Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-:1].[C:2]([NH:5][C:6]1[CH:25]=[CH:24][C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([N+:21]([O-])=O)[CH:19]=3)[NH+:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)(=[O:4])[CH3:3]>CO.[Pd]>[Cl-:1].[C:2]([NH:5][C:6]1[CH:25]=[CH:24][C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH2:21])[CH:19]=3)[NH+:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)Nc1ccc(Nc2cc[nH+]c3ccc([N+](=O)[O-])cc23)cc1
Agent: [Pd]
Agent: [Cl-]
Solvent: CO
Product: CC(=O)Nc1ccc(Nc2cc[nH+]c3ccc(N)cc23)cc1
Reaction time: 2 h
Yield: 78.2 %

Procedure:
To a suspension of (A3 (1.75 g, 4.88 mmol) in MeOH (10 mL) was added 10% Pd/C (0.1 g) and hydrogenated (under 40 psi). for 2 h. The reaction mixture was filtered and washed with more MeOH. The filtrated was concentrated to half the volume, diluted with EtOAc and the rest of the MeOH was evaporated. The Resulting precipitate was filtered washed with more EtOAc and dried to give essentially pure (A4) (1.255 g 78%); mp (MeOH/EtOAc)>280° C.; 1H NMR [(CD3)2SO] δ13.95 (br, 1 H, N+H), 10.14 (s, 1 H, NH), 10.01 (s, 1H, NH), 8.10 (d, J=6.7 Hz, 1 H, ArH), 7.74 (d, J=8.9 Hz, 3 H, ArH), 7.43 (d, J=2.2 Hz, 1 H, ArH), 7.38-7.32 (m, 3 H, ArH), 6.61 (d, J=6.7 Hz, 1 H, ArH), 5.94 (s, 2 H, NH2), 2.08 (s, 3 H, COCH3); APCI+ve 293.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:17]([O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([Br:29])=[C:24]([CH3:30])[CH:23]=1)(=[O:20])[C:18]#[CH:19]>C1COCC1.[Cu]I>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:19]#[C:18][C:17]([O:21][C:22]2[CH:23]=[C:24]([CH3:30])[C:25]([Br:29])=[C:26]([CH3:28])[CH:27]=2)=[O:20])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C#CC(=O)Oc1cc(C)c(Br)c(C)c1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(OC(=O)C#Cc2ccc([N+](=O)[O-])cc2)cc(C)c1Br
Temperature: 65 °C
Yield: 72.5 %

Procedure:
1-Iodo-4-nitrobenzene (550 mg, 2.17 mmol) in THF (4 mL) was degassed under reduced pressure at −78° C., and then nitrogen gas was introduced. To the solution was added K2CO3 (552 mg, 298.6 mmol), CuI (30 mg, 0.16 mmol) and PdCl2(Ph3P)2 (14 mg, 0.020 mmol), and the mixture was stirred at 65° C. 4-bromo-3,5-dimethylphenyl propiolate (6-1) (506 mg, 2.03 mmol) in THF (2.5 mL) was added by syringe pump over a period of 6 h. After being cooled to room temperature, the mixture was filtered and washed with EtOAc. The filtrate was concentrated and purified by silica gel column chromatography to give the title compound 7-1 (551 mg, 74% yield) as a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].Cl[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=2)=[C:3]([CH3:10])[CH:4]=1)=[O:7]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(C=O)ccc1Oc1ccc(C#N)cn1
Temperature: 25 °C
Yield: 89.4 %

Procedure:
Combine 4-hydroxy-3-methyl-benzaldehyde (0.502 g, 3.69 mmol), 6-chloro-nicotinonitrile (0.510 g, 3.68 mmol), and potassium carbonate (1.28 g, 9.26 mmol) in dimethylacetamide (18 mL) and warm to 100° C. After 1 h. cool to ambient temperature, dilute reaction mixture with water (40 mL), and extract with ethyl acetate (3×50 mL). Wash combined organic extracts with water and brine successively, dry over anhydrous magnesium sulfate, filter, and concentrate. Purify the residue by silica gel chromatography (hexanes→ethyl acetate gradient/1.5 L) to provide 0.784 g (89%) of the title compound as a light brown solid: mass spectrum (electrospray): m/z=239.0 (M+1); 1H NMR (CDCl3): 10.01 (s, 1H), 8.44 (d, 1H, J=2.4 Hz), 7.99 (dd, 1H, J=2.0, 8.3 Hz), 7.86 (s, 1H), 7.81 (dd, 1H, J=1.5, 8.3 Hz), 7.23 (d, 1H, J=8.3 Hz), 7.13 (d, 1H, J=8.8 Hz), 2.25 (s, 3H).
Reaction SMILES: ClCl.[C:3]([Cl:7])(Cl)(Cl)Cl.[CH:8]([C:11]1[NH:12][C:13]([CH2:18][OH:19])=C(CO)[N:15]=1)([CH3:10])[CH3:9]>C(O)C>[CH:8]([C:11]1[NH:12][C:13]([CH2:18][OH:19])=[C:3]([Cl:7])[N:15]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1nc(CO)c(CO)[nH]1
Reactant: ClC(Cl)(Cl)Cl
Agent: ClCl
Solvent: CCO
Product: CC(C)c1nc(Cl)c(CO)[nH]1
Reaction time: 1 h

Procedure:
26.3 Grams (15.6 mmol) of a 4.2% chlorine-carbon tetrachloride solution was dropwisely added to a solution consisting of 2.52 g (14.8 mmol) of the 2-isopropyl-4,5-bis(hydroxymethyl) imidazole and 200 ml of ethanol maintaining a temperature of 40° C. with stirring. After the dropwise addition has been finished, the stirring was continued at 40° C. for one hour and, then, the solvent was distilled off under reduced pressure. After the residual brown oil was dissolved in water, sodium carbonate was added thereto to make the mixture alkaline. The mixture was evaporated again under reduced pressure. The obtained resulting solid product was extracted with ethanol, the extract was evaporated under reduced pressure, and the resulting solid product was extracted with cold water. 0.71 Grams of the starting 2-isopropyl-4,5-bis(hydroxymethyl) imidazole was recovered as the extraction residue, and the extract after evaporate under reduced pressure was subjected to the column chromatography (silica gel-acetone) to obtain a 2-isopropyl-4-chloro-5-(hydroxymethyl) imidazole in an amount of 0.56 g (yield, 30.3% with respect to the starting material consumed). By using acetonitrile, the compound was further refined. The TLC and spectra of this compound were measured to be the same as those of Example 4.
Reaction SMILES: CS[C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](OC)([O:22]C)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=1)([CH3:8])[C:4]([O:6]C)=[O:5].[OH-].[K+]>[Zn].O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].O>[C:15]([C:11]1[CH:10]=[C:9]([CH:3]([CH3:8])[C:4]([OH:6])=[O:5])[CH:14]=[CH:13][CH:12]=1)(=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)C(C)(SC)c1cccc(C(OC)(OC)c2ccccc2)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Reaction time: 44 h
Yield: 85.4 %

Procedure:
Water (4 ml) was added to a mixture consisting of 269 mg of methyl α-methylthio-α-(m-(α,α-dimethoxybenzyl)phenyl)propionate, 500 mg of zinc powder and 80 mg of copper sulfate pentahydrate. Then, 500 mg of potassium hydroxide (85%) was added, and the mixture was stirred at the refluxing temperature for 44 hours. Water (4 ml) was further added, and with stirring, the mixture was heated under reflux for 3 hours. After cooling, the insoluble matter was separated by filtration, and washied with 20 ml of water. The filtrate and the washing were combined and adjusted to pH 1 with 2.0 ml of conc. hydrochloric acid. The mixture was stirred at 60° C. for 40 minutes and then, extracted three times with 20 ml of diethyl ether. The extract was washed with 10 ml of water, and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column using methylene chloride as an eluent to afford 162 mg of α-(m-benzoylphenyl) propionic acid in a yield of 85%.
Reaction SMILES: [CH:1]([N:4]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:5](=[O:36])[CH2:6][N:7]1[C:13](=[O:14])[C:12]([CH3:24])([CH2:15][CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11](=[O:25])[N:10]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:9]2[CH:32]=[CH:33][CH:34]=[CH:35][C:8]1=2)([CH3:3])[CH3:2]>C(O)C.[Pd]>[CH:1]([N:4]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:5](=[O:36])[CH2:6][N:7]1[C:13](=[O:14])[C:12]([CH3:24])([CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11](=[O:25])[N:10]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:9]2[CH:32]=[CH:33][CH:34]=[CH:35][C:8]1=2)([CH3:3])[CH3:2]
Reactant: CC(C)N(C(=O)CN1C(=O)C(C)(CC=Cc2ccccc2)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)N(C(=O)CN1C(=O)C(C)(CCCc2ccccc2)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To a stirring solution of 40 mg (71.7 mmol) of N-Isopropyl-2-[3-methyl-2,4-dioxo-5-phenyl-3-(3-phenyl-allyl)-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-phenyl acetamide, prepared as in Example 11, in 3 mL absolute ethanol is added 10 mg of 10% palladium on carbon. The reaction vessel is placed on a Parr hydrogenation apparatus, evacuated, and then pressurized with H2 gas to 40 psi and shaken for 2 h at RT. The reaction mixture is filtered through Celite to remove the catalyst and the solvent removed in vacuo. Purification of the resulting material via reverse phase MPLC using a C-18 column and 70% acetonitrile/30% H2O with 0.1% TFA as eluent followed by lyophilization afforded 29 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ7.49-6.96 (m, 19H), 6.72 (d, 1H, J=8.0), 5.09 (m, 1H), 4.38 (d, 1H, J=16.3), 3.92 (d, 1H, J=16.3), 2.28 (m, 2H), 1.67-1.50 (m, 6H), 1.34 (m, 1H), 1.12 (m, 6H); low resolution MS (FAB)m/e 560 (MH+), 425, 397, 223.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([N:41]1[N:45]=[N:44][C:43]([CH3:46])=[N:42]1)[CH2:20][O:21]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC1N=NN(C(COC(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)CO)N=1>CO.O1CCCC1>[CH2:1]([S:17][CH2:18][CH:19]([N:41]1[N:45]=[N:44][C:43]([CH3:46])=[N:42]1)[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCSCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)n1nnc(C)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1nnn(C(CO)COC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCCCSCC(CO)n1nnc(C)n1

Procedure:
Using 10.2 g of crude 1-hexadecylthio-2-(5-methyl-2H-tetrazol-2-yl)-3-triphenylmethoxypropane 5h and 500 mg (2.6 mM) of p-toluene sulfonic acid monohydrate in 200 ml of methanol-tetrahydrofurane (1:1) mixture is converted to 3.17 g (49% from the compound 4h) of the title compound Vh1 by the same procedure as described in (81).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[C:25]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:3]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1[nH]c(-c2cccc(O)c2)nc2ccccc12
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc(-c2nc3ccccc3c(=O)[nH]2)c1
Temperature: 105 °C
Reaction time: 3.5 h

Procedure:
To 2-(3-hydroxyphenyl)quinazolin-4(3H)-one (11.0 g, 45.98 mmole) was added pyridine (16.06 mL, 15.71 g, 0.199 mmole) followed by addition of acetic anhydride (145 mL) and the reaction mixture was heated to 105° C. and stirred for 3.5 h. The reaction mixture was cooled to ambient temperature and then poured onto ice-water (800 mL) and stirred for 2 h. The solid was then filtered and washed with water, ethanol, ether and finally hexane and dried for several hours under high vacuum to give 3-(4-oxo-3,4-dihydroquinazolin-2-yl)phenyl acetate. (8.4 g, mmol, 65%).
Reaction SMILES: [ClH:1].C(OCC)(=O)C.[F:8][C:9]1[CH:10]=[C:11]([NH:20][C:21]([C@H:23]2[C:32]3[C:27](=[CH:28][C:29]([CH2:33][O:34][CH3:35])=[CH:30][CH:31]=3)[CH2:26][CH2:25][N:24]2C(OC(C)(C)C)=O)=[O:22])[CH:12]=[C:13]2[C:17]=1[C:16]([CH3:19])([CH3:18])[CH2:15][CH2:14]2>C(OCC)(=O)C>[ClH:1].[F:8][C:9]1[CH:10]=[C:11]([NH:20][C:21]([C@H:23]2[C:32]3[C:27](=[CH:28][C:29]([CH2:33][O:34][CH3:35])=[CH:30][CH:31]=3)[CH2:26][CH2:25][NH:24]2)=[O:22])[CH:12]=[C:13]2[C:17]=1[C:16]([CH3:19])([CH3:18])[CH2:15][CH2:14]2
Reactant: COCc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COCc1ccc2c(c1)CCN[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 109 %

Procedure:
4N Hydrogen chloride/ethyl acetate (4 mL) was added to a solution of tert-butyl (R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.77 g, 1.60 mmol) in ethyl acetate (2 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the obtained precipitate was washed with ethyl acetate/hexane to give (R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride (0.730 g, 1.743 mmol, 109%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:19]([N:21]3C(=O)C4C(=CC=CC=4)C3=O)[CH3:20])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.NN>CCO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:19]([NH2:21])[CH3:20])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](c1cc2ccc(F)cc2nc1-c1cccc(F)c1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Product: C[C@H](N)c1cc2ccc(F)cc2nc1-c1cccc(F)c1
Temperature: 80 °C

Procedure:
To a solution of 2-((S)-1-(7-fluoro-2-(3-fluorophenyl)quinolin-3-yl)ethyl)-isoindoline-1,3-dione (60.0 mg, 145 μmol) in EtOH (2 mL) was added NH2NH2 (1.0 mL, 1.45 mmol, 10 eq) and the resulting solution was heated to 80° C. for 2 h. A precipitate was filtered away and the filtrate was removed under reduce pressure to afford (1S)-1-(7-fluoro-2-(3-fluorophenyl)quinolin-3-yl)ethanamine. To the crude residue of (1S)-1-(7-fluoro-2-(3-fluorophenyl)quinolin-3-yl)-ethanamine in DMF (2 mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile (22 mg, 145 μmol) and DIEA (0.06 mL, 319 μmol). The resulting mixture was heated to 100° C. overnight. Solvent was removed under reduce pressure and purified via preparatory HPLC using 15-60% MeCN/H2O w/0.01% TFA to afford a white solid of 4-amino-6-((S)-1-(7-fluoro-2-(3-fluorophenyl)-quinolin-3-yl)ethylamino)pyrimidine-5-carbonitrile (9.3 mg, 16%). 1H NMR (500 MHz, CD3OD) δ ppm 1.63 (d, J=6.85 Hz, 3H) 5.70 (q, J=7.01 Hz, 1H) 7.25-7.34 (m, 1H) 7.44-7.54 (m, 2H) 7.55-7.63 (m, 2H) 7.74 (dd, J=9.78, 2.45 Hz, 1H) 8.05 (s, 1H) 8.18 (dd, J=9.05, 5.87 Hz, 1H) 8.72 (s, 1H). Mass Spectrum (ESI) m/e=403 (M+1).
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[NH:22][N:21]=[N:20][N:19]=3)=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1CCCCC=1.[N+:29]([O-:34])([N+]([O-])=O)=[O:30]>C(O)(=O)C>[N+:29]([C:2]1[O:3][C:4]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[NH:22][N:21]=[N:20][N:19]=3)=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([O-:34])=[O:30]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: Brc1oc2ccc(Cc3nnn[nH]3)cc2c1-c1ccccc1
Solvent: CC(=O)O
Solvent: C1=CCCCC1
Product: O=[N+]([O-])c1oc2ccc(Cc3nnn[nH]3)cc2c1-c1ccccc1

Procedure:
To a stirred solution of 1.9 g. (0.005 mole) of 2-bromo-3-phenyl-5-tetrazolylmethylbenzofuran in 50 ml. of warm acetic acid and 1 ml. of cyclohexene is added 1 g. of dinitrogen tetraoxide. The mixture is heated on a steam bath for 30 minutes, then cooled to ice bath temperature. The product is separated by filtration, washed with acetic acid and diethyl ether and recrystallized from ethanol to provide yellow needles of 2-nitro-3-phenyl-5(1H-tetrazol-5-ylmethyl)benzofuran, m.p. 245°-247° C. having the structure ##STR38##
Reaction SMILES: C([O:5][CH2:6][C@H:7]([CH3:35])[O:8][C:9]1[CH:10]=[C:11]([CH:21]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[CH:23]=1)[C:12]([NH:14][C:15]1[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=1)=[O:13])(C)(C)C.[ClH:36]>C(#N)C>[ClH:36].[OH:5][CH2:6][C@H:7]([CH3:35])[O:8][C:9]1[CH:10]=[C:11]([CH:21]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:27][CH:26]=2)[CH:23]=1)[C:12]([NH:14][C:15]1[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=1)=[O:13]
Reactant: C[C@@H](COC(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Agent: Cl
Solvent: CC#N
Product: C[C@@H](CO)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 30 °C
Reaction time: 0.17 h
Yield: 73.4 %

Procedure:
A solution of 3-[(1S)-2-tert-butoxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[4-(methylsulfonyl)phenoxy]benzamide (456.32 g of an 11.41% w/w solution in acetonitrile; 103.80 mmol) was charged to a jacketed vessel. The stirred mixture was heated to between 93° C. and 101° C. (jacket temperature) and solvent was removed by distillation under atmospheric pressure until a total of 370 mL of distillate was collected. The mixture was then cooled (jacket temperature 30° C.) and MTBE (500 mL) was added to give a cloudy mixture. The jacket temperature was set to 20° C. and aqueous hydrochloric acid (250 mL of a 2.10M solution) was added when the temperature of the reaction mixture reached 23.6° C. The mixture was stirred for 10 minutes then separated. The upper organic layer washed with water (250 mL) and the layers were separated. The retained organic layer was heated (jacket temperature 68° C.) and solvent removed by distillation under atmospheric pressure until a total of 440 mL of distillate was collected. Isopropyl alcohol (300 mL) was then added to the mixture in the vessel. The jacket temperature was set to 95° C. and solvent removed by distillation under atmospheric pressure until a total of 250 mL of distillate was collected. The mixture was cooled to between 20 and 21° C. and a solution of hydrogen chloride (5.52 M in isopropanol, 616 mL) was added. The mixture was heated to 50° C. over 40 minutes. The mixture was maintained at 50° C. for a further 70 minutes before addition of a seed of 3-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[4-(methylsulfonyl)phenoxy]benzamide (66 mg). The mixture was stirred for a further 15 min then seeded once more (53 mg). The mixture was set on a pre-programmed cooling ramp to 15° C. over 400 min. The product started to crystallise approximately 40 minutes after initiation of the cooling profile. After stirring for approximately 20 hours after initiation of the cooling ramp, the crystallised product was collected by filtration. The collected solid was washed with MTBE (150 mL). The product cake was sucked dry on the filter then subjected to further drying in vacuum for approximately 18 hours at 45° C. to give the title product (40.52 g; with a purity of 94.22% w/w by HPLC assay (73.4% yield after correction for assay)).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3](O)O.[CH3:8][N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[Na+].[Na+].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O>[F:1][C:2]([F:7])([F:6])[CH:3]=[CH:8][N+:9]([O-:11])=[O:10]
Reactant: C[N+](=O)[O-]
Reactant: OC(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])C=CC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
A mixture of 2,2,2-trifluoroethane-1,1-diol (75% aq solution, 20 g, 0.13 mol), CH3NO2 (24 g, 0.39 mol) and Na2CO3 (0.85 g, 8 mmol) was stirred overnight at RT. Water (50 mL) was added and the mixture was extracted with diethyl ether (3×30 mL) and dried over Na2SO4. After concentrating the organic extract at low temperature and under reduced pressure, P2O5 (20.0 g, 0.14 mol) was added to the residue oil, which was distilled at atmospheric pressure to give a green-yellow oil (4 g, 50% purity, 10% yield). Boiling point 85-90° C.; 1H NMR (400 MHz, CDCl3) δ ppm 7.09-7.17 (m, 1H), 7.50 (dd, J=2.0 Hz, 12.0 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]2[N:27]([CH3:28])[N:26]=[C:25]([O:29][CH2:30][CH2:31][OH:32])[C:24]=2[C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:32][CH2:31][CH2:30][O:29][C:25]2[C:24]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)=[C:23]([NH:22][S:19]([C:16]3[CH:15]=[CH:14][C:13]([C:9]([CH3:11])([CH3:10])[CH3:12])=[CH:18][CH:17]=3)(=[O:20])=[O:21])[N:27]([CH3:28])[N:26]=2)=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: COc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: COc1ccc(-c2c(OCCOc3ncc(Br)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
The title compound was made according to the procedure used for Example 13 except that (60 mg) of 5-bromo-2-chloropyrimidine was used and 4-(tert-butyl)-N-[3-(2-hydroxyethoxy)-4-(4-methoxyphenyl)-1-methyl-1H-pyrazol-5-yl]benzenesulfonamide (Example 21) (85 mg) was used in place of 4-(tert-butyl)-N-{3-(2-hydroxyethoxy)-1-methyl-4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}benzenesulfonamide (Example 12). The crude material was purified by HPLC on a 5μ ODS Phenomenex Magellen column with a gradient elution of acetonitrile (5% to 95%) and 0.1M NH4OAc (95% to 5%) to yield the desired product as an off white solid (30.2 mg).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:20][C:21]1[N:25]([CH2:26][C:27]([N:29]2[CH2:34][CH2:33][CH:32]([C:35]3[S:36][CH:37]=[C:38]([C:40](Cl)=[O:41])[N:39]=3)[CH2:31][CH2:30]2)=[O:28])[N:24]=[C:23]([C:43]([F:46])([F:45])[F:44])[CH:22]=1>ClCCl>[CH3:1][N:2]([CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)[C:40]([C:38]1[N:39]=[C:35]([CH:32]2[CH2:33][CH2:34][N:29]([C:27](=[O:28])[CH2:26][N:25]3[C:21]([CH3:20])=[CH:22][C:23]([C:43]([F:44])([F:46])[F:45])=[N:24]3)[CH2:30][CH2:31]2)[S:36][CH:37]=1)=[O:41]
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)Cl)cs2)CC1
Reactant: CNC1CCCc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)C3CCCc4ccccc43)cs2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.1 %

Procedure:
To a stirred solution of 1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine (145 mg, 0.9 mmol) and triethylamine (0.16 mL, 1.13 mmol) in dichloromethane (2 mL) at 0° C. was gradually added 2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarbonyl chloride (316 mg, 0.75 mmol) (i.e. the product of Example 2, Step D). The reaction mixture was stirred at room temperature for 16 h and then diluted with dichloromethane (4 mL). The mixture was washed with water, 1 N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and brine, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to provide crude product, which was purified by medium-pressure liquid chromatography on silica gel using 60-100% of ethyl acetate in hexanes as eluant to give 242 mg of the title compound as white foam.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.Cl.[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]([CH:36]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:37]([OH:39])=[O:38])[CH3:35])=[CH:30][CH:29]=1.[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48](O)[CH2:47]2>C1COCC1>[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48]([O:38][C:37](=[O:39])[CH:36]([N:34]([C:31]1[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=1)[CH3:35])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:47]2
Reactant: CN(c1ccc(F)cc1)C(C(=O)O)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CN(c1ccc(F)cc1)C(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
PS-DCC (1.02 g, 1.35 mmol, loading: 1.33 mmol/g) is suspended in dry THF (13.5 mL). Then HOBT (0.21 g, 1.35 mmol), [(4-fluoro-phenyl)-methyl-amino]-phenyl-acetic acid hydrochloride (I71) (0.20 g, 0.68 mmol) and (R)-quinuclidin-3-ol (0.26 g, 2.03 mmol) are added. The mixture is shaken at RT overnight. PS-DCC is filtered off, washed with EtOAc and THF. The solution is evaporated and the residue is portioned between EtOAc and water. The organic phase is washed with sat. NaHCO3, dried (Na2SO4) and evaporated. The crude is purified by flash chromatography (DCM/MeOH=95/5) to afford the title compound as a colorless oil (209 mg, 84% yield, mixture of diastereoisomers).