Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[O:11][C:12]=2[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4][CH:3]=1.I[CH2:26][CH3:27]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([S:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[O:11][C:12]=2[CH2:13][CH2:14][C:15]([O:17][CH2:26][CH3:27])=[O:16])=[CH:6][CH:7]=1
Reactant: CCI
Reactant: O=C(O)CCc1oc(Sc2ccccn2)nc1-c1ccc(Cl)cc1
Solvent: O
Product: CCOC(=O)CCc1oc(Sc2ccccn2)nc1-c1ccc(Cl)cc1
Yield: 96 %

Procedure:
Water was added to a mixture which was obtained by reacting 4-(4-chlorophenyl)-2-(2-pyridylthio)-5-oxazolepropionic acid with iodoethane in the same manner as Example 52. This was extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried (MgSO4). The residue obtained by evaporated the solvent was subjected to silica gel column chromatography. From the fraction eluted with ethyl acetate-hexane (1:4, v/v), obtained was ethyl 4-(4-chlorophenyl)-2-(2-pyridylthio)-5-oxazolepropionate(yield: 96%) as an oily substance.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[O:14]=[S:15]1(=[O:32])[CH2:20][CH2:19][N:18]2[CH:21]=[CH:22][CH:23]=[C:24]([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[C:17]2=[N:16]1.C(N(CC)CC)C>CN(C=O)C.C(O[Cu]OC(=O)C)(=O)C>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([O:31][C:28]2[CH:27]=[CH:26][C:25]([C:24]3[C:17]4=[N:16][S:15](=[O:32])(=[O:14])[CH2:20][CH2:19][N:18]4[CH:21]=[CH:22][CH:23]=3)=[CH:30][CH:29]=2)=[CH:5][CH:4]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(O)cc3)C2=N1
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccc(C(F)(F)F)cc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.3 %

Procedure:
A mixture of 4-(trifluoromethyl)phenylboronic acid (495 mg), 4-(2,2-dioxido-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (240 mg), diacetoxycopper (316 mg), triethylamine (0.60 mL), and powdered 4A MS (1.5 g) in DMF (10 mL) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (45 mg) as a white solid.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10][CH:11]=1)[CH:3]([OH:5])[CH3:4]>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[C:2]([O:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10][CH:11]=1)[CH:3]([O:5][C:12](=[O:13])[CH3:9])[CH3:4])(=[O:1])[CH3:3]
Reactant: COC(=O)c1ccc(C(O)C(C)O)cn1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc(C(OC(C)=O)C(C)OC(C)=O)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 5-(1,2-dihydroxypropyl)-2-pyridinecarboxylate (6 mg) in pyridine (0.1 ml), acetic anhydride (50 μl) was added at room temperature. After stirring for 1 hour at room temperature, the reaction mixture was evaporated under N2 gas. The residue was applied to a silica gel plate (Kiesselgel GF254, 10×10 cm, Merck trademark) and developed with chloroform-methanol (95:5) to give methyl 5-(1,2-diacetoxypropyl)-2-pyridinecarboxylate: white amorphous powder; molecular formula C14H17NO6 ; LRFAB-MS m/z 296 [M+H]+ ; 1H-NMR (CDCl3) δ 8.68 (1H, d, J=2.2 Hz), 8.16 (1H, d, J=8.1 Hz), 8.03 (1H, dd, J=8.1 and 2.2 Hz), 5.95 (1H, d, J=4.3 Hz), 5.28 (1H, dq, J=6.5 and 4.3 Hz), 3.97 (3H, s), 2.12 (3H, s), 1.99 (3H, s), 1.18 (3H, d,J=6.5 Hz).
Reaction SMILES: [Mg].Br[CH:3]([CH2:5][CH3:6])[CH3:4].[CH3:7][C:8](=[CH:11][CH2:12][CH3:13])[CH:9]=[O:10]>CCOCC>[CH3:7][C:8]([CH:9]([OH:10])[CH:3]([CH3:4])[CH2:5][CH3:6])=[CH:11][CH2:12][CH3:13]
Reactant: CCC=C(C)C=O
Reactant: CCC(C)Br
Agent: [Mg]
Solvent: CCOCC
Product: CCC=C(C)C(O)C(C)CC

Procedure:
A Grignard reagent, prepared by reacting 18.7 g (0.77 g atom) of magnesium in 100 ml of ether and 105.4 g (0.77 mol) of 2-bromobutane in 300 ml of ether, is reacted with 62.72 g (0.64 mol) of 2-methyl-2-pentenal in 200 ml of ether in a manner analogous to Example 5. Fractional distillation of the crude product (98.8 g) over a 20 cm Widmer column gives 68.4 g (68.5%) of olfactorily good 4,6-dimethyl-3-octen-5-ol of boiling point 83° C./12 mm Hg.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH:11]([CH3:13])[CH3:12])[CH:9]=[N:10][C:5]2=[C:4]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:3]=1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[N:29][CH:30]=1>>[F:24][C:25]1[CH:26]=[C:27]([C:2]2[N:7]=[C:6]3[N:8]([CH:11]([CH3:13])[CH3:12])[CH:9]=[N:10][C:5]3=[C:4]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH:3]=2)[CH:28]=[N:29][CH:30]=1
Reactant: CC(C)n1cnc2c(NCCc3ccc(O)cc3)cc(Cl)nc21
Reactant: OB(O)c1cncc(F)c1
Product: CC(C)n1cnc2c(NCCc3ccc(O)cc3)cc(-c3cncc(F)c3)nc21

Procedure:
Following the procedure of Example 161d, 4-(2-(5-chloro-3-isopropyl-3H-imidazo[4,5-b]pyridin-7-ylamino)ethyl)phenol (c) (15 mg, 0.047 mmol) was reacted with 5-fluoropyridin-3-ylboronic acid. The crude residue was purified preparative TLC (1:1 hexanes/ethyl acetate eluant) to afford the title compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[O:17])[CH:11]=[CH:12][C:13]=1[OH:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[O:17])[CH:11]=[CH:12][C:13]=1[O:14][CH2:49][CH2:48][N:47]([CH3:51])[CH3:46]
Reactant: CN(C)CCO
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
To a solution of 1-[3-(4-chloro-2-methyl-2H-pyrazol-3yl)-4-hydroxy-phenyl]-3-(2,4-difluoro-phenyl)urea (see above) (0.035 g, 0.09 mmol) in THF (3 mL), triphenyl phosphine (0.071 g, 0.27 mmol) and 2-dimethylamino ethanol (27.1 μL, 0.27 mmol) were added followed by dropwise addition of diisopropyl azodicarboxylate (DIAD) (52.3 μL, 0.27 mmol). The reaction mixture was stirred at room temperature for 2 hours, concentrated to give a crude product that was purified via preparative HPLC. The corresponding fractions were collected, neutralized with 1N NaOH and extracted with EtOAc. A second purification by flash chromatography (SiO2, CH2Cl2/MeOH gradient elution) afforded Compound 132 as an off-white solid in 45.9% yield. LCMS m/z (%)=450 (M+H 35Cl, 100), 452 (M+H 37Cl, 32). 1H NMR (400 MHz. DMSO-d6) δ: 9.11 (s, 1H), 8.56 (s, 1H), 8.06-8.00 (m, 1H), 7.60 (s, 1H), 7.52 (d, J=8.95 Hz, 1H), 7.38 (s, 1H), 7.33-7.27 (m, 1H), 7.17 (d, J=9.04 Hz, 1H), 7.05-6.98 (m, 1H), 4.12-3.95 (m, 2H), 3.65 (s, 3H), 2.55-2.51 (m, 2H), 2.10 (s, 6H).
Reaction SMILES: O(C)[Na].[Br-].[O:5]1CCCO[CH:6]1[CH2:11][P+](CCCC)(CCCC)CCCC.[CH3:25][O:26][C:27]1[C:34]([O:35][CH3:36])=[CH:33][C:30]([CH:31]=O)=[C:29]([N+:37]([O-:39])=[O:38])[CH:28]=1.O>CN(C=O)C>[CH3:25][O:26][C:27]1[C:34]([O:35][CH3:36])=[CH:33][C:30](/[CH:31]=[CH:11]/[CH:6]=[O:5])=[C:29]([N+:37]([O-:39])=[O:38])[CH:28]=1
Reactant: CCCC[P+](CCCC)(CCCC)CC1OCCCO1
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Agent: CO[Na]
Agent: [Br-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(/C=C/C=O)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.3 %

Procedure:
At room temperature, NaOCH3 (335 mg, 6.19 mmol) was added to a solution of 1,3-dioxan-2-ylmethyltributylphosphoniumbromide (C. Spangler; R. McCoy, Synthetic communications, 18, 51, (1988)) (5.17 ml, 1 M in DMF, 5.71 mmol) and 4,5-dimethoxy-2-nitro-benzaldehyde (1.25 g, 4.76 mmol) in DMF (20 ml). After heating the mixture at 50° for overnight, the mixture was poured over water, and extracted with ether, washed with brine and dried over MgSO4. The solvent was evaporated and the residue was dissolved in THF (100 ml) and treated with 2 N HCl (50 ml). After stirring the mixture at room temperature for 2 h, the THF was evaporated, and the yellow solid was filtered, and suspended in ether/ethylacetate 4:1. The suspension stirred at room temperature for 1 h, filtered and washed with ether to afford (E)-3-(4,5-dimethoxy-2-nitro-phenyl)-propenal (624 mg, 55%) as a yellow solid, m.p. 103-105°. IR (KBr): 1689, 1605 cm-1. MS (EI): 237 (M).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:38][CH2:39][CH2:40][OH:41])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([NH:17][C@@H:18]([CH2:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:19][N:20]([CH3:30])[C:21](=[O:29])[O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.Cl[C:52]([O:54][C:55]1[CH:60]=[CH:59][C:58]([N+:61]([O-:63])=[O:62])=[CH:57][CH:56]=1)=[O:53]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:38][CH2:39][CH2:40][O:41][C:52]([O:54][C:55]2[CH:56]=[CH:57][C:58]([N+:61]([O-:63])=[O:62])=[CH:59][CH:60]=2)=[O:53])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([NH:17][C@@H:18]([CH2:31][CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]3)[CH2:19][N:20]([CH3:30])[C:21](=[O:29])[O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:28])[CH3:26])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN(C[C@H](CC1CCCCC1)NC(=O)N1CCC[C@@H]([C@@H](OCCO)c2cccc(Cl)c2)C1)C(=O)OCC[Si](C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C[C@H](CC1CCCCC1)NC(=O)N1CCC[C@@H]([C@@H](OCCOC(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccc(Cl)c2)C1)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-(trimethylsilyl)ethyl (S)-2-((R)-3-((R)-(3-chlorophenyl)(2-hydroxyethoxy)methyl)piperidine-1-carboxamido)-3-cyclohexylpropyl(methyl)carbamate (0.1880 g, 0.3 mmol, 1.0 equiv), DMAP (0.150 g, 1.2 mmol, 4 equiv), DIEA (1 mL, 6 mmol, 20 equiv), and 4-nitrophenyl chloroformate (0.1346 g, 0.67 mmol, 2.2 equiv) in CH2Cl2 (6 mL) was stirred at rt for 24 h. The reaction mixture was directly used in the next step without further purification. LC-MS (3 min) tR=2.68 min, m/z 777, 775 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][S:6][C:5]2([CH2:11][CH2:10][CH:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8]2)[O:4]1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1.CCOCC>[CH3:28][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:1][CH2:2][CH:3]2[CH2:7][S:6][C:5]3([CH2:11][CH2:10][CH:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8]3)[O:4]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)CC1CCC2(C1)OC(CO)CS2
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)CC1CCC2(C1)OC(COS(=O)(=O)c1ccc(C)cc1)CS2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold stirred solution of the product of Example O (2.60 g, 10 mmol) in pyridine (30 ml) is added p-toluenesulfonyl chloride (1.91 g, 10 mmol) in portions over 15 minutes. When the addition is completed the reaction is stirred at room temperature for 2 hrs. The reaction mixture is diluted with ether and washed with water, 0.5N aqueous sodium bisulfate solution, 5% aqueous sodium bicarbonate solution and water. The organic layer is dried over sodium sulfate, filtered, and the filtrate is concentrated on a rotary evaporator to give the titled compound.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([CH2:9][NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)=O)=[N:4][N:3]=1.O=P(Cl)(Cl)Cl>ClCCCl>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]2=[CH:9][N:10]=[C:11]([C@H:13]3[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]3)[N:4]2[N:3]=1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)NCc2nnc(N)[nH]c2=O)CC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COC(=O)[C@H]1CC[C@H](c2ncc3c(=O)[nH]c(N)nn32)CC1

Procedure:
A solution of methyl trans-4-{[(3-amino-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)methyl]carbamoyl}cyclohexanecarboxylate (2.00 g, 0.00646 mol) in 1,2-dichloroethane (130 mL) was charged with POCl3 (4.2 mL, 0.045 mol) and heated to reflux for 3 h. The reaction mixture was concentrated in vacuo then partitioned between EtOAc and sat. NaHCO3 and separated. The aqueous was re-extracted with EtOAc (3×) and the combined organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo resulting in 1.43 g, (76% yield) of the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (q, J=11.79 Hz, 2H), 1.61 (q, J=12.55 Hz, 2H), 1.85-2.11 (m, 4H), 2.38 (t, J=11.87 Hz, 1H), 2.98 (t, J=11.75 Hz, 1H), 3.61 (s, 3H), 6.17 (br. s., 2H), 7.49 (s, 1H) and 10.90 (br. s., 1H); MS (ES+): m/z 292.25 [MH+].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].I[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>>[N:30]1[CH:31]=[CH:32][C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:28][CH:29]=1
Reactant: Ic1ccncc1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(C#Cc4ccncc4)c3n2)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 4-iodopyridine [CAS 15854-87-2; commercially available] (225 mg, 1.1 mmol) according to general procedure II. Obtained as a yellow solid (92 mg, 21%). MS (ISP) 433.2 [(M+H)+]; mp 252-256° C.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:36])/[CH:23]=[C:24](\[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=2)/[CH:25]([CH3:27])[CH3:26])=[CH:17][CH:16]=1)(=[O:8])=[O:7])(C)(C)C.C(OCC)(=O)C.C([O-])(=O)C.[NH4+:47]>CO>[CH3:27][CH:25](/[C:24](/[C:28]1[CH:29]=[C:30]([C:34]([NH2:35])=[NH:47])[CH:31]=[CH:32][CH:33]=1)=[CH:23]/[C:22](=[O:36])[NH:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6](=[O:8])(=[O:7])[NH2:5])=[CH:20][CH:19]=1)[CH3:26]
Reactant: CC(C)/C(=C/C(=O)Nc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)c1cccc(C#N)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)/C(=C/C(=O)Nc1ccc(-c2ccccc2S(N)(=O)=O)cc1)c1cccc(C(=N)N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
To a solution of crude (2Z)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3-cyanophenyl)-4-methylpent-2-enamide (190 mg, 0.379 mmol) in 10 ml 1:1 ethyl acetate:anhydrous methanol cooled to −78° C. was bubbled HCl gas until saturation was achieved. Reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated in vacuo and dried under hi vacuum. The dried methyl imidate residue was dissolved in 5 ml anhydrous methanol to which ammonium acetate (115 mg, 1.5 mmol) was added and the reaction heated to reflux for 2 hours. The reaction was concentrated and purified on a 2×25 cm Vydac C18 HPLC column to give 3-((1Z)-1-(methylethyl)-2-{N-[4-(2-sulfamoylphenyl)phenyl]carbamoyl}vinyl)benzene carboxamidine (75 mg, 43%) as a fluffy white powder after lyophilization. ES-MS (M+H+): 463.2.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][C@H:14]([C@@H:27]([OH:29])[CH3:28])[C:15]([NH:17][NH:18][C:19](=O)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])=[CH:5][CH:4]=1)#[N:2].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>C1COCC1>[OH:29][C@@H:27]([CH3:28])[C@@H:14]([NH:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:15]1[O:16][C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:18][N:17]=1
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c2ccccc12)C(=O)NNC(=O)c1ccccc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c2ccccc12)c1nnc(-c2ccccc2)o1
Temperature: 25 °C
Yield: 27.9 %

Procedure:
The crude material of N′-((2R,3S)-2-(4-cyanonaphthalen-1-ylamino)-3-hydroxybutanoyl)benzohydrazide (intermediate 13b) (602 mg, 1.5501 mmol) was added to THF (100 mL) stirred at room temperature. PS-BEMP (2.11 g, 4.65 mol base) was added to the solution followed by slow addition of p-TSCl (355 mg, 1.8601 mmol). The reaction mixture was stirred for 2 h and the progress of the reaction was monitored by TLC. After the completion of the reaction the BEMP reagent was filtered off and the solution concentrated to get the crude material. The crude material was chromatographed with hexanes:EtOAc (6:4) to give the product (160 mg, 28%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.11 (d, J=9 Hz, 1H), 8.01 (d, J=9 Hz, 1H), 7.83 (d, J=9 Hz, 2H), 7.69 (d, J=9 Hz, 1H), 7.62 (t, J=9 Hz, 1H), 7.52 (t, J=9 Hz, 1H), 7.45 J=9 Hz, 1H), 7.36 (t, J=9 Hz, 2H), 6.64 (d, J=9 Hz, 1H), 6.20 (d, J=9 Hz, 1H), 4.93 (dd, J=5.0, 9.0 Hz, 1H), 4.70 (m, 1H), 4.06 (d, J=5 Hz, 1H), 1.47 (d, J=6 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21]2([OH:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:40].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:40][C:9]1[C:8]2[N:17]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:18][CH2:19][CH2:20][C:21]3([OH:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCCC1(O)CCCCC1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCC1(O)CCCCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 53 %

Procedure:
To a solution of 1-{3-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}cyclohexanol (1.10 g, 2.99 mmol) in chloroform (15 mL) at rt was added m-CPBA (0.96 g, 3.89 mmol) in portions. The reaction was stirred for 1.5 h, then was cooled to 0° C. and concentrated ammonium hydroxide (5 mL) was added followed by portionwise addition of p-toluenesulfonyl chloride (0.630 g, 3.29 mmol). The mixture was stirred at 0° C. for 1 h, then was filtered. The filtrate was diluted with dichloromethane (30 mL) and saturated aqueous sodium bicarbonate (30 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (20 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated to afford an orange solid, which was purified by HPFC (silica gel, eluted with 0-35% CMA/chloroform). The appropriate fractions were concentrated to afford a tan solid that was crystallized from chloroform/hexanes and dried at 75° C. under vacuum to afford 1-{3-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}cyclohexanol as white crystals (600 mg, 53%), mp 175-176° C. Anal. calcd for C22H30N4O2: C, 69.08; H, 7.91; N, 14.65.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[S:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])=[N:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.Br[CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].O>CN(C=O)C>[Si:33]([O:32][CH2:31][CH2:30][NH:2][C@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[S:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])=[N:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@H]4N)s2)cc1C#N
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@H]4NCCO[Si](C)(C)C(C)(C)C)s2)cc1C#N
Temperature: 95 °C
Reaction time: 12 h
Yield: 15.6 %

Procedure:
Prepared using General Procedure 9. To a suspension of (R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 5 (50 mg, 0.12 mmol) in anhydrous DMF (5 mL) was added TEA (36.7 mg, 0.36 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (34.6 mg, 0.14 mmol). The solution was stirred at 95° C. After 16 h more (2-bromoethoxy)(tert-butyl)dimethylsilane (34.6 mg, 0.14 mmol) was added and heating continued for 12 h. Water (5 mL) was added and the reaction mixture was extracted with EA (2×5 mL). The organic layers were washed with brine, dried, and purified by column chromatography (EA/hexanes) to afford 10 mg (15%) of (R)-5-(5-(1-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile. LCMS-ESI (m/z) calculated for: C29H38N4O2SSi: 534.3; found 535.3 [M+H]+, tR=3.08 min.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[C:6]([CH3:12])=[N:7]2.[Br:20]N1C(C)(C)C(=O)N(Br)C1=O.C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:20][CH2:12][C:6]1[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[N:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])[N:7]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Cc1nc2cccc(Cl)c2nc1-c1cccc(F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cccc(-c2nc3c(Cl)cccc3nc2CBr)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-chloro-3-(3-fluorophenyl)-2-methylquinoxaline (0.3907 g, 1.433 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (0.2458 g, 0.8596 mmol) were suspended in carbon tetrachloride (14.33 mL, 1.433 mmol). To the mixture was added benzoyl peroxide (0.04627 g, 0.1433 mmol) and the mixture was heated at reflux. After 24 h, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 9% gradient of EtOAc in hexane over 1.3 min, then 9% isocratic of EtOAc for 7.6 min, then 9 to 100% gradient of EtOAc in hexane over 12.7 min, then 100% isocratic of EtOAc for 10 min as eluent to give 2-(bromomethyl)-5-chloro-3-(3-fluorophenyl)quinoxaline as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (1 H, dd, J=8.4, 1.2 Hz), 8.12 (1 H, dd, J=7.6, 1.4 Hz), 7.92 (1 H, dd, J=8.4, 7.8 Hz), 7.64-7.70 (3 H, m), 7.43-7.50 (1 H, m), 4.91 (2 H, s); LC-MS (ESI) m/z 351.0 and 352.9 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[C:13]=1[F:26].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[C:13]=1[F:26]
Reactant: Cc1cc(CNc2c(F)ccc(O)c2C)c(F)c(-c2cccc(F)c2)c1
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2C)c(F)c(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
To a solution of 4-fluoro-3-[[2-fluoro-3-(3-fluorophenyl)-5-methyl-phenyl]methylamino]-2-methyl-phenol (180 mg, 0.5 mmol, 1.0 eq) in DMF (3 mL) was added Cs2CO3 (246 mg, 0.75 mmol, 1.5 eq). The reaction was stirred for 30 min at room temperature then isopropyl 2-bromoacetate (99 mg, 0.55 mmol, 1.1 eq) was added. The reaction was stirred a further h then diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 1:0 to 25:1) to give the title compound as a colorless oil (100 mg, 43%).