Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH2:25]([O:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)[CH2:26][CH3:27]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([O:28][CH2:25][CH2:26][CH3:27])[CH:34]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CCCOc1cccc(B(O)O)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CCCOc1cccc(-c2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)c1
Yield: 16 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 3-propoxy phenyl boronic acid (47 mg, 0.26 mmol) to give the title compound (10 mg, 16%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][NH:8][C:9]2[C:10]([N+:24]([O-])=O)=[C:11]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1.[CH3:29]O>[Ni]>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:9]3=[N:19][C:18]([C:20]([F:23])([F:22])[F:21])=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]3[N:24]=[CH:29]2)=[CH:5][CH:4]=1
Reactant: CO
Reactant: CCOC(=O)c1cc(C(F)(F)F)nc(NCc2ccc(OC)cc2)c1[N+](=O)[O-]
Agent: [Ni]
Product: CCOC(=O)c1cc(C(F)(F)F)nc2c1ncn2Cc1ccc(OC)cc1
Temperature: 150 °C
Reaction time: 6 h
Yield: 60 %

Procedure:
Ethyl 2-[(4-methoxybenzyl)amino]-3-nitro-6-(trifluoromethyl)isonicotinate x193 (2.6 g, 6.5 mmol) is dissolved in methanol (100 ml), and Raney nickel (0.8 g) is added. The starting compound is hydrogenated in a Parr apparatus under a hydrogen pressure of 3 atm until the conversion of x193 is complete (1.5-2 h). The catalyst is filtered off and washed with methanol. The filtrate is evaporated to dryness. Triethyl orthoformate (100 ml) and p-toluene sulfonic acid (0.15 g) are added. The flask is equipped with a reflux condenser. The apparatus is flushed with argon, and the obtained reaction mixture is heated under vigorous stirring to 150° C. for 6 h. The reaction solution is evaporated in vacuum. The residue is partitioned between dichloromethane and a saturated aqueous solution of NaHCO3. The organic layer is dried with anhydrous sodium sulfate and evaporated. The target product is purified by chromatography on silicagel (dichloromethane/acetone) to afford 1.5 g of ethyl 3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine-7-carboxylate x196.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:2].C(N(C(C)C)CC)(C)C.[C:20](Cl)([Cl:22])=[O:21]>C(Cl)Cl>[CH2:1]([N:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:20]([Cl:22])=[O:21])[CH3:2]
Reactant: CCNCc1ccccc1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1ccccc1)C(=O)Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
N-Ethylbenzylamine (0.56 mL, 3.8 mmol) and diisopropylethylamine (1 mL, 5.7 mmol) were combined in CH2Cl2 (12 mL) and cooled to 0° C. Phosgene (20% in toluene; 2.4 mL, 4.6 mmol) was added, and the reaction was stirred overnight at room temperature. The mixture was concentrated, and the residue was dissolved in Et2O and washed twice with H2O. The organic layer was dried, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:28])[C@@H:10]([CH2:19][O:20]CC1C=CC=CC=1)[NH:11]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>ClCCl>[CH2:1]([NH:8][C:9](=[O:28])[C@@H:10]([CH:19]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:20])[NH2:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)NCc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: N[C@@H](C(=O)NCc1ccccc1)C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 124.4 %

Procedure:
To a solution of N-benzyl-O-benzyl-N2-Boc-D-serinamide (1 g) and dichloromethane (5 mL), aq.HCl (35%) (5 mL) was added. The solution was stirred for 2 hours at room temperature for completion of reaction. The solution was concentrated under vacuum to remove dichloromethane and subsequently water was added. The aqueous layer was basified to pH 8-10 with 5% sodium hydroxide. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with brine solution. Organic layer was concentrated under vacuum to obtain an oily residue 0.46 g of N-benzyl-β-benzyl-D-serinamide.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.Cl.[NH:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1)[NH2:15]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[N:15][NH:14][C:16]3[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:23])=[O:24])=[CH:18][CH:17]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Br)ccc2C1=O
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3cc(Br)ccc32)cc1

Procedure:
The title compound was prepared from 6-bromo-1H-indole-2,3-dione(Meth-Cohn and Goon, Tetrahedron Letters 1996, 37, 9381-4) and 4-hydrazinobenzenesulfonamide hydrochloride according to Procedure G: mp>250° C.; 1H NMR (DMSO-d6): δ 7.05 (s, 1H), 7.23 (d, J=8.1 Hz, 1H), 7.50 (d, J=8.1 Hz, 1H), 7.56 (d, J=8.7 Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 11.2 (s, 1H), 12.7 (s, 1H); APCI−MS m/z 395 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-].C(C1C=C[N:20]=[C:19](CN)C=1)(C)C>>[CH3:1][C:2]1[N:3]=[C:4]([C:19]#[N:20])[CH:5]=[CH:6][C:7]=1[CH2:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: Cc1c(CS(C)(=O)=O)ccc[n+]1[O-]
Reactant: CC(C)c1ccnc(CN)c1
Product: Cc1nc(C#N)ccc1CS(C)(=O)=O

Procedure:
6-methyl-5-(methylsulfonylmethyl)picolinonitrile was synthesized from 2-methyl-3-(methylsulfonylmethyl)pyridine N-oxide following the general procedure as described for the 4-isopropyl-2-pyridylmethylamine.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([C@H:11]1[O:13][CH2:12]1)[Cl:10]>>[CH2:1]([NH:8][CH2:12][C@H:11]([OH:13])[CH2:9][Cl:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC[C@@H]1CO1
Reactant: NCc1ccccc1
Product: O[C@H](CCl)CNCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 50.1 %

Procedure:
A scintillation vial was charged with benzylamine (1 g, 10 mmol), anhydrous petroleum ether (10 ml) and a stir bar. To this was added (S)-(+)-epichlorohydrin (0.925 g, 10 mmol) dropwise over a period of 20 min and the mixture was allowed to stir at room temperature. After 15 h, the white crystals precipitated from solution. These were collected by suction filtration, rinsed with cold petroleum ether (10 ml) and dried under vacuum to provide the title compound (1.0 g, 50%). Mass spectrum (ESI) 200.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.O.[NH2:10][NH2:11]>CO>[NH:10]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[N:3]=1)[NH2:11]
Reactant: Clc1cccc(Cl)n1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNc1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2 g of 2,6-dichloropyridine were dissolved in 60 ml of methanol and mixed with 10 ml of 80% hydrazine hydrate. The solution was firstly stirred for 3 days at room temperature and then refluxed for 10 days. Rotation in took place, the residue was taken up with methanol, followed by rotation in again and finally recrystallization from methanol/water. 0.25 g of 2-hydrazino-6-chloropyridine was obtained.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]O.[BrH:13]>O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][Br:13]
Reactant: OCc1ccccc1C(F)(F)F
Reactant: Br
Solvent: O
Product: FC(F)(F)c1ccccc1CBr

Procedure:
A solution of 2-trifluoromethyl benzyl alcohol (1 g, 5.67 mmol) in aqueous HBr (6 mL) was stirred at 50° C. for 4 hrs. The reaction mixture was diluted with cold water and the product extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulphate and concentrated to afford 780 mg of 2-trifluoromethylbenzyl bromide.
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[C:15]([F:20])[CH:16]=2)[N:11]([CH2:27][CH3:28])[C:10]1=[O:29])C1C=CC=CC=1.[H][H]>C1COCC1.CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH2:27]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([F:20])=[C:14]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:13]=2)[C:18](=[O:19])[N:9]([OH:8])[C:10]1=[O:29])[CH3:28]
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCOCC3)cc21
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Solvent: C1CCOC1
Product: CCn1c(=O)n(O)c(=O)c2cc(F)c(N3CCOCC3)cc21
Yield: 94.8 %

Procedure:
Five percent Pd/BaSO4 (50 mg) was added to a solution of 3-benzyloxy-1-ethyl-6-fluoro-7-morpholino-1H-quinazoline-2,4-dione (Example G, 0.23 g, 0.58 mmol) in 70 mL of THF and 5 mL methanol. The mixture was shaken under 50 PSI of hydrogen for 16 hours, filtered, and concentrated to afford 0.17 g of the title compound as a solid, mp 162-163° C.
Reaction SMILES: [Cl-].[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH3+:22])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.CCN(CC)CC.[N:30]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)=[C:31]=[O:32]>C(Cl)Cl>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:31]([NH:30][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)=[O:32])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1
Reactant: COc1ccc(CN=C=O)cc1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OCCCCCC[NH3+])c21
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CNC(=O)NCCCCCCOc2cccc3c2C(N)=NS(=O)(=O)N3)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 0.1 %

Procedure:
To a suspension of 6-(4-amino-2,2-dioxo-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)hexan-1-aminium chloride (166 mmol, 52 mg) (Example 280) in dry DCM (6 mL) was successively added Et3N (332 mmol, 46 μL) and 1-(isocyanatomethyl)-4-methoxybenzene (183 mmol, 26 μL). The reaction was stirred for 48 hours at room temperature then concentrated in vacuo. The residue was washed with water, dried, then purified on silica gel (20% to 100% EtOAc in hexanes) to give the desired product (64 mg, 81.0% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.296 (m, 2H), 1.371 (m, 4H), 1.791 (pentet, J=8 Hz, 2H), 2.980 (q, J=6 Hz, 2H), 3.695 (s, 3H), 4.086 (d, J=6 Hz, 2H), 4.131 (t, J=6 Hz, 2H), 5.836 (br. t, J=5 Hz, 1H), 6.141 (br. t, J=6 Hz, 1H), 6.585 (d, J=8 Hz, 1H), 6.727 (d, J=8 Hz, 1H), 6.840 (d, J=9 Hz, 2H), 7.137 (d, J=9 Hz, 2H), 7.433 (t, J=8 Hz, 1H), 7.803 (br. s, 1H), 8.321 (br. s, 1H), 10.926 (s, 1H). MS 476 (MH+).
Reaction SMILES: Cl.[C:2](/[C:4](/[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)=[O:20])=[C:5](/[NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=1)\[S:6][CH3:7])#[N:3].C([OH:31])C>ClCCl>[OH:31][C:2]1[C:4]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[O:20])=[C:5]([S:6][CH3:7])[N:8]=[C:9]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)[N:3]=1
Reactant: CCO
Reactant: CS/C(NC(=O)c1ccc(SC)cc1)=C(\C#N)C(=O)Nc1ccc(C)cc1
Agent: Cl
Solvent: ClCCl
Product: CSc1ccc(-c2nc(O)c(C(=O)Nc3ccc(C)cc3)c(SC)n2)cc1
Yield: 90 %

Procedure:
Dry HCl gas was passed through a solution of N-[(1E)-2-Cyano-3-[(4-methylphenyl)amino]-1-(methylthio)-3-oxoprop-1-en-1-yl]-4-(methylthio)benzamide (2 g, 5 mmol, prepared according to the procedure described in preparation 1) in ethanol (50 ml) at 0° C. for 4 hours. The reaction mixture was then refluxed for 4 hours until completion; subsequently the resultant solid was filtered and washed with ethanol. The solid thus obtained was suspended in dichloromethane (50 ml), filtered, and finally dried under vacuum to yield the title compound (1.8 g, 90%, purity 99.78% by HPLC), m.p.: 302-305° C. 1H-NMR (CDCl3) δ (ppm): 2.29 (s, 3H), 2.33 (s, 3H), 2.63 (s, 3H), 7.12-7.14 (d, 2H), 7.23-7.26 (m, 2H), 7.47-7.49 (d, 2H), 8.13-8.15 (d, 2H), 11.38 (s, 1H, D2O exchangeable), 12.45 (s, 1H, D2O exchangeable). IR (KBr) cm−1: 3436, 3320, and 1646. MS m/z: 398.1(M++1).
Reaction SMILES: Cl.N1C=CC=C[CH:3]=1.[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:16][C:15]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[CH:14][CH:13]=2>C1(C)C=CC=CC=1>[CH2:33]([O:32][C:15]1[CH:14]=[CH:13][C:12]2[N:11]=[CH:10][C:9]3[N:8]=[CH:3][N:19]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:18]=3[C:17]=2[CH:16]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2ccc(OCc3ccccc3)cc12
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCCCn1cnc2cnc3ccc(OCc4ccccc4)cc3c21

Procedure:
For Examples 70-72, the following procedure was used. Under a nitrogen atmosphere, the reagent from the table below (1.5 equivalents) and pyridine hydrochloride (0.01-0.02 equivalents) were added to a solution of tert-butyl {4-[3-amino-6-(benzyloxy)quinolin-4-ylamino]butyl}carbamate (29-36 mmol, 1 equivalent) in toluene (200 mL), and the reaction was heated at reflux for three to five hours. The toluene was removed under reduced pressure. The residue was dissolved in a small amount of toluene, which was removed under reduced pressure. This was repeated three times. The resulting solid was dried under high vacuum at 100° C. to provide the tert-butyl {4-(8-benzyloxy-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamate with the substituent indicated in the table below.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.C1OCCOCCOCCOCCOCCOC1.[F-].[K+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: N#Cc1ccc(F)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(Oc2ccc(Br)cc2)cc1
Temperature: 25 °C
Yield: 51.1 %

Procedure:
A mixture of 4-bromophenol (4.56 g, 0.0264 mol), 4-fluorobenzonitrile (0.0264 mol), 18-Crown-6 (0.7 g, 0.00264 mol) and 40% potassium fluoride on alumina (10.8 g) in anhydrous acetonitrile (100 mL) was heated at reflux under an atmosphere of nitrogen for twelve hours. It was cooled to ambient temperature, filtered through a Celite pad and concentrated under reduced pressure. The residue was partitioned between diethyl ether (120 mL) and water (100 mL), the organic phase was further washed with saturated solution of potassium chloride in water, dried with magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (3:97) as mobile phase to yield 4-(4-bromophenoxy)benzonitrile (3.7 g, 0.0135 mol) as a white solid.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([CH2:15][C:16]([CH3:24])([CH3:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H-].[Na+].[CH3:27]I>O1CCOCC1>[CH2:7]([O:6][P:4]([C:9]([CH3:27])([CH2:15][C:16]([CH3:24])([CH3:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOC(=O)CC(C)(C)CC(C(=O)OCC)P(=O)(OCC)OCC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)CC(C)(C)CC(C)(C(=O)OCC)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Diethyl 2-diethylphosphono-4,4-dimethyladipate (3.6 parts) (See Example 9) was added dropwise to a suspension of sodium hydride (0.6 parts, 50% in oil) in dry dioxan (100 parts by volume) containing methyliodide (14.2 parts) over 2 hr. at room temperature. The resulting solution was stirred at room temperature for 18 hr. then heated to reflux for 2 hr., cooled, the solids removed by filtration and the filtrate concentrated in vacuo. Distillation of the residual oil gave 3 parts of diethyl 2-diethylphosphono-2,4,4-trimethyladipate, boiling at 137°-8° C./0.03 mm having a 31P chemical shift of -26 ppm and having the following elemental analysis by weight.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][CH:10]=[N:9][CH:8]=1.[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[O:23][CH2:24][C:25](O)=[O:26])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[O:23][CH2:24][C:25]([C:10]1[O:11][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:8][N:9]=1)=[O:26])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(-c2cnco2)nc1
Reactant: O=C(O)COc1cccc(OCc2ccccc2)c1
Product: O=C(COc1cccc(OCc2ccccc2)c1)c1ncc(-c2ccccn2)o1
Yield: 7 %

Procedure:
The title compound was prepared from 5-(2-pyridyl)oxazole and 2-(3-(benzyloxy)phenoxy)acetic acid (Baker, B. R.; Neenan, J. P. J. Med. Chem. 1972, 15, 940-944) using General Procedure B. Column chromatography (SiO2, 2.5×6 cm, 20-40% EtOAc-hexanes gradient) followed by PTLC (SiO2, 50% EtOAc-hexanes) afforded 11d (26 mg, 0.07 mmol, 7%) as a pale yellow solid: 1H NMR (CDCl3, 500 MHz) 8.70 (app d, 1H, J=4.0 Hz), 8.03 (d, 1H, J=8.1 Hz), 7.86 (td, 1H, J=7.7, 1.5 Hz), 7.55-7.52 (m, 1H), 7.45-7.32 (m, 6H), 7.22 (t, 1H, J=8.2 Hz), 6.68 (dd, 1H, J=8.2, 2.4 Hz), 6.61 (t, 1H, J=2.2 Hz), 6.54 (dd, 1H, J=7.8, 2.5 Hz), 5.45 (s, 2H), 5.06 (s, 2H); 13C NMR (CDCl3, 100 MHz) 192.7, 169.7, 162.1 (2C), 158.3, 151.5, 149.2, 137.0, 136.7, 130.3, 128.6, 128.0, 127.5, 122.2, 106.9 (2C), 102.1, 70.1, 67.9; ESI-TOF m/z 387.1349 (C23H19N2O4+H+ requires 387.1345).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].CS(O[CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]1)(=O)=O>CN(C=O)C.C(OCC)(=O)C>[C:36]([O:35][C:33]([N:29]1[CH2:30][CH2:31][CH2:32][CH:27]([CH2:26][O:1][C:2]2[CH:3]=[C:4]([O:8][S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=2)[CH2:28]1)=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: O=S(=O)(Oc1cccc(O)c1)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(COS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(COc2cccc(OS(=O)(=O)c3ccccc3Cl)c2)C1
Reaction time: 0.17 h
Yield: 52.9 %

Procedure:
To a solution of 2-chlorobenzenesulfonic acid 3-hydroxyphenyl ester (570 mg, 2.0 mmol), as prepared in step d of Example 1, in DMF (8 mL) was added NaH (95%, 53 mg, 2.2 mmol). The reaction mixture was stirred under nitrogen for 10 min. N-(tert-Butoxycarbonyl)-3-piperidinemethanol methanesulfonate (586 mg, 2.0 mmol), as prepared in step b, was added and the reaction mixture was stirred at 40° C. under nitrogen overnight. The reaction mixture was diluted with ethyl acetate (150 mL), washed sequentially with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (2:1 hexane:ethyl acetate) to give the title compound as a colorless syrup (510 mg, 54%). 1H-NMR (300 MHz, CDCl3) δ 1.32 (m, 1H), 1.45 (s, 9H), 1.65-1.98 (m, 4H), 2.88 (m, 2H), 3.73 (m, 2H), 3.79 (d, 2H), 6.69 (m, 2H), 7.13 (t, 1H), 7.37 (t, 1H), 7.61 (m, 2H), 7.94 (d, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1)#[CH:2].[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15](Br)[CH:16]=1>C(N(CC)CC)C.C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=2)[CH:16]=1
Reactant: C#Cc1cccc(F)c1
Reactant: Brc1cncc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Fc1cccc(C#Cc2cncc(Br)c2)c1
Temperature: 70 °C
Yield: 27.5 %

Procedure:
Add 1-ethynyl-3-fluorobenzene (250 mg, 2.11 mmol) to a mixture of 3,5-dibromopyridine (500 mg, 2.11 mmol) in triethylamine (4 mL) containing bis(triphenylphosphine)palladium (II) dichloride (28 mg, 0.04 mmol) and copper (I) iodide (15 mg, 0.08 mmol) and heat at 70° C. for 2 h. Cool to room temperature, dilute with ethyl acetate and an aqueous solution of ammonium chloride and separate the resulting layers. Wash the organic layer with an aqueous saturated solution of sodium chloride, dry (magnesium sulfate), filter and concentrate. Purify by silica gel chromatography, eluting with 0.5% ethanol in 50:50 dichloromethane:hexanes to give the title compound (160 mg, 28%).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:28])([CH3:27])[C@@H:14]([O:19]CC1C=CC=CC=1)[C:15]([O:17][CH3:18])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2]>[Pd].C(O)C>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:28])([CH3:27])[C@@H:14]([OH:19])[C:15]([O:17][CH3:18])=[O:16])(=[O:9])=[O:10])(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCNC(C)=O
Agent: [Pd]
Solvent: CCO
Product: COC(=O)[C@H](O)C(C)(C)COS(=O)(=O)CCCNC(C)=O
Reaction time: 8 h
Yield: 39.1 %

Procedure:
Following the general procedure for the hydrogenolysis of benzyl ethers of Description 18, a mixture of methyl (2R)-4-{[3-(acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-(phenylmethoxy)butanoate acid (24c) (0.45 g, 1.1 mmol) and 400 mg of 10 wt.-% of palladium on activated carbon in 20 mL of ethanol (EtOH) was stirred overnight under a hydrogen atmosphere. After purification by mass-guided preparative HPLC, 140 mg (39% yield) of the title compound (24) was obtained as a colorless, viscous oil. 1H NMR (400 MHz, CDCl3): δ=0.97 (s, 3H), 1.12 (s, 3H), 2.01 (s, 3H), 2.04-2.13 (m, 2H), 2.94-3.08 (br. s, 1H), 3.13-2.26 (m, 2H), 3.33-3.48 (m, 2H), 3.83 (s, 3H), 3.97 (d, J=8.8 Hz, 1H), 4.06 (br. s, 1H), 3.97 (d, J=9.6 Hz, 1H), 6.02-6.09 (br. m, 1H) ppm. MS (ESI) m/z: 325.95 (M+H)+, 323.97 (M−H)−. The analytical data was consistent with the proposed structure.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:7]=1[NH2:21])=O)C.[NH4+:22].[OH-]>CO.C1COCC1>[NH2:21][C:7]1[C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[N:9][O:10][C:6]=1[C:4]([NH2:22])=[O:3]
Reactant: CCOC(=O)c1onc(-c2ccc(S(C)(=O)=O)cc2)c1N
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)c1ccc(-c2noc(C(N)=O)c2N)cc1
Reaction time: 24 h

Procedure:
To a solution of 4-amino-3-(4-methanesulfonyl-phenyl)-isoxazole-5-carboxylic acid ethyl ester (4.0 g, 12.9 mmol) in methanol (50 mL) and THF (50 mL), was added a NH4OH solution (100 mL) at room temperature. The reaction was stirred for 24 h. The precipitates were filtered and washed with H2O (100 mL). The compound was dried in vacuo to afford the crude product which was used for the next step without further purification. LCMS 282.1 [M+H].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])=[O:5])[CH3:2].[CH:18]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:23][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(C)cccc2c1Cl
Reactant: NC1CCCC1
Product: CCOC(=O)c1cnc2c(C)cccc2c1NC1CCCC1

Procedure:
4-Chloro-8-methyl-quinoline-3-carboxylic acid ethyl ester (125 mg, 0.5 mmol) was treated with cyclopentylamine following general procedure B to afford 4-Cyclopentylamino-8-methyl-quinoline-3-carboxylic acid ethyl ester (120 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid using general procedure D and then transformed into the corresponding ethylamide (90 mg) following general procedure E.