Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[Li].O.[F:4][C:5]1([F:15])[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([NH2:14])[C:7]=2[O:6]1.[N+:16]([C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[C:21]([C:28]([F:31])([F:30])[F:29])[C:20]=1Cl)([O-:18])=[O:17].Cl>CS(C)=O.O>[F:15][C:5]1([F:4])[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([NH:14][C:20]3[C:21]([C:28]([F:30])([F:31])[F:29])=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:19]=3[N+:16]([O-:18])=[O:17])[C:7]=2[O:6]1
Reactant: Nc1cccc2c1OC(F)(F)O2
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: [Li]O
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2cccc3c2OC(F)(F)O3)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
20.8 g of LiOH.H2O are added at 0° C. to a solution of 24.5 g of 2,2-difluoro-4-amino-1,3-benzodioxole in 70 ml of dimethyl sulfoxide. The mixture is then stirred for 20 minutes. Subsequently, a solution of 38.3 g of 2,4-dinitro-6-trifluoromethylchlorobenzene in 70 ml of dimethyl sulfoxide is added, and the resultant reaction mixture is stirred at 0° C. for 20 minutes and then heated to room temperature. After 5 hours, the mixture is poured into 350 ml of water, acidified with dilute hydrochloric acid and extracted several times with diethyl ether. The combined ether phases are washed three times with a 5% solution of sodium carbonate and then with 5% hydrochloric acid and dried over sodium sulfate, and the solvent is evaporated off in vacuo. The residue comprises 51.6 g of orange-brown crystals which are recrystallised in toluene. Yield: 41.6 g; melting point: 144°-146° C.
Reaction SMILES: [CH2:1]([N:5]1[C:12](=[O:13])[C:11]2[CH2:14][CH:15]3[CH2:17][CH:6]1[CH:7]=[C:8]([S:18]([NH2:21])(=[O:20])=[O:19])[S:9][C:10]=2S3)[CH:2]([CH3:4])[CH3:3].OO[S:24]([O-:26])=[O:25].[K+].CO>O>[CH2:1]([N:5]1[C:12](=[O:13])[C:11]2[CH2:14][CH:15]3[CH2:17][CH:6]1[CH:7]=[C:8]([S:18]([NH2:21])(=[O:20])=[O:19])[S:9][C:10]=2[S:24]3(=[O:26])=[O:25])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN1C(=O)C2=C3SC(S(N)(=O)=O)=CC1CC(C2)S3
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)CN1C(=O)C2=C3SC(S(N)(=O)=O)=CC1CC(C2)S3(=O)=O
Reaction time: 24 h

Procedure:
5-Isobutyl-4-oxo-3,4,5,6-tetrahydro-2H-2,6-methanothieno[3,2-g]-l,5-thiazocine-8-sulfonamide (2 g, 5.8 mmol) was added to a mixture of Oxone® (10 g, 16.3 mmol) and methanol (25 ml). After 24 hours, the reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). After drying over sodium sulfate, the solvent was evaporated under reduced pressure to yield 2.13 of a foam. A sample triturated with 1-chlorobutane gave material with mp 239°-241° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:5][S:11]([CH3:10])(=[O:13])=[O:12]
Reactant: OCc1ccccc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To a solution of 2-fluorobenzyl alcohol (4.40 g, 34.9 mmol) in dichloromethane (40 mL) was added methanesulfonyl chloride (3.24 mL, 41.9 mmol) and triethylamine (5.84 mL, 41.9 mmol) on an ice bath, the solution was warmed to room temperature and stirred overnight. The reaction solution was diluted with dichloromethane, washed with an aqueous solution of 5% sodium bicarbonate, then, dried over anhydrous magnesium sulfate, the solvent was evaporated, and the title compound (4.62 g, 65%) was obtained as a brown oil. This was used in the next reaction without purification.
Reaction SMILES: C([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[CH:15]=[N:16][C:17]([C:18]3[O:22][N:21]=[C:20]([CH3:23])[CH:19]=3)=[C:7]2[C:6]1=[O:24])(C)(C)C.O>C(O)C.Cl>[CH3:23][C:20]1[CH:19]=[C:18]([C:17]2[N:16]=[CH:15][N:8]3[C:9]4[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=4)[NH:5][C:6](=[O:24])[C:7]=23)[O:22][N:21]=1
Reactant: Cc1cc(-c2ncn3c2c(=O)n(C(C)(C)C)c2ccccc23)on1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(-c2ncn3c2c(=O)[nH]c2ccccc23)on1
Temperature: 25 °C

Procedure:
A stirred suspension of 5-tert-butyl-4,5-dihydro-3-(3methyl-5isoxazolyl)-4oxo-imidazo[1,5-a]quinoxaline (0.65 g) in a mixture of ethanol (10 ml) and 4 M hydrochloric acid (1 ml) was refluxed for 10 min. Then the mixture was cooled to room temperature and water (10 ml) was added. The precipitated product was collected by filtration and dried to give the title compound as a white solid, m.p. 393° C. (Compound 18).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.[C:17]1(=[O:27])[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.C1(C)C=CC=CC=1>C(OCC)C>[C:8]([C:6]1[CH:7]=[C:2]([NH:1][C:17]([C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20]([OH:22])=[O:21])=[O:27])[CH:3]=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]=1[OH:12])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)c1cc(NC(=O)c2ccccc2C(=O)O)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
A solution of 5.60 g (0.03 mole) of the known compound 4-amino-2,6-di-t-butylphenol in 100 ml of diethyl ether was added dropwise over a period of twenty minutes to a solution of 4.44 g (0.03 mole) of phthalic anhydride in 200 ml of a 1:2 mixture of diethyl ether:toluene. The reaction mixture was stirred at room temperature for about sixteen hours. The resulting precipitate was collected, rinsed with a mixture of diethyl ether and hexane, and dried to give 6.8 g of a white solid. This material was recrystallized from a mixture of ethyl acetate and hexane to give 5.9 g of white solid 2-[N-(3,5-di-t-butyl-4-hydroxyphenyl)carbamoyl]benzoic acid, m.p. 191°-192° C. Analysis: Calculated for C22H27NO4 : %C, 71.5; %H, 7.4, %N, 3.8; Found: %C, 71.8; %H, 7.3; %N, 3.7.
Reaction SMILES: [CH:1]1[C:6](N)=[CH:5][C:4]2[C:8]([NH:10][NH:11][C:12](=[O:13])[C:3]=2[CH:2]=1)=[O:9].C[N:15](C=O)C>>[CH:1]1[CH:6]=[C:5]([NH2:15])[C:4]2[C:8]([NH:10][NH:11][C:12](=[O:13])[C:3]=2[CH:2]=1)=[O:9]
Reactant: CN(C)C=O
Reactant: Nc1ccc2c(=O)[nH][nH]c(=O)c2c1
Product: Nc1cccc2c(=O)[nH][nH]c(=O)c12
Temperature: 25 °C

Procedure:
About 1 mg of Vitamin D binding protein, DBP, is buffer exchanged three times with 100 mM PBS at pH 8.2. The final volume was 200 uL. Succinyl-amino-buty-ethyl-isoluminol NHS ester (4.6 mg) is dissolved in DMF. The isoluminol (17 uL) is added to the DBP and the mixture is maintained at room temperature for about 1 hour with occasional shaking. The unreacted label is removed by size exclusion chromatography using SEPHADEX-G25 (23×1 cm) and 100 mM PBS, pH 6.0 as the mobile phase.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][NH2:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:12]([C:16]1[C:17]([C:28](Cl)=[O:29])=[N:18][C:19]2[C:24]([C:25]=1[OH:26])=[CH:23][CH:22]=[C:21]([Cl:27])[CH:20]=2)(OC)=[O:13]>O1CCCC1.O.Cl>[Cl:27][C:21]1[CH:22]=[CH:23][C:24]2[C:25](=[O:26])[C:16]3[C:12]([OH:13])=[N:11][N:10]([C:4]4[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=4)[C:28](=[O:29])[C:17]=3[NH:18][C:19]=2[CH:20]=1
Reactant: COC(=O)c1c(C(=O)Cl)nc2cc(Cl)ccc2c1O
Reactant: COc1ccc(NN)cc1Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(O)c3c(=O)c4ccc(Cl)cc4[nH]c3c2=O)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
To a solution of 3-chloro-4-methoxyphenylhydrazine (4.26 g, 24.7 mM) in 35b.) in tetrahydrofuran (200 mL) was added a solution of 3-carbomethoxy-7-chloro-4-hydroxyquinoline-2-carbonyl chloride (3.54 g, 11.8 mM, as prepared in Example 35b.) in tetrahydrofuran (100 mL) at 0° C. The resulting yellow suspension was stirred at 0° C. for 30 minutes and diluted with water (200 mL) to give a yellow solution. This solution was further diluted with hydrochloric acid (600 mL, 1N) to give a tan suspension which was stirred for 1 hour. The suspension was filtered (the filtrate was saved) and the collected solids were washed with water and then ether to give the title compound (2.30 g, 45%) as a tan powder, MS(CI): 436 (M+H), which was used above in the synthesis described for 7-chloro-3-(3-chloro-4-methoxyphenyl)-1-hydroxy-3,4,5,10-tetrahydropyridazino[4,5-b]quinoline-4,10-dione. 1H NMR 12.69 (s, 1H, exchangeable), 10.72 (s, 1H, exchangeable), 8.14 (d, J=8.50 Hz, 1H), 8.00 (br s, 1H, exchangeable), 7.76 (s, 1H), 7.48 (d, J=8.50 Hz, 1H), 7.05 (d, J=8.80 Hz, 1H), 6.98 (d, J=2.28 Hz, 1H), 6.85 (dd, J=2.28, 8.80 Hz, 1H), 3.78 (s, 3H), 3.70 (s, 3H). After sitting for five days, further precipitation occurred in the above saved acidic filtrate. The solids were collected to provide material (1.80 g) consisting of a mixture of the title compound (60%), 7-chloro-2-(3-chloro-4-methoxyphenyl)-1-hydroxy-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione (35%) and 7-chloro-3-(3-chloro-4-methoxyphenyl)-1-hydroxy-3,4,5,10-tetrahydropyridazino[4,5-b]quinoline-4,10-dione (5%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2.[CH3:21][N:22](C)C=O>[C-]#N.[Zn+2].[C-]#N.C(OCC)(=O)C>[C:21]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2)#[N:22]
Reactant: CCOC(=O)C1=Cc2cc(I)ccc2NC1C(F)(F)F
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2cc(C#N)ccc2NC1C(F)(F)F
Temperature: 80 °C
Yield: 48 %

Procedure:
N,N-Dimethylformamide (5 mL) was degassed with nitrogen for thirty minutes in a three neck round bottom flask equipped with a condenser, temperature monitoring, nitrogen purge and heating mantle. Ethyl 6-iodo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate (Example 158) (0.522 g, 1.32 mmol) and zinc cyanide (0.102 g, 0.792 mmol) were added to the N,N-dimethylformamide and stirred vigorously for ten minutes. Tetrakis(triphenyl-phosphine)palladium(0) (0.068 g, 0.53 mmol) was added and the contents gently warmed to 80° C. for 2 hours under a nitrogen atmosphere. Ethyl acetate (20 mL) was added, followed by extraction with aqueous 2 N ammonium hydroxide (2×10 mL), water (2×10 mL), saturated ammonium chloride (2×mL), dried over sodium sulfate and solvent removed in vacuo to yield a yellow solid. The product was purified by flash chromatography (silica gel, ethyl acetate-hexanes, 3:1) to yield, upon concentration of the appropriate fractions, ethyl 6-cyano-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate as a yellow solid (188 mg, 48%): mp 211-212° C. 1H NMR (CDCl3 /300 MHz) 7.68 (s, 1H), 7.43 (m, 2H), 6.69 (d, 1H, J=8.3 Hz), 5.22 (m, 1H), 4.98 (br s, 1H), 1.30 (m, 2H), 1.36 (t, 3H, J=7.1 Hz). EIHRMS m/z 314.1147 (M+NH4+, Calc'd 314.1116). Anal. Calc'd for C14H11F3N2O2 : C, 56.76; H, 3.74; N, 9.46. Found: C, 56.44; H, 4.03; N, 9.29.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)nc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To 6-chloro-nicotinoyl chloride (0.540 g, 3.07 mmoles) in dichloromethane (10 mL) was added of morpholine, (0.294 g, 1.1 equivalents) followed by triethylamine (940 uL, 2.2 equivalents). The reaction was stirred overnight at room temperature to give (6-chloro-pyridin-3-yl)-morpholin-4-yl-methanone. No starting material, 6-Chloro-nicotinoyl chloride, remained and mass spectrometry showed correct M+ion. An aqueous work-up was performed and the crude material was taken to the next step. The crude residue, (6-chloro-pyridin-3-yl)-morpholin-4-yl-methanone, weighed 0.610 g (88% yield) after aqueous work-up.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:12][CH:11]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccc(Cl)cc3)CC2)c1
Reactant: Oc1ccc(Br)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3ccc(Br)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-bromophenol and N-(3-{1-[5-(4-chlorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 597.2 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3][C:2]1=[O:9].F[B-](F)(F)F.[CH3:15][O+](C)C>ClCCl>[CH3:15][O:9][C:2]1[CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][N:1]=1
Reactant: C[O+](C)C
Reactant: O=C1CCC=CCCN1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC1=NCCC=CCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a sample of 103 mg (0.822 mmol) of 1H,3H,4H,7H,8H-azocin-2-one in 5 mL of dichloromethane was added 183 mg (1.234 mmol) of trimethyloxonium tetrafluoroborate. The reaction was stirred at room temperature for 16 h, after which time it was diluted with 15 mL of methylene chloride and extracted twice with 5 mL of saturated aqueous NaHCO3 and once with 5 mL of brine. The organic layer was dried over MgSO4, filtered, and the concentrated under reduced pressure. The 8-methoxy-2H,3H,6H,7H-azocine thus produced (92 mg) was used without purification in the next reaction. 1H NMR (500 MHz, CDCl3): δ 5.82 (m, 1H), 5.69 (m, 1H), 4.22 (s, 3H), 4.04 (q, 2H, J=6 Hz), 3.03 (t, 2H, J=6 Hz), 2.73 (br apparent q, 2H, J=6 Hz), 2.63 (apparent q, 2H, J=6 Hz).
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11][C:12](=[O:14])[CH3:13])=[C:6]([CH3:15])[C:5]=1[CH3:16].[N+:17]([O-])([OH:19])=[O:18].C(=O)([O-])O.[Na+]>>[CH3:2][NH:3][C:4]1[C:9]([N+:17]([O-:19])=[O:18])=[C:8]([CH3:10])[C:7]([O:11][C:12](=[O:14])[CH3:13])=[C:6]([CH3:15])[C:5]=1[CH3:16]
Reactant: O=[N+]([O-])O
Reactant: CNc1cc(C)c(OC(C)=O)c(C)c1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CNc1c(C)c(C)c(OC(C)=O)c(C)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4.3 g of N-methyl-4-acetoxy-2,3,5-trimethylaniline hydrochloride [prepared as described in step (h) above] were added to ice-cooled concentrated aqueous nitric acid, and the resulting mixture was stirred, whilst ice-cooling, for 10 minutes and then at room temperature for 10 minutes. At the end of this time, the reaction mixture was poured into ice-water and the aqueous mixture was neutralized by the addition of sodium hydrogencarbonate, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, after which 50 ml of diisopropyl ether and 50 ml of hexane were added to the residue. The mixture was then agitated ultrasonically for 5 minutes. Insoluble precipitates were triturated with a 1:1 by volume mixture of diisopropyl ether and hexane. The resulting crystals were collected by filtration, after which they were washed with a 1:1 by volume mixture of diisopropyl ether and hexane to give 2.76 g of the title compound, melting at 143°-146° C.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:5]=2[N:6]=1.[Cl-].[CH2:13]([O:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][NH2+:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:11][C:8]1[CH:9]=[CH:10][C:4]2[O:3][C:2]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][C@H:23]3[C:21]([O:20][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:22])=[N:6][C:5]=2[CH:7]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCC[NH2+]1
Reactant: Cc1ccc2oc(Cl)nc2c1
Agent: [Cl-]
Product: Cc1ccc2oc(N3CCCC[C@H]3C(=O)OCc3ccccc3)nc2c1

Procedure:
The title compound was prepared by a similar method to Preparation 2 from 2-chloro-5-methyl-1,3-benzoxazole [see J.Med.Chem, 1988, 31, 1719-1728] and (2S)-2-[(benzyloxy)carbonyl]piperidinium chloride [see EP 530167 A1 930303]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 90:10 changing to 70:30, by volume, hexane:ethyl acetate to afford benzyl (2S)-1-(5-methyl-1,3-benzoxazol-2-yl)-2-piperidinecarboxylate as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][OH:12])[NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:15]I>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][OH:12])[N:8]([CH3:15])[C:5]2=[N:6][CH:7]=1
Reactant: CI
Reactant: OCc1nc2cc(Br)cnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(CO)nc2cc(Br)cnc21

Procedure:
A procedure similar to that described in Preparation 15 was repeated, except that the reaction was conducted using 3.00 g of 6-bromo-2-hydroxymethyl-3H-imidazo-[5,4-b]pyridine (prepared as described in Preparation 58), 0.58 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 0.92 ml of methyl iodide and 60 ml of dimethylformamide. After completion of the reaction with methyl iodide, the reaction mixture was freed from dimethylformamide by distillation under reduced pressure. The residue was diluted with water, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 50:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 1.40 g of the title compound, melting at 142-144° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1)([O-:3])=[O:2]
Reactant: OB(O)c1ccccc1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cnn(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
4-Nitro-1H-pyrazole (1 g, 8.84 mmol), phenylboronic acid (2.223 g, 17.69 mmol), copper (II) acetate (2.409 g, 13.27 mmol) and pyridine (2.86 ml, 35.4 mmol) were combined in dichloromethane (40 ml) and the mixture stirred at ambient temperature open to the air with a drying tube. The mixture was filtered through a diatomaceous earth pad washing with dichloromethane; and the filtrate washed with water and brine, dried over MgSO4, filtered and concentrated to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[C:18]3[C:13](=[C:14]([F:19])[CH:15]=[CH:16][CH:17]=3)[O:12][CH2:11][CH2:10]2)[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][N:3]=1.[CH3:23][O:24][C:25]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:26]=1[CH2:27][NH:28][C:29]1[C:30]([NH2:36])=[CH:31][CH:32]=[C:33]([F:35])[CH:34]=1>C(#N)C.[Cl-].[Na+].O>[CH3:23][O:24][C:25]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:26]=1[CH2:27][NH:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[NH:36][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[C:18]3[C:13](=[C:14]([F:19])[CH:15]=[CH:16][CH:17]=3)[O:12][CH2:11][CH2:10]2)[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][N:3]=1
Reactant: COc1ccc(CNc2cc(F)ccc2N)c(OC)c1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1N[C@@H]1CCOc2c(F)cccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(CNc2cc(F)ccc2Nc2ncc([N+](=O)[O-])c(N[C@@H]3CCOc4c(F)cccc43)n2)c(OC)c1
Temperature: 65 °C
Yield: 37.7 %

Procedure:
A mixture of (R)-2-chloro-N-(8-fluorochroman-4-yl)-5-nitropyrimidin-4-amine (32 mg), N1-(2,4-dimethoxybenzyl)-5-fluorobenzene-1,2-diamine (28 mg) and KCO3 (41 mg) in ACN was heated at 65° C. for 3 hr, cooled to RT, diluted with brine and extracted with EtOAc (2×). The combined organics were evaporated, and purified by column chromatography (eluted with 30% EtOAc/Hex) to yield the titled product (21 mg). 1H-NMR (300 MHz, CDCl3) δ 9.0 (s, 1H), 8.6 (br d, 1H), 7.2-6.8 (m, 6H), 6.5-6.3 (m, 4H), 4.4-4.2 (m, 4H), 3.8 (s, 6H), 2.3-2.2 (m, 2H).
Reaction SMILES: [CH2:1]1[O:9][C@@H:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC(C)(O)[C:12]#[N:13].C(N(CC)CC)C>O1CCCC1>[C:3]1([C@@H:2]([OH:9])[CH2:1][C:12]#[N:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(O)C#N
Reactant: c1ccc([C@@H]2CO2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#CC[C@H](O)c1ccccc1
Yield: 70 %

Procedure:
A mixture of 40.0 g of (R)-styrene oxide, 31.12 g of acetone cyanohydrin, 36.96 g of triethylamine, and 150 ml of tetrahydrofuran was heated at reflux for 18 hours. The reaction mixture was cooled, concentrated in vacuo, diluted with 200 ml of 2N potassium hydroxide, and extracted with diethyl ether. The ether extracts were combined, dried over magnesium sulfate, and concentrated in vacuo providing 34.3 g of the title intermediate.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][CH:37]([NH:1][CH2:2][C@H:3]([OH:13])[CH2:4][O:5][C:6]4[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=4)[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: NC[C@H](O)COc1ccc(O)cc1
Reactant: COc1ccc(NS(=O)(=O)c2ccc(N3CCC(=O)CC3)cc2)cc1OC
Product: COc1ccc(NS(=O)(=O)c2ccc(N3CCC(NC[C@H](O)COc4ccc(O)cc4)CC3)cc2)cc1OC

Procedure:
The title compound was prepared from 4-((2S)-3-Amino-2-hydroxy-propoxy)-phenol and Reference Example 73, N-(3,4-dimethoxy-phenyl)-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as an off-white solid; mp 101-106° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.15-1.30 (m, 2H), 1.70-1.90 (m, 2H), 2.50-2.90 (m, 5H), 3.61 (s, 3H), 3.63 (s, 3H), 3.60-3.90 (m, 5H), 6.45 (dd, 1H), 6.60-6.80 (m, 8H), 6.90 (d, 1H), 7.45 (d, 1H); MS (ES) m/z: 557.9 (MH+); HRMS Calcd. for C28H36N3O7S (MH+): 558.2274. Found: 558.2293.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C.C(O)C.O>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(OCCCN2CCCCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(OCCCN2CCCCC2)cc1
Temperature: 28 °C
Reaction time: 8 h

Procedure:
To methyl 4-(3-piperidin-1-ylpropoxy)benzoate ax15 (4.41 g, 15.9 mmol, 1 eq) in ethanol (160 ml) is added a 5 N aqueous solution of sodium hydroxide (9.54 ml, 47.7 mmol, 3 eq) and the mixture is stirred at 60° C. for 4 h and at 28° C. overnight. The mixture is concentrated under vacuum to give a white solid, which is then dissolved in a 1:1 mixture of ethanol/water (100 ml). A solution of 5 N aqueous hydrochloric acid is then added until the pH of the mixture reaches 2-3. The ethanol is then evaporated under vacuum and the mixture filtered to give a white solid. This solid is washed with water and dried under vacuum at 40° C.