Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:24][C:25]1[O:29][C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[N:27][C:26]=1[CH2:42][CH2:43]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:23])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:43][CH2:42][C:26]2[N:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:32][CH:31]=3)[O:29][C:25]=2[CH3:24])=[CH:11][C:10]=1[CH2:16][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)([CH3:7])[CH3:6])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1CC1CCCCC1

Procedure:
A mixture of 2-(2-benzyl-4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester (1.14 g, 3.63 mmol) (see Ex. 35, part C), toluene-4-sulfonic acid 2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (4.71 mmol) (see Ex. 1, part F), and Cs2CO3 (1.77 g, 5.45 mmol) was heated at 55° C. in DMF (10 mL) for 72 h. The reaction mixture cooled and partitioned between ethyl acetate (30 mL) and H2O (10 mL). The organic layer was washed with brine (15 mL). The organic layer was dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography using hexanes:ethyl acetate (8:1) to give 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)-ethoxy]-2-cyclohexylmethyl-phenoxy}-2-methyl-propionic acid ethyl ester: MS (ES) m/e 582.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([C:34](=[O:41])[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:20][CH2:21]3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCNCC2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCN(C(=O)c3ccccc3)CC2)CC1
Reaction time: 5 h

Procedure:
To a solution of 4-amino-5-chloro-2-methoxy-N-[1-(4-piperidinylmethyl)-4-piperidinyl]benzamide (610 mg) and triethylamine (0.22 ml) in methylene chloride (30 ml) is added benzoyl chloride (0.19 ml) at room temperature, and the mixture is stirred for 5 hours. The reaction mixture is washed with water, and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform: methanol=20:1) to give the desired compound (610 mg).
Reaction SMILES: [CH:1]([C@H:4]1[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:7][N:6]2[C:17]3[CH:23]=[C:22]([S:24]([CH3:27])(=[O:26])=[O:25])[C:21]([C:28](OC)=[O:29])=[CH:20][C:18]=3[N:19]=[C:5]12)([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.CCOC(C)=O>C(Cl)Cl>[OH:29][CH2:28][C:21]1[C:22]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:23][C:17]2[N:6]3[CH2:7][CH2:8][N:9]([C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[C@H:4]([CH:1]([CH3:2])[CH3:3])[C:5]3=[N:19][C:18]=2[CH:20]=1
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(C(=O)OC(C)(C)C)[C@@H]3C(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)[C@@H]1c2nc3cc(CO)c(S(C)(=O)=O)cc3n2CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 3 h
Yield: 74.6 %

Procedure:
To a 50 mL three-necked flask containing (R)-2-tert-butyl 8-methyl 1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2,8(1H)-dicarboxylate (250 mg, 0.554 mmol, from preparation 2) in DCM (5 mL) was added DIBAL-H (1.70 mL, 1.67 mmol, 1.0 M in toluene) dropwise at −78° C. under N2. The mixture was stirred at −78° C. for 3 h. The reaction was quenched with sat. aq. ammonium chloride (10 mL) at −78° C. The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (15 mL) and brine, and then dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE: EtOAc 8:1˜2:1 to give (R)-tert-butyl 8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H)-carboxylate (175 mg, 74.1% yield) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:15]1[N:20]([CH3:21])[C:19](=[O:22])[CH:18]=[C:17]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[F:29])[N:16]=1>O1CCCC1>[F:29][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:23]=1[C:17]1[N:16]=[C:15]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:20]([CH3:21])[C:19](=[O:22])[CH:18]=1
Reactant: C1COCCN1
Reactant: Cn1c(Cl)nc(-c2ccncc2F)cc1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCOCC2)nc(-c2ccncc2F)cc1=O
Reaction time: 12 h
Yield: 94.8 %

Procedure:
To a solution of morpholine (3.2 g, 36.7 mmol) and triethylamine (10.2 g, 101 mmol) in tetrahydrofuran (80 ml) was added 2-chloro-6-(3-fluoropyridin-4-yl)-3-methyl-3H-pyrimidin-4-one (8.0 g, 32.4 mmol) portionwise and stirred for 12 hours. The resulting suspension was partitioned between chloroform and 1N sodium hydroxide and the aqueous layer was extracted with chloroform. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to furnish 6-(3-fluoropyridin-4-yl)-3-methyl-2-(morpholin-4-yl)-3H-pyrimidin-4-one (8.9 g, 30.7 mmol, 92%) as white crystals.
Reaction SMILES: [N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=4)[O:14][C:13]3=[O:32])[C:8](Br)=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][C:37]=1B1OCC(C)(C)CO1.N#N.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=4)[O:14][C:13]3=[O:32])[C:8]([C:37]3[CH:38]=[C:39]([N+:42]([O-:44])=[O:43])[CH:40]=[CH:41][C:36]=3[O:35][CH3:34])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc([N+](=O)[O-])cc1B1OCC(C)(C)CO1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(N2CCC2)ccc1Br
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc([N+](=O)[O-])cc1-c1ccc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (4S,5R)-3-{[6-azetidin-1-yl-3-bromopyridin-2-yl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (1.2 g, 2.229 mmol) and 2-(2-methoxy-5-nitrophenyl)-5,5-dimethyl-1,3,2-dioxaborinane in THF (20 mL) was degassed with N2 at 25° C. 1N K2CO3 (20 mL) was added followed by 1,1-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.073 g, 0.111 mmol) and the reaction was stirred vigorously at 25° C. under N2 for 4 h. The reaction was diluted with water (50 mL) and extracted with EtOAc (3×30 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 260 mL, gradient to 40% EtOAc in hexanes over 2240 mL) to give (4S,5R)-3-{[6-azetidin-1-yl-3-(2-methoxy-5-nitrophenyl)pyridin-2-yl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one. LCMS calc.=610.2. found=611.1 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:14]=1)[O:11][C:10]([C:22](O)=[O:23])=[CH:9][C:8]2=[O:25])[CH3:3].C(Cl)(=O)C([Cl:29])=O>CN(C=O)C.C(Cl)Cl>[CH2:2]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:14]=1)[O:11][C:10]([C:22]([Cl:29])=[O:23])=[CH:9][C:8]2=[O:25])[CH3:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOc1cc(N2CCN(C)CC2)c2oc(C(=O)O)cc(=O)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1cc(N2CCN(C)CC2)c2oc(C(=O)Cl)cc(=O)c2c1
Reaction time: 2 h

Procedure:
Into a 100 mL round bottom flask equipped with a reflux condenser, nitrogen inlet and magnetic stirrer is placed 250 mg (0.68 mmol, 1.0 equiv.) of 6-Ethoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride salt (Reference Example 23d) and 20 mL of methylene chloride. To the stirring suspension is then added 129.5 mg, 164 L(1.02 mmol, 1.5 equiv.) of oxalyl chloride followed by addition of one drop of DMF from a 50 microliter syringe to act as catalyst. The mixture is stirred for 2 hours, then concentrated to dryness on a rotary evaporator under a nitrogen atmosphere, followed by drying under high vacuum. The completeness of the reaction was ascertained by analysis of an aliquot, which was quenched with a THF solution of methylamine, by LC/MS. The crude material was used as obtained in the subsequent amidation reaction.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:6](=[O:13])[CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][CH:10]=1.[C:14](OCC)(=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>O1CCCC1.O>[CH3:3][O:4][C:5]1[C:6](=[O:13])[CH:7]([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:8]([CH3:11])([CH3:12])[CH2:9][CH:10]=1
Reactant: COC1=CCC(C)(C)CC1=O
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C1C(=O)C(OC)=CCC1(C)C
Reaction time: 0.25 h
Yield: 2084.3 %

Procedure:
60% sodium hydride in mineral oil (2.41 g, 60.3 mmol) was suspended in anhydrous tetrahydrofuran (60 mL) under argon atmosphere and treated with a solution of 2-methoxy-5,5-dimethyl-cyclohex-2-enone (6.20 g, 40:2 mmol) in anhydrous tetrahydrofuran (50 mL). After 15 minutes, a solution of diethyl oxalate (8.17 mL, 60.3 mmol) in anhydrous tetrahydrofuran (50 mL) was added and the mixture was refluxed for 1 hour. The slurry was diluted with water (800 mL), acidified with 1 N HCl (50 mL) and extracted with ethyl acetate (500 mL×2). The organic layers were collected, washed with brine, dried on Na2SO4 and evaporated to dryness to obtain the crude title compound (10.60 g) as an orange oil, which was used without further purification.
Reaction SMILES: [BrH:1].S(=O)(=O)(O)O.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15]O>>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][Br:1]
Reactant: OCCc1ccccc1F
Reactant: Br
Agent: O=S(=O)(O)O
Product: Fc1ccccc1CCBr
Temperature: 0 °C

Procedure:
To a mixture of aqueous hydrobromic acid (48%, 360 mL) and concentrated sulfuric acid (103.6 mL) at room temperature was added dropwise 2-(2-fluorophenyl)ethanol (250 g, 1.78 mol, Aldrich). The reaction mixture was refluxed for 7 h, poured onto 600 ml of ice and the mixture was extracted with diethyl ether. The diethyl ether extracts were washed successively with saturated sodium carbonate and brine. The organic phase was dried (MgSO4) and concentrated in vacuo to give 359.9 g (99%) of 2-(2-fluorophenyl-ethylbromide as a brown oil. This product was used without further purification. NMR (CDCl3 : d 7.6-6.9 (m, 4H, ArH), 3.6 (t, 2H, CH2), 3.2 (t, 2H, CH2).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:13]([C:14](Cl)=[O:15])=[CH:12][S:11][N:10]=2)[CH:4]=1.[CH2:19]([OH:22])[CH2:20][CH3:21]>>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:13]([C:14]([O:22][CH2:19][CH2:20][CH3:21])=[O:15])=[CH:12][S:11][N:10]=2)[CH:4]=1
Reactant: CCCO
Reactant: O=C(Cl)c1csnc1-c1cccc(C(F)(F)F)c1
Product: CCCOC(=O)c1csnc1-c1cccc(C(F)(F)F)c1
Yield: 100.5 %

Procedure:
A solution of 2.92 g (0.010 mol) of 3-(α,α,α-trifluoro-m-tolyl)-4-isothiazolecarbonyl chloride and 4 g (0.0667 mol) of 1-propanol was heated on a steam bath for 1 hour and was concentrated under vacuum to 70° (0.5 torr) to give 3.17 g of clear oil, nD20.8 =1.5261, infrared (film) 5.80μ.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:7]=1.Br[CH2:20][CH2:21][O:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>CCOC(C)=O>[CH3:23][O:22][CH2:21][CH2:20][O:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: COC(=O)c1cc(O)cc(-c2ccc(C)cc2)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COCCOc1cc(C(=O)OC)cc(-c2ccc(C)cc2)c1
Temperature: 135 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 5-hydroxy-4′-methylbiphenyl-3-carboxylate (400 mg, 1.65 mmol), 1-bromo-2-methoxyethane (436 mg, 3.14 mmol), potassium carbonate (434 mg, 3.14 mmol), and dimethyl sulfoxide (5 mL) was stirred at 135° C. overnight. After cooling, the mixture was diluted with EtOAc and washed with aq. NaHCO3 (sat.), dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (0-100% EtOAc/hexane) to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[CH:10]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([Cl:28])[CH:19]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][C:14](=O)[CH2:13]2)=[N:6][CH:7]=1.Cl.[NH2:31][OH:32]>CO.N1C=CC=CC=1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[CH:10]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([Cl:28])[CH:19]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][C:14](=[N:31][OH:32])[CH2:13]2)=[N:6][CH:7]=1
Reactant: NO
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)C2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCC(=NO)C2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Temperature: 25 °C
Yield: 77 %

Procedure:
A solution of N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-propionamide (prepared as in Example 49, 190 mg, 0.38 mmol) and hydroxylamine hydrochloride (40 mg, 0.57 mmol) in methanol (0.90 mL) and pyridine (0.90 mL) was heated under reflux for 3 h. The reaction mixture was allowed to cool to 25° C. and was then concentrated in vacuo. The resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic layers were washed with a 1N aqueous hydrochloric acid solution (50 mL) and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 75% ethyl acetate/hexanes) afforded the N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-hydroxyimino-cyclopentyl)-propionamide 77%) as a yellow foam: mp 100–106° C.; (ES)+-HRMS m/e calcd for C19H20BrClN4O4S (M+H)+ 515.0150 found 515.0154.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.[NH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[CH:24][CH:23]=[CH:22]2.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9]([NH:16][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:26]=2[N:25]=[CH:24][CH:23]=[CH:22]3)(=[O:11])=[O:10])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: Nc1cccc2cccnc12
Reactant: Cc1cc(S(=O)(=O)Cl)c([N+](=O)[O-])cc1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(S(=O)(=O)Nc2cccc3cccnc23)c([N+](=O)[O-])cc1F
Yield: 29.6 %

Procedure:
In a similar fashion using route 14 general procedure 27, 4-fluoro-5-methyl-2-nitro-benzenesulfonyl chloride (Intermediate 452) (1.6 g, 6.3 mmol), 8-aminoquinoline (700 mg, 4.86 mmol), DMAP (cat.), pyridine (5 ml) and DCM (5 ml) gave the title compound (520 mg, 52%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH:28]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH2:30][C:31]1([C:34]([OH:36])=[O:35])[CH2:33][CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][NH:30][C:31]3([C:34]([OH:36])=[O:35])[CH2:33][CH2:32]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CC=O)cn(C)c34)no2)cc1Cl
Reactant: NC1(C(=O)O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCNC5(C(=O)O)CC5)cn(C)c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 3 h
Yield: 13.2 %

Procedure:
To a stirred solution of [7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]acetaldehyde (D88) (50 mg), 1-aminocyclopropanecarboxylic acid (25 mg) and acetic acid (0.1 mL) in DCM (10 mL) was added sodium triacetoxyborohydride (52 mg). The reaction was stirred at 20° C. for 3 h. The mixture was concentrated and the residue was partitioned between ethyl acetate (25 mL) and aqueous HCl (2 M, 25 mL). The organic phase was washed with water (25 mL) and brine (25 mL), dried over anhydrous sodium sulphate and evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford 1-({2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl}amino)cyclopropanecarboxylic acid (E68) (8 mg, TFA salt). δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 1.41 (4H, m), 3.06 (2H, t), 3.31 (2H, t), 3.65 (3H, s), 4.88 (1H, m), 7.22 (1H, t), 7.33 (1H, s), 7.46 (2H, m), 7.81 (1H, dd), 8.12 (1H, dd), 8.19 (1H, d). MS (ES): C26H27ClN4O4 requires 494; found 495.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](Cl)=[O:6].[CH3:12][C:13]1[C:18]2[NH:19][C:20](=[O:22])[O:21][C:17]=2[CH:16]=[CH:15][CH:14]=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([C:15]1[CH:14]=[C:13]([CH3:12])[C:18]2[NH:19][C:20](=[O:22])[O:21][C:17]=2[CH:16]=1)=[O:6]
Reactant: Cc1cccc2oc(=O)[nH]c12
Reactant: O=C(Cl)c1ccc(F)c(Br)c1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C(=O)c2ccc(F)c(Br)c2)cc2oc(=O)[nH]c12
Temperature: 25 °C

Procedure:
2.23 g (9.40 mmol) 3-bromo-4-fluoro-benzoic acid chloride, 1.40 g (9.40 mmol) 4-methyl-3H-benzoxazol-2-one and 5.01 g (37.60 mmol) aluminium trichloride were heated to 125° C. for 1.5 h with stirring. After cooling to RT the mixture was mixed with ice water. The precipitate formed was suction filtered and washed with water. Then the precipitate was triturated with MeOH, suction filtered, washed with MeOH and dried i. vac.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:23]=[C:21]([CH3:22])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[OH:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:45]1[C:49](=[O:50])[C:48]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:47]2[C:46]1=[O:55].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOCC>[Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:23]=[C:21]([CH3:22])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[O:24][N:45]1[C:46](=[O:55])[C:47]2=[CH:54][CH:53]=[CH:52][CH:51]=[C:48]2[C:49]1=[O:50])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cn([C@H]2C[C@H](ON3C(=O)c4ccccc4C3=O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Yield: 62 %

Procedure:
To a solution of 5'-O-t-butyldimethylsilylthymidine [1, 21.36 g, 60 mmol, prepared according to the procedure of Nair, V., and Buenger, G. S., Org. Prep. Procedures Int., 22:57 (1990) in dry THF (750 ml)], triphenylphosphine (17.28 g, 66 mmol) and N-hydroxyphthalimide (10.74 g, 66 mmol) were added. The solution was cooled to OIC and diisopropylazodicarboxylate (15.15 g, 75 mmol) was added dropwise over a period of 3 hr while stirring under nitrogen. The reaction mixture was then stirred at room temperature for 12 hr. The solution was evaporated and the residue was dissolved in CH2Cl2 (750 ml), extracted with sat. NaHCO3 (200 ml), and water (200 ml), dried (MgSO4), filtered and concentrated to furnish yellow oily residue. Silica gel column chromatography (100% hexanes, and then hexanes:Et2O gradient to 90% Et2O) of the residue gave compound 2 as a colorless glass (18.68 g, 62%); 1H NMR (CDCl3) δ0.05 [2s, 6, (CH3)2 ], 0.91 [s, 9, (CH3)3 ], 2.0 (s, 3, CH3), 2.5-2.65 (m, 2, 2' CH2), 4.05-4.2 (m, 2, 5'CH2), 4.25-15 4.35 (m, 1, 4'H), 5.0 (m,1,3'H), 6.15 (m, 1, 1'H), 8.6 (br s, 1, NH), and aromatic protons. Anal. Calcd. for C24H31N3O7Si: C, 57.46;H , 6.23; N, 8.37. found : C, 57.20; H, 6.26; N, 8.27.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([OH:17])=O)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1.[CH3:18][C:19]([CH3:26])([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[NH2:20]>>[CH3:18][C:19]([NH:20][C:15]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:6]=1)=[O:17])([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[CH3:26]
Reactant: O=C(O)c1ccc(Cl)c(-c2cccc(Cl)c2)n1
Reactant: CC(C)(N)c1nccs1
Product: CC(C)(NC(=O)c1ccc(Cl)c(-c2cccc(Cl)c2)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (LC/MS): 392.0 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]([C:7]1[C:8]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=2[O:28]CC=C)=[C:9]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:10]2=[N:11][C:12]=1[CH3:13])[OH:6])C.I[CH2:34][CH3:35]>CC#N.[Ag]=O.[Ag-]=O>[CH2:34]([O:6][CH:5]([C:7]1[C:8]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=2[OH:28])=[C:9]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:10]2=[N:11][C:12]=1[CH3:13])[C:4]([OH:3])=[O:32])[CH3:35]
Reactant: CCI
Reactant: C=CCOc1cc(C)ccc1-c1c(C(O)C(=O)OCC)c(C)nc2sc3c(c12)CCCC3
Agent: O=[Ag-]
Agent: O=[Ag]
Solvent: CC#N
Product: CCOC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1O)CCCC3
Temperature: 60 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
To a stirred solution of [4-(2-Allyloxy-4-methyl-phenyl)-2-methyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-b]pyridin-3-yl]-hydroxy-acetic acid ethyl ester (100 mg, 221 μmols, 1 eq) in MeCN (5 mL) was added silver oxide (102 mg, 442 μmols, 2 eq) followed by iodoethane (172 mg, 89 uL, 5 eq) and the reaction was stirred for 16 hours at 60° C. Additional iodoethane (1 mL, 50 eq) and silver (I) oxide (102 mg, 2 eq) was added and the reaction was continued to be heated at 60° C. for 16 hours. The reaction was diluted with MeCN (5 mL), and filtered. The filtrate was then concentrated in vacuo. The residue was purified using ISCO Companion with a Redisep silica gel 12 g cartridge and a gradient of heptane and ethyl acetate (0% to 30%). Fractions containing (4-(2-allyloxy-4-methyl-phenyl)-2-methyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-b]pyridin-3-yl)-ethoxy-acetic acid ethyl ester were combined and concentrated in vacuo to give the desired product as a pale orange oil, 22 mg (22% yield). LC-MS (12 min acidic) 7.55 mins 100% pure by UV, ES+/APCI+ 480.