42 (s, 9H), 2.20-2.40 (m, 2H), 3.43 (d, 2H, J=6.5 Hz), 3.88 (t, 2H, J=7.0 Hz), 4.12 (m, 1H), 4.30 (m, 1H), 4.50 (m, 1H), 5.10-5.20 (m, 2H), 5.92 (m, 1H), 7.18 (d, J=3.0 Hz), 7.98 (d, 1H, J=3.0 Hz); MS (CI/NH3) m/z 339 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.CON(C)[C:21](=[O:30])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]([C:21](=[O:30])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: CON(C)C(=O)COc1ccccc1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)COc2ccccc2)c(C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with N-methoxy-N-methyl-2-phenoxyacetamide. The product is used in crude form in the following reaction.