Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:21]([CH3:23])([CH3:22])[NH:20][CH2:19][CH2:18][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:32](Cl)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[CH2:32]([O:16][C:15]1[C:14](=[O:17])[N:13]2[CH2:18][CH2:19][NH:20][C:21]([CH3:22])([CH3:23])[C:12]2=[N:11][C:10]=1[C:8]([NH:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:25][CH:24]=1)=[O:9])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC1(C)NCCn2c1nc(C(=O)NCc1ccc(F)cc1)c(O)c2=O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)NCCn2c1nc(C(=O)NCc1ccc(F)cc1)c(OCc1ccccc1)c2=O
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N-(4-fluorobenzyl)-3-hydroxy-9,9-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrazino[1,2-a]pyrimidine-2-carboxamide (see Example 1) in DMF was added K2CO3 (2 eq.) followed by BnCl (1.1 eq.). The mixture was stirred at 65° C. overnight, after which time additional BnCl (0.3 eq.) was added and the mixture was left for a further 6 hours. The solvent was removed under reduced pressure and the brown oil was taken into EtOAc, washed with 1N HCl and brine, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography, eluting with 2% MeOH/DCM to afford the title product. 1H NMR (300 MHz, d6-DMSO) δ 8.88 (t, J=6.2 Hz, 1H), 7.30-7.44 (m, 7H), 7.06 (t, J=8.8 Hz, 2H), 5.05 (s, 2H), 4.41 (d, J=6.2 Hz, 2H), 3.80 (t, J=5.4 Hz, 2H), 3.09 (br. s, 2H), 1.44 (s, 6H); MS (ES) C24H25FN4O3 requires 436. Found: 437 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:5][CH:4]=1.[CH:23]1([CH:26]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([OH:39])[CH:33]=2)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH:23]1([CH:26]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([O:39][CH2:2][C:3]3[CH:4]=[CH:5][C:6]([C:14]4[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=4[F:22])=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:8]=3)[CH:33]=2)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH2:25]1
Reactant: COc1ccc(F)c(-c2ccc(CCl)nc2CC(C)(C)C)c1
Reactant: COC(=O)CC(c1ccc(F)c(O)c1)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)CC(c1ccc(F)c(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1)C1CC1
Yield: 82.7 %

Procedure:
To a solution of 6-(chloromethyl)-2-(2,2-dimethylpropyl)-3-(2-fluoro-5-methoxyphenyl)pyridine (320 mg) in acetonitrile (30 mL) were added methyl 3-cyclopropyl-3-(4-fluoro-3-hydroxyphenyl)propanoate (220 mg) and cesium carbonate (550 mg), and the mixture was heated under reflux for 15 hr. The reaction mixture was concentrated, and water was added to the residue. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (400 mg) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12](O)[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(Br)(Br)(Br)[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCCCC>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH:12]([Br:16])[CH3:13])[CH:3]=1
Reactant: CC(O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(Br)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (±)-1-(3-bromo-5-(trifluoromethyl)phenyl)ethanol (390 mg, 1.45 mmol) and carbon tetrabromide (577 mg, 1.74 mmol) in tetrahydrofuran (2 mL) at 0° C. was added triphenylphosphine (456 mg, 1.74 mmol). The resulting solution was stirred at room temperature for 2 h. The reaction was treated with an additional portion of carbon tetrabromide (289 mg, 0.87 mmol)) and triphenylphosphine (228 mg, 0.87 mmol). The reaction was stirred at room temperature for 1 h, diluted with several volumes of pentane, and filtered to remove undissolved solids. The organics were concentrated and purified by column chromatography (1→3% ethyl acetate/hexanes) to give 439 mg (91%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ ppm 7.76 (s, 1H), 7.68 (s, 1H), 7.60 (s, 1H), 5.12 (q, J=7.0 Hz, 1H), 2.03 (d, J=7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 146.4, 133.5, 132.9 (q, J=32.6 Hz), 128.4 (q, J=3.8 Hz), 123.0, 123.0 (q, J=273 Hz), 122.6 (q, J=3.8 Hz), 46.1, 26.6.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[O:7]=[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])N1C(OCC)=O>C1COCC1>[OH:6][CH2:5][CH2:4][CH2:3][CH2:2][N:1]1[C:8](=[O:7])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:17]
Reactant: NCCCCO
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCCO
Temperature: 25 °C
Yield: 67.8 %

Procedure:
A solution of 4-aminobutan-1-ol (18 g, 201.94 mmol, 1.00 equiv), ethyl 1,3-dioxo-2,3-dihydro-1H-isoindole-2-carboxylate (44.5 g, 203.02 mmol, 1.01 equiv) and TEA (28 g, 276.71 mmol, 1.37 equiv) in 500 mL of THF was heated to reflux overnight. The reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. The solids were filtered out and the filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with PE/EtOAc (10:1 to 1:1) to give 30 g (68%) of 2-(4-hydroxybutyl)-2,3-dihydro-1H-isoindole-1,3-dione as a white solid. MS (ES): m/z 220 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:3]=2)[NH:7][CH:6]=1
Reactant: Clc1ncccn1
Reactant: CN(C)CCc1c[nH]c2ccc(N)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)CCc1c[nH]c2ccc(Nc3ncccn3)cc12
Yield: 11 %

Procedure:
5-Amino-3-(2-dimethylaminoethyl)-1H-indole and 2-chloropyrimidine were used, Sodium acetate was used as base, acetic acid was used as solvent, and the reaction was heated at reflux for 12 hours. Column chromatography afforded the title compound (11%) as a yellow solid: 13C NMR (CD3OD) δ162.6, 159.2, 135.4, 132.2, 128.9, 124.0, 118.6, 113.7, 112.6, 112.4, 112.3, 61.3, 45.4, 24.3; HRMS calculated for C16H19N5 281.1642, found 281.1660. Anal. calcd for C16H19N5.0.5C2H4O2 [acetic acid]: C, 65.62; H, 6.80; N, 22.51. Found: C, 65.74; H, 6.68; N, 22.60.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:11][N:12]2[CH:17]([C:18](=[O:22])[CH:19]=[N+]=[N-])[CH2:16][N:15]([CH3:23])[C:14](=[O:24])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:30]>CCOCC.C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:11][N:12]2[CH:17]([C:18](=[O:22])[CH2:19][Cl:30])[CH2:16][N:15]([CH3:23])[C:14](=[O:24])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl
Reactant: CCOC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2C(=O)C=[N+]=[N-]
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2C(=O)CCl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of ethyl 3-benzyloxy-7-diazoacetyl-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (90 mg, 0.226 mmol) in Et2O (5 mL) and anhydrous CH2Cl2 (5 mL) was added 1.0M HCl in Et2O (272 μL, 0.272 mmol). The reaction was stirred at room temperature for 15 minutes, and the solvent was removed in vacuo to afford the title product as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 7.49-7.48 (m, 2H), 7.39-7.30 (m, 3H), 7.12 (br s, 1H), 6.03 (s, 1H), 5.57 (s, 1H), 5.22 (dd, J=11.4, 26.0 Hz, 2H), 4.28-4.24 (m, 2H), 4.09 (dd, J=4.6, 13.4 Hz, 1H), 3.88 (dd, J=4.6, 13.4 Hz, 1H), 2.98 (s, 3H), 1.26 (t, J=7.2, 3H); ES MS (M+Na)=428.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:3]=1.[N+:17]([O-])([O-:19])=[O:18].[K+].Cl>OS(O)(=O)=O.[OH-].[Na+]>[OH:12][C:11]1[C:2]([OH:1])=[N:3][C:4]2[C:9](=[CH:8][C:7]([C:13]([F:16])([F:14])[F:15])=[C:6]([N+:17]([O-:19])=[O:18])[CH:5]=2)[N:10]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Oc1nc2ccc(C(F)(F)F)cc2nc1O
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc2nc(O)c(O)nc2cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
A solution of 1 g (4.4 mmol) 2,3-dihydroxy-6-trifluoromethylquinoxaline in 10 ml concentrated H2SO4 is ice-cooled and 438 mg (4.4 mmol) KNO3 is added. The mixture is stirred at 0° C. for 0.5 and at 24Z° C. for 3 h. The reaction mixture is poured into ice-water to give 1.02 g. The crude product is dissolved in 2N NaOH. Addition of 4N HCl to pH 5 gives 0.86 g (72%) 2,3-dihydroxy-6-nitro-7-trifluoromethylquinoxaline, m.p. >300° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]3[N:12]([CH:14]=[N:15][N:16]=3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[CH3:17][C:9]1[C:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[NH:1][C:18](=[O:20])[CH3:19])=[N:13][N:12]2[CH:14]=[N:15][N:16]=[C:11]2[CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc2nncn2nc1-c1cccc(N)c1
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(-c2nn3cnnc3cc2C)c1

Procedure:
A 1.5 g. portion of 6-(m-aminophenyl)-7-methyl-1,2,4-triazolo[4,3-b]pyridazine (prepared as in Example 6) is dissolved in 30 ml. of pyridine at room temperature. To the solution is added 6.0 ml. of acetic anhydride and the reaction mixture is heated on a steam bath for 1 hour. The reaction mixture is cooled in an ice bath and is filtered. The filter cake is washed with petroleum ether and is dried to afford the product of the example as cream colored crystals, m.p. 298°-301° C.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C@H:16]([CH2:24][OH:25])[O:15][C:14]3=[O:26])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH:29]([N:32]=[C:33]=[O:34])([CH3:31])[CH3:30].O.C(OCC)(=O)C>CN(C=O)C>[CH:29]([NH:32][C:33](=[O:34])[O:25][CH2:24][C@@H:16]1[O:15][C:14](=[O:26])[N:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:28][CH:27]=3)=[CH:12][CH:11]=2)[C@H:17]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:31])[CH3:30]
Reactant: O=C1O[C@@H](CO)[C@H](c2ccccc2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CC(C)N=C=O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)OC[C@@H]1OC(=O)N(c2ccc(Oc3ccc(Cl)cc3)cc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.8 %

Procedure:
To (4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(hydroxymethyl)-4-phenyloxazolidin-2-one (33 mg, 0.08 mmol) in 0.3 mL DMF was added isopropyl isocyanate (0.015 mL, 0.16 mmol). The reaction was stirred for 3 h at room temperature until reaction completed as judged by TLC. Water and ethyl acetate were added and the phases separated. The organic phase was washed with brine, dried (MgSO4), and concentrated. 13 mg (33%) of the title compound was obtained as a white solid after Prep-LC purification (10-90 Acetonitrile/water (0.05% ammonium acetate). 1H NMR (CDCl3) δ (ppm) 7.30-7.39 (m, 7H), 7.23-7.26 (m, 2H), 6.84-6.90 (m, 4H), 5.14 (d, 1H, J=5.6 Hz), 4.67 (d, 1H, J=7.2 Hz), 4.34-4.53 (m, 3H), 3.77-3.85 (m, 1H), 1.17 (d, 3H, J=6.5 Hz), 1.13 (d. 3H, J=6.5 Hz). HPLC-MS calculated C26H25ClN2O5 (M+H+): 481.2, found: 481.1.
Reaction SMILES: C(OC([O:11][C:12]1([CH2:47][CH3:48])[C:17]2[CH:18]=[C:19]3[N:27]([C:28](=[O:29])[C:16]=2[CH2:15][O:14][C:13]1=[O:46])[CH2:26][C:25]1[C:24]([CH2:30][CH2:31][Si:32]([CH3:41])([CH3:40])[CH2:33][CH2:34][CH2:35][O:36][C:37](=[O:39])[CH3:38])=[C:23]2[CH:42]=[CH:43][CH:44]=[CH:45][C:22]2=[N:21][C:20]3=1)=O)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH2:47]([C:12]1([OH:11])[C:17]2[CH:18]=[C:19]3[N:27]([C:28](=[O:29])[C:16]=2[CH2:15][O:14][C:13]1=[O:46])[CH2:26][C:25]1[C:24]([CH2:30][CH2:31][Si:32]([CH3:40])([CH3:41])[CH2:33][CH2:34][CH2:35][O:36][C:37](=[O:39])[CH3:38])=[C:23]2[CH:42]=[CH:43][CH:44]=[CH:45][C:22]2=[N:21][C:20]3=1)[CH3:48]
Reactant: [H][H]
Reactant: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCOC(C)=O
Agent: [Pd]
Solvent: CCO
Product: CCC1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCOC(C)=O

Procedure:
A mixture of Compound 59 (180 mg, 0.27 mmol), 10% palladium on carbon (36 mg, 20%) in 6 mL of ethanol was hydrogenated for 18 hours at a balloon pressure of hydrogen at 21° C. The catalyst was removed by filtration over celite and the filtrate was evaporated to give a crude product, which was chromatographed to give the desired product.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)#[CH:17]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[I:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]#[C:16][C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)=[CH:3][CH:4]=1
Reactant: C#Cc1ccc(N)cc1
Reactant: Ic1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(C#Cc2ccc(I)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 354.1 %

Procedure:
1,4-Diiodobenzene (4.95 g, 1.0 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.07 g, 0.10 mmol), copper(I) iodide (0.019 g, 0.10 mmol), triethylamine (5 mL), THF (10 mL) and 4-ethynylaniline 0.585 g, 5.00 mmol) were used following the general procedure for couplings. For the synthesis of 4-ethynylaniline, please see Tour et al. Chem. Eur. J. 2001, vol. 7, pp. 5118-5134 incorporated herein by reference. The tube was capped and stirred room temperature for 12 h. Flash column chromatography (CH2Cl2—hexanes as eluent) afforded the desired product as light yellow needles (1.13 g, 71% yield). IR (KBr) 3441, 3356, 2210, 1612, 1515, 1281, 1135, 1003, 842, 811, 512 cm−1. 1H NMR (400 MHz, CDCl3) δ 7.650 (m, AA′ part of AA′XX′ pattern, J=8.7, 2.4, 1.8, 0.7 Hz, 2H), 7.324 (m, XX′ part of AA′XX′ pattern, J=8.7, 2.4, 1.8, 0.7 Hz, 2H), 7.208 (m, AA′ part of AA′XX′ pattern, J=8.6, 2.4, 1.8, 0.6 Hz, 2H), 6.630 (m, XX′ part of AA′XX′ pattern, J=8.6, 2.4, 1.8, 0.6 Hz, 2H), 3.833 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 147.05, 137.60, 133.20, 133.07, 123.67, 114.95, 112.39, 93.45, 91.83, 86.69.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1.[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([C:7]2[CH:2]=[CH:3][C:4]([C:21]([F:24])([F:23])[F:22])=[C:5]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][C@H:11]3[CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:9])[CH:6]=2)=[CH:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: O=C(c1ccc(Br)cc1C(F)(F)F)N1CCC[C@H]1CN1CCCC1
Product: CS(=O)(=O)c1ccc(-c2ccc(C(F)(F)F)c(C(=O)N3CCC[C@H]3CN3CCCC3)c2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Example 14 via Procedure F′ from (4-bromo-2-trifluoromethyl-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 4-methanesulfonylbenzene boronic acid (CAS 149104-88-1). MS (FIA) 481 (MH+)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24]([O:26]C)=[O:25])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[OH-].[Li+]>O1CCCC1.O>[NH2:1][C:2]1[C:3]([C:24]([OH:26])=[O:25])=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([N:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)(=[O:16])=[O:15])=[CH:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(-c2ccc(S(=O)(=O)N3CCN(C)CC3)cc2)cnc1N
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(S(=O)(=O)c2ccc(-c3cnc(N)c(C(=O)O)n3)cc2)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
Methyl 3-amino-6-[4-[(4-methyl-1-piperazinyl)sulfonyl]phenyl]pyrazine-2-carboxylate was dissolved in anhydrous tetrahydrofuran (10 mL). Lithium hydroxide (0.113 g, 4.72 mmol) in water (19 mL) was added at room temperature and the resulting mixture was stirred at 50° C. for 3 h. The tetrahydrofuran was evaporated and the pH of the water phase was adjusted to 6 with HCl (aq). The precipitated product was filtered and washed with water and dried to give 0.763 g (86% yield) of the title compound as a pale yellow solid: 1HNMR (TFA) δ 8.83 (s, 2H), 8.23 (m, 2H), 7.97 (m, 2H), 4.09 (m, 2H), 3.76 (m, 2H), 2.25 (m, 2H), 3.04 (m, 5H); 13CNMR (TFA) δ 165.81, 147.39, 139.5, 139.2, 135.7, 132.1, 131.1, 128.5, 127.3, 53.9, 43.5, 43.2; MS (ESP) m/z 378 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][CH2:8][CH:9]=[CH:10][CH2:11][C@@H:12]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([CH3:32])[CH:26]=2)[C:13]([N:15]2[C@@H:19]([CH:20]([CH3:22])[CH3:21])[CH2:18][O:17][C:16]2=[O:23])=[O:14])=[CH:4][C:3]=1[CH3:35]>C1C=CC=CC=1>[F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([CH3:32])[CH:26]=2)[C:13]([N:15]2[C@@H:19]([CH:20]([CH3:21])[CH3:22])[CH2:18][O:17][C:16]2=[O:23])=[O:14])=[CH:4][C:3]=1[CH3:35]
Reactant: Cc1cc(COCC=CC[C@@H](Oc2ccc(F)c(C)c2)C(=O)N2C(=O)OC[C@@H]2C(C)C)ccc1F
Solvent: c1ccccc1
Product: Cc1cc(COCCCC[C@@H](Oc2ccc(F)c(C)c2)C(=O)N2C(=O)OC[C@@H]2C(C)C)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
(S)-3-((R)-6-(4-fluoro-3-methylbenzyloxy)-2-(4-fluoro-3-methylphenoxy)hex-4-enoyl)-4-isopropyloxazolidin-2-one (430 mg, 0.88 mmol) was dissolved into 4 mL benzene and to it added Wilkinson catalysis (81.0 mg, 0.088 mmol). The solution was saturated with H2 (stream of H2 bubbled through solution) and then stirred for 8 h at room temperature under an atmosphere of hydrogen balloon. The solvent was removed under reduced pressure and the product isolated by flash column chromatography eluting with 0% to 30% ethyl acetate/hexane to give 418 mg of the title compound as a colorless oil.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([Cl:20])=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[C:26]([F:31])[CH:25]=1>C1CCCCC1>[ClH:20].[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:28][C:27]3[CH:29]=[CH:30][C:24]([Cl:23])=[CH:25][C:26]=3[F:31])=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: C1CCCCC1
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ccnc2cc1OCc1ccccc1
Yield: 20.9 %

Procedure:
A mixture of 7-benzyloxy-4-chloro-6-methoxyquinoline hydrochloride (300 mg, 0.89 mmol), (prepared as described for the starting material in Example 3), and 4-chloro-2-fluoroaniline (160 mg, 1.1 mmol) was heated at reflux in cyclohexane (20 ml) for 24 hours. The solvent was removed by evaporation and the residue was triturated with ether. The solid crude product was collected by filtration and purified by column chromatography eluting with methylene chloride/methanol (100/0 increasing to 95/5) to give 7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-methoxyquinoline hydrochloride (83 mg, 21%).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:21][C:22]([F:46])([O:27][C:28]([F:45])([F:44])[C:29]([F:43])([F:42])[O:30][C:31]([F:41])([F:40])[CH2:32][O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]Br)[C:23]([F:26])([F:25])[F:24]>O>[CH2:1]([O:7][C:8]1[CH:13]=[N:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:33][CH2:32][C:31]([O:30][C:29]([F:42])([F:43])[C:28]([F:44])([F:45])[O:27][C:22]([F:21])([F:46])[C:23]([F:24])([F:25])[F:26])([F:41])[F:40])=[CH:18][CH:19]=2)=[N:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: FC(F)(COCCCCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F
Reactant: CCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Solvent: O
Product: CCCCCCOc1cnc(-c2ccc(OCCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-hexyloxy-2-(4-hydroxyphenyl)pyrimidine (2.26 g, 8.3 mmol) with 5-(2-(2-(pentafluoroethoxy) tetrafluoroethoxy)-2,2-difluoroethoxy)-1-bromopentane (4.08 g, 8.3 mmol; prepared by combining 1,5-dibromopentane with 2-(2-(pentafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethanol). Product was isolated by addition of water (160 mL) to the resulting mixture, followed by filtration and recrystallization from ethanol. The recrystallized precipitate was dried at about 130° C., and the resulting product was further purified by Kugelrohr distillation (b.p. 190°-205° C. at 0.3 torr; yield of 15.2 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:13]C(=O)OC(C)(C)C)[CH:8]=[C:9]([C:11]#[N:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>Cl.O1CCOCC1>[NH2:13][C:7]1[CH:8]=[C:9]([CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1)[C:11]#[N:12]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(C(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(N)cc(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 186.8 %

Procedure:
A solution of tert-butyl (3-tert-butyl-5-cyanophenyl)carbamate (4.29 g, 0.0133 mol) in 4M HCl in dioxane (18 mL) was allowed to stir at rt for 2 h. The reaction mixture was concentrated to give 3-amino-5-tert-butylbenzonitrile (4.33 g, 93%) which was used without further purification. 1H NMR (300 MHz, CD3OD) δ: 7.99 (m, 1H), 7.72 (m, 1H), 7.56 (m, 1H), and 1.37(s, 9H). LCMS ES+ 175.1, ES− 173.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[S:10])[NH2:9])[CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.CI.[CH3:15]C(C)=O.CCCCCC>C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([S:10][CH3:15])=[NH:9])[CH:5]=[C:4]([O:11][CH3:12])[N:3]=1
Reactant: CC(C)=O
Reactant: COc1cc(C(N)=S)cc(Cl)n1
Solvent: CCCCCC
Solvent: CI
Solvent: CCOCC
Product: COc1cc(C(=N)SC)cc(Cl)n1
Temperature: 25 °C

Procedure:
In a 100-mL, 3N round-bottomed flask equipped with Thermometer pocket fitted with water condenser, nitrogen inlet and a rubber septum, 2-chloro-6-methoxypyridine-4-carbothioamide (0.58 g, 1.0 eq.), methyl iodide (0.89 mL, 5.0 eq.) was dissolved in diethyl ether (60 mL) resulting reaction mixture was stir at RT. The progress of the reaction was followed by TLC analysis on silica gel with 20% acetone: hexane as mobile phase which shows that starting material was consumed after 15 h. Precipitate was observed that was collected by filtration on Buchner funnel. Solid was separated and compound was collected by filtration on a Buchner funnel and washed with hexane (100 mL); Yield: 0.257 g (41.44%); LCMS (%): 27.07% [M+H]+ 217.92 RT: 4.216 min. (Crude).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][NH:6][CH:7]1[CH:12]2[CH2:13][CH2:14][CH:8]1[CH2:9][CH:10]([C:15]1[NH:23][C:22]3[C:21](=[O:24])[N:20]([CH2:25][CH2:26][CH3:27])[C:19](=[O:28])[N:18]([CH2:29][CH2:30][CH3:31])[C:17]=3[N:16]=1)[CH2:11]2)C.[OH-].[K+]>CO.C1COCC1>[O:28]=[C:19]1[N:18]([CH2:29][CH2:30][CH3:31])[C:17]2[N:16]=[C:15]([CH:10]3[CH2:11][CH:12]4[CH:7]([NH:6][CH2:5][C:4]([OH:32])=[O:3])[CH:8]([CH2:14][CH2:13]4)[CH2:9]3)[NH:23][C:22]=2[C:21](=[O:24])[N:20]1[CH2:25][CH2:26][CH3:27]
Reactant: CCCn1c(=O)c2[nH]c(C3CC4CCC(C3)C4NCC(=O)OCC)nc2n(CCC)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C3CC4CCC(C3)C4NCC(=O)O)nc2n(CCC)c1=O

Procedure:
[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.2.1]oct-8-ylamino]-acetic acid ethyl ester (Example 40a) was hydrolyzed using 1N KOH in MeOH/THF. Mass (ES+418)