Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:5]=[C:6]([C:10]2[CH2:14][CH:13]([C:15]([N:17]3[CH2:21][CH2:20][C@H:19]([NH2:22])[CH2:18]3)=[O:16])[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1.[OH:25][C:26]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1.C(N(CC)CC)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>C(Cl)Cl>[N:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:26]1([OH:25])[CH2:31][CH2:30][CH:29]([NH:22][C@H:19]2[CH2:20][CH2:21][N:17]([C:15]([CH:13]3[O:12][N:11]=[C:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([F:23])([F:2])[F:24])[CH:5]=4)[CH2:14]3)=[O:16])[CH2:18]2)[CH2:28][CH2:27]1
Reactant: N[C@H]1CCN(C(=O)C2CC(c3cccc(C(F)(F)F)c3)=NO2)C1
Reactant: O=C1CCC(O)(c2ccccn2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CC(c2cccc(C(F)(F)F)c2)=NO1)N1CC[C@H](NC2CCC(O)(c3ccccn3)CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3S)-1-(3-[3-(trifluoromethyl)phenyl]-4,5-dihydroisoxazol-5-ylcarbonyl)pyrrolidin-3-amine hydrochloride (178 mg, 0.489 mmol) and 4-hydroxy-4-pyridin-2-yl-cyclohexanone (95.1 mg, 0.498 mmol) in methylene chloride (6 mL) was added triethylamine (50.3 mg, 0.498 mmol) and then NaBH(OAc)3 (120 mg, 0.54 mmol). After being stirred at room temperature for 2 h, the reaction mixture was neutralized with 1 N NaOH to pH 7, and extracted with ethyl acetate (2×25 mL). The organic extracts were combined, washed with saline solution (20 mL), dried over sodium sulfate, concentrated in vacuo, and chromatographed on silica gel, eluting with 1% NH4OH in ethyl acetate/methanol (95/5 to 80/20). The appropriate fractions were combined and concentrated in vacuo to give two fractions of the desired compounds: peak 1 (100 mg) and peak 2 (85 mg). Both fractions were further purified by HPLC on a C18 column, eluting with 1% NH4OH in water/acetonitrile, to give peak 1 (68 mg) and peak 2 (65 mg) as white solids. Both compounds have LCMS: (M+H)+ 503.3. Peak 1 shows two peaks in a 1 to 1 ratio in a chiral analytical column. Peak 2 shows two peaks in a 1 to 10 ratio in a chiral analytical column.
Reaction SMILES: NC(N)=[S:3].S(=O)(=O)(O)O.Br[C:11]1[S:12][C:13]2[CH:19]=[C:18]([C:20]3[CH:21]=[C:22]([CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[CH:23]=[CH:24][C:25]=3[O:26][CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31]C[CH2:29]3)[CH:17]=[CH:16][C:14]=2[N:15]=1.[OH-].[Na+]>C(#N)C.O>[CH:28]1([CH2:27][O:26][C:25]2[CH:24]=[CH:23][C:22]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:21][C:20]=2[C:18]2[CH:17]=[CH:16][C:14]3[NH:15][C:11](=[S:3])[S:12][C:13]=3[CH:19]=2)[CH2:33][CH2:32][CH2:31][CH2:29]1
Reactant: NC(N)=S
Reactant: CCOC(=O)CCc1ccc(OCC2CCCCC2)c(-c2ccc3nc(Br)sc3c2)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: O=C(O)CCc1ccc(OCC2CCCC2)c(-c2ccc3[nH]c(=S)sc3c2)c1
Temperature: 90 °C
Reaction time: 20 h
Yield: 55.3 %

Procedure:
A solution obtained beforehand by adding thiourea (52 mg, WAKO) to 1 M sulfuric acid (5 ml) and mixing them was added with a solution of Intermediate 76 (101 mg) in acetonitrile (5 ml), and stirred at 90° C. for 20 hours. The reaction mixture was poured into water (20 ml), neutralized by addition of 1 N aqueous sodium hydroxide under ice cooling, and then extracted with ethyl acetate (80 ml×3). The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, methylene chloride:ethanol=30:1) to obtain the title compound (Compound No. V-91, 46 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:21])[C:16](OCC)=[O:17])=[CH:11][C:10]=1[OH:22].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.S(=O)(=O)(O)O>CCOCC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:21])[CH2:16][OH:17])=[CH:11][C:10]=1[OH:22]
Reactant: CCOC(=O)C(C)c1ccc(-c2ccc(F)cc2F)c(O)c1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CC(CO)c1ccc(-c2ccc(F)cc2F)c(O)c1

Procedure:
A solution of ethyl 2-(2',4'-difluoro-2-hydroxy-4-biphenylyl)propionate (2.0 g.), from the previous Example, in dry ether (40 ml.) was added over 15 minutes in dry ether (40 ml.). After stirring under reflux for 1.5 hours, excess lithium aluminium hydride was decomposed by the cautious addition of water and finally with 2N sulphuric acid (10 ml.). The product was isolated in ether, washed, dried, evaporated and distilled to give a thick translucent oil, setting to a hard glass on cooling. Trituration with boiling light petroleum (b.p. 62°-68° C.) gave a crystalline solid. This was recrystallised from methylene chloride/light petroleum (b.p. 40°-60° C.) to give 2-(2',4'-difluoro-2-hydroxy-4-biphenylyl)propan-1-ol, m.p. 118°-118.5° C.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([OH:20])=[C:14]([CH:19]=1)[C:15]([O:17]C)=O>CCOCC>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([OH:20])=[C:14]([C:15]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[OH:17])[CH:19]=1
Reactant: Br[Mg]C1CCCCC1
Reactant: COC(=O)c1cc(Cl)ccc1O
Solvent: CCOCC
Product: Oc1ccc(Cl)cc1C(O)(C1CCCCC1)C1CCCCC1

Procedure:
270 ml of a solution of cyclohexyl magnesium bromide titrating 1.3 M/liter in ether were added dropwise with stirring at room temperature to a mixture of 18.7 g of methyl 5-chloro-2-hydroxy-benzoate in 150 ml of ether and the ether was distilled while replacing it with 270 ml of benzene. The mixture was then refluxed for 20 hours and was cooled and poured into a mixture of 500 g of ice and 300 ml of an aqueous solution containing 105 g of ammonium chloride. The mixture was extracted once with 250 ml of ether, twice with 150 ml of ether and 3 times with 100 ml of methylene chloride. The organic phases were washed 3 times with 100 ml of water, were dried over magnesium sulfate in the presence of activated carbon and was evaporated to dryness. The residue was taken up in 50 ml of cyclohexane and the mixture was vacuum filtered. The product was dried to obtain 20,200 g of 5-chloro-α,α-dicyclohexyl-2-hydroxybenzene-methanol melting at 230° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@H:15]3[CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[C:4](=[O:27])[C:3]1=[O:28].C(Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@H:15]3[CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:12])=[O:13])=[CH:8][CH:9]=2)[C:4](=[O:27])[C:3]1=[O:28])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)ccc21
Reactant: BrCc1ccccc1
Product: O=C1C(=O)N(Cc2ccccc2)c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)cc21
Yield: 64 %

Procedure:
(S)-1-Benzyl-5-(2-phenoxymethyl-pyrrolidine-1-sulfonyl)-1H-indole-2,3-dione (2) was prepared according to the same procedure for compound 11a, except using benzyl bromide, and purified with hexanes-ether (1:2) to afford 152 mg (64%) of 2 as a yellow solid, mp 97.2-99.1° C. 1H NMR (300 MHz, CDCl3) δ 8.01 (d, J=1.5 Hz, 1H), 7.94 (dd, J=8.4 Hz, J=1.8 Hz, 1H), 7.36 (m, 5H), 7.22 (m, 2H), 6.95-6.79 (m, 4H), 4.92 (s, 2H), 4.15 (dd, J=8.85 Hz, J=2.4 Hz, 1H), 3.97-3.87 (m, 2H), 3.49 (m, 1H), 3.23 (m, 1H), 2.01 (m, 2H), 1.78 (m, 2H). Anal. Calcd for C26H24N2O5S: C, 65.53, H, 5.08; N, 5.88. Found: C, 65.27, H, 5.32; N, 5.58.
Reaction SMILES: [Li]CCCC.[S:6]1[CH2:11][CH2:10][CH2:9][S:8][CH2:7]1.[C:12]1([CH:18]=[CH:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[S:6]1[CH2:11][CH2:10][CH2:9][S:8][CH:7]1[CH:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Reactant: C1CSCSC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CC(c1ccccc1)C1SCCCS1)c1ccccc1
Temperature: -20 °C

Procedure:
n-BuLi (2.5 M in hexanes; 7.50 mL; 18.8 mmol) was added over 2 min to [1,3]dithiane (1.876 g; 15.6 mmol) in dry THF (20 mL) at −78° C. The rxn warmed to −20° C. over 1.5 h then was cooled to −78° C. and chalcone (3.239 g; 15.6 mmol) was added in one portion. After 6 h the rxn was quenched with satd NH4Cl. Aq/organic extractions were followed by partial purification by MPLC (silica eluting with a dichloromethane in hexanes gradient) affording a mixture of [1,2] and [1,4] addition products. 1H NMR (CDCl3; partial spectrum for major product) δ 4.38 (d, J=6.8 Hz, 1H), 3.50 (dd, J=8.2, 17.4 Hz, 1H).
Reaction SMILES: Br[CH:2]([C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=1)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:18][C:19]([NH2:21])=[S:20]>C(O)C>[NH2:21][C:19]1[S:20][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=2)[N:18]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Br)C(=O)c1cccc(C#N)c1
Solvent: CCO
Product: CCOC(=O)c1sc(N)nc1-c1cccc(C#N)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a solution of ethyl 2-bromo-3-(3-cyanophenyl)-3-oxopropionate (2.0 g, 6.75 mmol) in 100 mL of absolute ethanol was added thiourea (0.51 g, 6.75 mmol). The resulting mixture was stirred at 80° C. for 3 h. The reaction was allowed to cool and the solvent was evaporated in vacuo. The residue was taken up in ethyl acetate, washed with saturated aq NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo to yield a solid. Trituration with hexanes/ethyl ether left the title compound as an off-white solid (1.55 g, 65%). 1H NMR (DMSO-d6) δ: 8.03 (s, 1H); 7.93 (s, 2H) ; 7.91 (d, 1H); 7.82 (d, 1H); 7.58 (t, 1H); 4.05 (q, 2H); 1.10 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28]I>O1CCCC1.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)[CH3:28])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNS(=O)(=O)c2ccc(F)cc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 93.9 %

Procedure:
4-(N-((4-Fluorophenyl)sulfonyl)aminomethyl)-1-tert-butoxycarbonylpiperidine (100 mg, 0.27 mmol, from Example 87, Step A) was added to a slurry of sodium hydride (12 mg, 60% in mineral oil, 0.30 mmol) in 5 mL of dry tetrahydrofuran at 0° C. under nitrogen. Methyl iodide (0.022 mL, 0.35 mmol) was then added. The reaction mixture was then allowed to warm to room temperature overnight. The mixture was diluted with diethyl ether and washed with 1N NaOH and brine. The solution was dried over Na2SO4, filtered and concentrated to provide 98 mg (94% yield) of the title compound. ESI−MS. M/z; (M+H)=387.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[NH:7][C:8]([N:17]1[CH2:22][CH2:21][CH:20]([O:23][NH:24][C:25]([C@@H:27]2[CH2:33][CH2:32][C@@H:31]3[CH2:34][N:28]2[C:29](=[O:43])[N:30]3[O:35]CC2C=CC=CC=2)=[O:26])[CH2:19][CH2:18]1)=[N:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:12]([O:11][C:10](=[O:16])[NH:9][C:8]([N:17]1[CH2:18][CH2:19][CH:20]([O:23][NH:24][C:25]([C@@H:27]2[CH2:33][CH2:32][C@@H:31]3[CH2:34][N:28]2[C:29](=[O:43])[N:30]3[OH:35])=[O:26])[CH2:21][CH2:22]1)=[N:7][C:6](=[O:44])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)CC1
Reaction time: 3 h
Yield: 95 %

Procedure:
A mixture of di-tert-butyl[{4-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidin-1-yl}methylylidene]biscarbamate 66 (0.26 g, 0.42 mmol) and Pd/C (0.080 g) in methanol (10 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to provide 67 (0.21 g, 98%) as a white solid.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N:27]([CH2:30][C@@H:31]([O:55][Si:56]([CH2:61][CH3:62])([CH2:59][CH3:60])[CH2:57][CH3:58])[CH2:32][S:33][C:34]1[N:35]=[CH:36][N:37]2[CH:41]=[C:40]([Sn](CCCC)(CCCC)CCCC)[S:39][C:38]=12)=[N+:28]=[N-:29]>>[N:27]([CH2:30][C@@H:31]([O:55][Si:56]([CH2:59][CH3:60])([CH2:61][CH3:62])[CH2:57][CH3:58])[CH2:32][S:33][C:34]1[N:35]=[CH:36][N:37]2[CH:41]=[C:40]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]4[C:7]=3[C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])[S:39][C:38]=12)=[N+:28]=[N-:29]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SC[C@@H](CN=[N+]=[N-])O[Si](CC)(CC)CC)c2s1
Product: CC[Si](CC)(CC)O[C@H](CN=[N+]=[N-])CSc1ncn2cc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Yield: 48.8 %

Procedure:
The procedure of Example 1a) was repeated, except that 582 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.11 g of 7-((2R)-3-azido-2-triethylsilyloxypropyl)thio-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 560 mg of 4-nitrobenzyl (1S,5R,6S)-2-[7-((2R)-3-azido-2-triethylsilyloxypropyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[S:10]([NH:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2)(=[O:12])=[O:11].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[F:8][C:6]1[CH:7]=[C:2]2[C:3]([S:10](=[O:11])(=[O:12])[NH:13][C:14]3[C:15]2=[CH:16][CH:17]=[C:18]2[C:23]=3[N:22]=[CH:21][CH:20]=[CH:19]2)=[CH:4][C:5]=1[CH3:9]
Reactant: Cc1cc(S(=O)(=O)Nc2cccc3cccnc23)c(N)cc1F
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc2c(cc1F)-c1ccc3cccnc3c1NS2(=O)=O
Yield: 15.4 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-4-fluoro-5-methyl-N-quinolin-8-yl-benzenesulfonamide (Intermediate 299) (340 mg, 1.03 mmol), t-butyl nitrite (0.18 ml, 1.54 mmol), AcOH (3.4 ml) and THF (3.4 ml) gave the title compound (50 mg, 15%) after purification by column chromatography with DCM/MeOH (90:10) as the eluent.
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:5][N:4]=1)[NH2:2].[CH3:19][C:20](=O)[CH2:21][CH2:22][C:23](=O)[CH3:24]>C(O)(=O)C>[CH3:24][C:23]1[N:2]([NH:1][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:5][N:4]=2)[C:20]([CH3:19])=[CH:21][CH:22]=1
Reactant: CC(=O)CCC(C)=O
Reactant: NNc1nnc(N2CCOCC2)c2ccccc12
Solvent: CC(=O)O
Product: Cc1ccc(C)n1Nc1nnc(N2CCOCC2)c2ccccc12
Temperature: 65 °C

Procedure:
To 4.9 grams (20 m moles) of 1-hydrazino-4-morpholino phthalazine (prepared from 1,4-dichlorophthalazine) according to the procedure of U.K. Pat. No. 1.157.642; M.p. 255°-260° C.) dissolved in 30 ml of acetic acid, 2.74 g (24 m moles) of 2,5-hexanedione are added and the mixture is heated at 65° C. for 3 hours.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Li+].[Br-].[CH2:14]1CCN2C(=NCCC2)CC1>C(O)C>[CH2:1]([O:2][C:3](=[O:11])[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH3:14]
Reactant: C1CCC2=NCCCN2CC1
Reactant: COC(=O)Cc1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: CCO
Product: CCOC(=O)Cc1ccccc1
Temperature: 25 °C

Procedure:
Following method A, phenylacetic acid methyl ester (4.51 g, 30 mmol) and LiBr (13.03 g, 150 mmol) were dissolved in ethanol (150 ml). DBU (2.28 g, 15 mmol) was added and the reaction mixture was agitated at room temperature for an hour. It was then hydrolysed and processed as described. Vacuum distillation yielded 4.40 g (90% of the theoretical yield) of pure phenylacetic acid ethyl ester, b.p. 65.5-66° C./l Torr.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:9])=O.[NH2:10][C:11]1[N:16]=[N:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([NH:10][C:11]1[N:16]=[N:15][C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:23](=[O:24])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[CH2:21][CH2:22]2)=[CH:13][CH:12]=1)=[O:9]
Reactant: COCCOCC(=O)O
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: COCCOCC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 2, making variations only as required to use (2-methoxyethoxy)acetic acid in place of benzyloxyacetic acid to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (72% yield). 1H NMR (300 MHz, CDCl3) δ 9.53, 8.34, 7.74, 7.63, 7.56, 7.34, 7.02, 4.16, 4.04-3.89, 3.80-3.77, 3.69-3.65, 3.63-3.61, 3.59-3.56, 3.46, 3.34-3.32. MS (ES+) m/z 468.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]([CH:18]2[C:23](=[O:24])[CH2:22][CH2:21][CH2:20][C:19]2=O)=[O:17])=[CH:4][CH:5]=[C:6]2[C:11]=1[S:10](=[O:13])(=[O:12])[CH2:9][CH2:8][C:7]2([CH3:15])[CH3:14].C(Cl)(=O)C([Cl:29])=O>C(Cl)Cl.CN(C)C=O>[Cl:29][C:19]1[CH2:20][CH2:21][CH2:22][C:23](=[O:24])[C:18]=1[C:16]([C:3]1[C:2]([Cl:1])=[C:11]2[C:6]([C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][S:10]2(=[O:13])=[O:12])=[CH:5][CH:4]=1)=[O:17]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C)CCS(=O)(=O)c2c1ccc(C(=O)C1C(=O)CCCC1=O)c2Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)CCS(=O)(=O)c2c1ccc(C(=O)C1=C(Cl)CCCC1=O)c2Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.0 g (5.2 mmol) of 2-(8-chloro-4,4-dimethyl-1,1-dioxothiochroman-7-yl)carbonyl-1,3-cyclohexanedione were dissolved in 30 ml of methylene chloride and 2.2 g (17.3 mmol) of oxalyl chloride and 2 drops of dimethylformamide were added. After 1 hour of stirring at 25° C., the solvent was removed. This gave 2.1 g of colored crystals.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[CH2:11][C@@H:12]([OH:15])[CH2:13][CH3:14])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>O>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[CH2:11][C@@H:12]([O:15][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:25])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH2:13][CH3:14])=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC[C@H](O)CC(=O)Nc1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: c1ccncc1
Product: CC[C@@H](CC(=O)Nc1ccc(C(F)(F)F)cc1)OS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 49 %

Procedure:
To a solution containing 300 mg (1.15 mmol) of (S)-N-[4-(trifluoromethyl)phenyl]-3-hydroxypentanoic acid amide produced in Example 2 and pyridine (0.9 mL), 328.4 mg (1.72 mmol) of 4-methylbenzenesulfonyl chloride was added at 0° C. After stirring at 0° C. for 5 hours and at room temperature for further 5 hours, water (5 mL) was added and the resultant was stirred at room temperature for 2 hours. Extraction was carried out with ethyl acetate and after the organic layer was washed with saturated brine, the product was dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and purifying was carried out on silica gel column chromatography to obtain (S)-N-[4-(trifluoromethyl)phenyl]-3-(4-methylphenyl)sulfonyloxypentanoic acid amide as a white solid (455.1 mg, isolated yield: 49%). 1H-NMR (CDCl3, 400 MHz/ppm): δ 0.86 (3H, t), 1.75-1.82 (2H, m), 2.38 (3H, s), 2.72-2.83 (2H, m), 4.87-4.93 (1H, m), 7.23-7.26 (2H, m), 7.54-7.59 (4H, m), 7.74-7.78 (3H, m)
Reaction SMILES: B(O)O.Br[C:5]1[N:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][CH:6]=1.[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1B(O)O>>[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1[C:5]1[N:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][CH:6]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: O=Cc1cccc(Br)n1
Agent: OBO
Product: O=Cc1cccc(-c2cc3ccccc3o2)n1

Procedure:
6-(benzofuran-2-yl)picolinaldehyde was prepared using the general boronic acid coupling procedure for 6-bromopicolinaldehyde and benzofuran-2-ylboronic acid (41 mg, 120.1 mg theoretical, 34.1%). LC-MS m/z 224.2 (M+1).
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[N:7][C:8](=[O:10])[CH2:9][C:4]2=[CH:3][CH:2]=1.[I:11]N1C(=O)CCC1=O>CN(C=O)C>[I:11][C:3]1[CH:2]=[N:1][N:5]2[C:4]=1[CH2:9][C:8](=[O:10])[N:7]=[CH:6]2
Reactant: O=C1Cc2ccnn2C=N1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: O=C1Cc2c(I)cnn2C=N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
Pyrazolo[1,5-c]pyrimidin-5(4H)-one (1.0 g, 7.4 mM, 1.0 equiv) and N-iodosuccinimide (1.67 g, 7.4 mM, 1.0 equiv) were combined with 20 mL of DMF and warmed slightly. Within minutes a heavy precipitate formed. The reaction mixture was stirred an additional 1 h at ambient temperature then cooled on an icewater bath and filtered. The collected solid was washed with 20 mL of dichloromethane and air dried to give 1.66 g (86%) of 3-iodopyrazolo[1,5-c]pyrimidin-5(4H)-one. LCMS (ESI) m+H=262.2; 1H NMR (400 MHz, DMSO-d6) δ: 12.1 (s, 1H), 8.5 (d, 1H, J=7.6), 7.84 (s, 1H), 6.01 (d, 1H, J=7.1).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[N:7][CH:6]=1)[NH2:4].[F:11][C:12]1[C:20]([F:21])=[C:19]([F:22])[CH:18]=[CH:17][C:13]=1[C:14](Cl)=O.N>>[N:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:4]=[C:14]([C:13]3[CH:17]=[CH:18][C:19]([F:22])=[C:20]([F:21])[C:12]=3[F:11])[O:1][N:2]=2)=[CH:6][N:7]=1
Reactant: NC(=NO)c1ccnnc1
Reactant: O=C(Cl)c1ccc(F)c(F)c1F
Agent: N
Product: Fc1ccc(-c2nc(-c3ccnnc3)no2)c(F)c1F

Procedure:
The titled compound was prepared according to the procedure of Method D using the product of Example 83D and 2,3,4-trifluorobenzoyl chloride (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.40-7.50 (m, J=9.3, 9.3, 7.0, 2.2 Hz, 1 H), 8.10-8.20 (m, 1 H), 8.39 (dd, J=5.4, 2.4 Hz, 1 H), 9.46 (dd, J=5.3, 1.2 Hz, 1 H), 9.87 (dd, J=2.2, 1.2 Hz, 1 H) ppm; MS (DCI/NH3) m/z=279 (M+H)+.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][CH:6]([CH2:9][OH:10])[CH2:5][CH2:4]2)[CH2:2]1.C([O-])(O)=O.[Na+].C([O-])([O-])=O.[K+].[K+].CC1(C)N([O])C(C)(C)CCC1.C1C(=O)N(Cl)C(=O)C1>ClCCl>[CH2:2]1[C:3]2([CH2:8][CH2:7][CH:6]([CH:9]=[O:10])[CH2:5][CH2:4]2)[CH2:1]1
Reactant: OCC1CCC2(CC1)CC2
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: O=CC1CCC2(CC1)CC2
Temperature: 0 °C

Procedure:
To a solution of spiro[2.5]octan-6-ylmethanol (1.83 g, 13 mmo) in dichloromethane (60 mL) was added NaHCO3 (30 mL of a 0.5 M aqueous solution) and K2CO3 (30 mL of a 0.05M aqueous solution) and tehn cooled to 0°C. TEMPO (0.203 g, 1.3 mmol), TBAC1 (0.361 g, 1.3 mmol), and NCS (0.36 g, 1.3 mmol) were added successively, and the reaction mixture was stirred at rt fo(4 h. Using a separation funnel the organic layer was collected and then washed with brine, dried over Na2SO4. The organics were concentrated in vacuo and the crude residue was purified by column chromatography on silica gel with a gradient of 20 to 60% hexane-DCM as eluant to afford the desired product spiro[2.5]octane-6-carbaldehyde. 1H NMR (400 MHz, CDCl3) δ 9.66 (d, J=0.8 Hz, 1H), 2.30 (m, 1H), 1.91-1.88 (m, 2H), 1.67-1.48 (m, 4H), 1.09-104 (m, 2H), 0.31-0.29 (m, 2H), 0.22-0.20 (m, 2H). MS m/z 139.0 (M+1).