Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.O[CH2:4][C:5]1[O:9][C:8]([C:10](=[O:12])[CH3:11])=[CH:7][CH:6]=1.CCN(CC)CC.S([Cl:24])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:24][CH2:4][C:5]1[O:9][C:8]([C:10](=[O:12])[CH3:11])=[CH:7][CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1ccc(CO)o1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(CCl)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(5-hydroxymethyl-furan-2-yl)-ethanone (2.00 g, 14.27 mmol) in dry CH2Cl2 (29 mL) was treated at 0° C. with Et3N (2.58 mL, 18.55 mmol) followed by DMAP (178 mg, 1.43 mmol) and Ms-Cl (1.33 mL, 17.13 mmol). After stirring at rt for 3 h, the reaction was quenched with water. The layers were separated and the aq. layer extracted with CH2Cl2 (3×). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude 1-(5-chloromethyl-furan-2-yl)-ethanone as a brown oil. Part of this crude material (2.33 g, 14.72 mmol) was dissolved in dry DMF (50 mL) and treated with NaN3 (2.90 g, 44.16 mmol) at 80° C. for 24 h. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the aq. layer extracted with EA (1×). The combined org. extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to give crude 1-(5-azidomethyl-furan-2-yl)-ethanone as a brown oil. LC-MS-conditions 02: tR=0.81 min; [M+AcCN+H]+=207.50.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:16])[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(O)=O>CO.C(OCC)(=O)C.C(=O)(O)[O-].[Na+].O>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:16])[CH2:9][N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CN1CCOCC1)c1cccc(Br)n1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: OC(CN1CCOCC1)c1cccc(Br)n1
Reaction time: 0.5 h

Procedure:
To a solution of 1-(6-bromopyridin-2-yl)-2-morpholin-4-ylethanone (234 mg, 0.82 mmol) in methanol at 0° C. was added sodium borohydride (31.0 mg, 0.82 mmol). After 30 minutes, formic acid (0.1 mL) was added and then the reaction mixture was diluted with ethyl acetate (40 mL), saturated aqueous sodium bicarbonate (10 mL), and water (10 mL). The layers were separated and the organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated to give the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([Cl:12])=[N:4][N:3]=1.[NH2:13][C:14]1[CH:34]=[CH:33][C:17]([O:18][C:19]2[C:24]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH3:32])[N:26]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:16][CH:15]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:12][C:5]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:2]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:18][C:19]3[C:24]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH3:32])[N:26]=4)=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:33][CH:34]=2)=[N:3][N:4]=1
Reactant: Clc1nnc(Cl)c2c1CCCC2
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(N)cc2)n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(Cl)c4c3CCCC4)cc2)n1
Temperature: 150 °C

Procedure:
A resealable reaction tube was charged with 1,4-dichloro-5,6,7,8-tetrahydrophthalazine (0.050 g, 0.246 mmol), 4-(2-(4-aminophenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (0.072 g, 0.246 mmol), tris(dibenzylideneacetone)dipalladium (0)(0.011 g, 0.012 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (0.020 g, 0.049 mmol), and sodium tert-butoxide (0.033 g, 0.345 mmol). The vial was purged with nitrogen for several minutes, followed by addition of 0.50 mL of toluene. The vial was capped and heated to 150° C. for 16 h. The reaction mixture was allowed to cool and was filtered through a plug of Celite, rinsing with dichloromethane. The filtrate was concentrated, and the crude material was purified by reverse phase chromatography, Gilson, 5-95% acetonitrile/H2O/0.1% TFA over 14 min. The product-containing fractions were combined, brought to basic pH by addition of 2M Na2CO3 and extracted with dichloromethane. The organic portion was dried with MgSO4, filtered, and concentrated to give 4-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-5,6,7,8-tetrahydrophthalazin-1-amine as a light brown solid. MS m/z=460 [M+H]+. Calc'd for C24H22ClN7O: 459.93.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[NH2:11][C:12]1[CH:16]=[C:15]([CH3:17])[NH:14][N:13]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>C(O)CCC>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([NH:11][C:12]2[NH:13][N:14]=[C:15]([CH3:17])[CH:16]=2)[CH:7]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: Cc1cc(N)n[nH]1
Agent: [I-]
Agent: [Na+]
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(Cl)cc(Nc2cc(C)n[nH]2)n1
Temperature: 120 °C
Reaction time: 15 h

Procedure:
To a solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine (5 g, 25.6 mmol) and 3-amino-5-methylpyrazole 2.61 g, 26.9 mmol) in BuOH (60 mL) is added diisopropylethylamine (4.69 mL, 26.9 mmol) followed by sodium iodide (3.84 g, 25.6 mmol). The reaction mixture is stirred for 15 hours at 120° C. The solvent is then removed in vacuo and the residue is purified by flash chromatography (SiO2, hexane/AcOEt gradient) to give [6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: C=O.Cl.CON=C[C@H:8]([F:33])[C@H:9]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C@@H:10]([Br:22])[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.[C:34](=O)([O-])[OH:35].[Na+]>CC(C)=O.C(OCC)(=O)C>[Br:22][C@@H:10]([CH2:11][O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C@@H:9]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C@H:8]([F:33])[CH:34]=[O:35]
Reactant: CON=C[C@H](F)[C@H](OCc1ccc(OC)cc1)[C@@H](Br)COCc1ccc(OC)cc1
Reactant: O=C([O-])O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(COC[C@H](Br)[C@@H](OCc2ccc(OC)cc2)[C@H](F)C=O)cc1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
4.2 mL of a 35% formaldehyde solution and 4.2 mL of 2 mol/L hydrochloric acid were added to a solution of 857 mg of (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis((4-methoxybenzyl)oxy)pentanal O-methyloxime in 17 mL of acetone at room temperature, and the obtained mixture was then stirred at room temperature for 1.75 hours. Thereafter, ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture. The organic layer was fractionated, and it was washed with a saturated sodium chloride aqueous solution and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 60/40), so as to obtain 598 mg of colorless oily (2S,3S,4S)-4-bromo-2-fluoro-3,5-bis((4-methoxybenzyl)oxy)pentanal and a water adduct thereof.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=2)=[O:5])[CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.O.[ClH:25].N1C=CC=CC=1>CC#N.C(OCC)(=O)C>[Cl:25][CH2:3][CH2:2][CH2:1][C:4]([C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: Cc1cccc(C(=O)C2CC2)c1
Reactant: Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1cccc(C(=O)CCCCl)c1
Yield: 46.9 %

Procedure:
A solution of Example 91A (2.56 g, 16.9 mmol), TsOH.H2O (3.2 g, 16.9 mmol) and pyridine hydrochloride (3.88 g, 33.8 mmol) in CH3CN (60 mL) was heated at 160° C. for 3 hours under microwave and the CH3CN was removed by reduced pressure to give a residue, which was re-dissolved in ethyl acetate (100 mL). The resulting organic solution was washed with aqueous NaHCO3 (50 mL) and brine (50 mL), dried over MgSO4, filtered, and concentrated to give a black oil. The oil was purified by chromatography on silica gel column (petroleum ether:ethyl acetate=20:1) to give the title compound (1.56 g, 50%). LC-MS (M+H): m/z 197. 1H NMR (400 MHz, CDCl3): δ ppm 7.765-7.786 (m, 2H), 7.354-7.397 (m, 2H), 3.679 (t, J=6.2 Hz, 2H), 3.170 (t, J=6.2 Hz, 2H), 2.419 (s, 3H), 2.194-2.260 (m, 2H).
Reaction SMILES: [CH3:1][C:2](=[O:7])[C:3]([CH3:6])([CH3:5])[CH3:4].[C:8](=O)([O:12]CC)[O:9][CH2:10][CH3:11].CN(C)P(=O)(N(C)C)N(C)C.C(O)C>C1C=CC=CC=1>[CH2:10]([O:9][C:8](=[O:12])[CH2:1][C:2](=[O:7])[C:3]([CH3:6])([CH3:5])[CH3:4])[CH3:11]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)C(C)(C)C
Solvent: c1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCO
Product: CCOC(=O)CC(=O)C(C)(C)C
Reaction time: 9 h
Yield: 54 %

Procedure:
A solution of 100 g of pinacolone in 500 cc of benzene was added dropwise over a period of 4 hours at 50° C/150 Torr to a solution of 500 cc of benzene, 900 cc of diethyl carbonate, 125 g of potassium-tert.-butylate and 200 cc of hexamethyl phosphoric acid triamide, and benzene and ethanol slowly distilled off. After the ketone had been added, another 500 cc of benzene were added dropwise. The total reaction time was 9 hours. The reaction mixture was then treated and distilled in the same way as described in 1 above. The yield was 54% of pivaloyl acetic acid ethyl ester.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][CH2:3]1.S(Cl)(Cl)=O.CN(C)C=O.[NH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[NH:28][CH:27]=[C:26]([C:30]([OH:32])=[O:31])[C:25]2=[O:33].C(N(CC)CC)C.Cl[Si](C)(C)C>ClCCl>[O:33]=[C:25]1[C:24]2[C:29](=[C:20]([NH:19][C:7]([CH:5]3[CH2:4][CH2:3][C:2](=[O:1])[NH:6]3)=[O:9])[CH:21]=[CH:22][CH:23]=2)[NH:28][CH:27]=[C:26]1[C:30]([OH:32])=[O:31]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: Nc1cccc2c(=O)c(C(=O)O)c[nH]c12
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C1CCC(C(=O)Nc2cccc3c(=O)c(C(=O)O)c[nH]c23)N1
Temperature: 25 °C
Yield: 53.9 %

Procedure:
A mixture of 3.87 g (30 mmol) of 5-oxo-L-proline, 2.19 ml (30 mmol) of thionyl chloride, 2.32 ml (30 mmol) of dimethylformamide, and 75 ml of dichloromethane is stirred with cooling for 1 hour. A mixture of 4.08 g (20 mmol) 8-amino-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 8.4 ml (60 mmol) of triethylamine, 7.6 ml (60 mmol) of chlorotrimethylsilane, and 100 ml of dichloromethane is stirred at room temperature for 40 minutes and then is cooled to 0°. The cold acid chloride solution is added to the cold silylated quinoline and the mixture is stirred with cooling for 4 hours and at room temperature overnight. The reaction mixture is evaporated to dryness and the residue is treated with ethanol to give 3.40 g of 1,4-dihydro-4-oxo-8-[[(5-oxo-2-pyrrolidinyl)carbonyl]amino]-3-quinolinecarboxylic acid.
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH2:7][C:8]1[N:9]=[CH:10][N:11]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1)=O.[OH-].[Na+]>O1CCCC1.CO.O>[C:13]([N:11]1[CH:12]=[C:8]([CH2:7][CH2:6][NH2:5])[N:9]=[CH:10]1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
The above amide (45.54 g; 0.101 mmol) was dissolved in tetrahydrofuran (1000 mL) and methanol (1200 mL). A solution of sodium hydroxide (20.26 g; 0.507 mol) in water (500 mL) was added. Mixture was stirred for 2 hrs at room temperature and then it was concentrated in vacuo. The residue was separated between chloroform (1200 mL) and water (800 mL). Aqueous layer was extracted with chloroform (3×400 mL). Organic layers were combined and dried over anhydrous magnesium sulfate. Evaporation of the solvent yielded brown oil, which was dried for 3 days in vacuo to give the title product as beige solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][CH2:5][CH2:6]OS(C)(=O)=O.[NH:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH:23][CH:24]1[CH2:29][CH2:28][N:27](C(OCC)=O)[CH2:26][CH2:25]1>>[F:1][C:2]([F:13])([F:12])[CH2:3][O:4][CH2:5][CH2:6][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: CS(=O)(=O)OCCOCC(F)(F)F
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Product: FC(F)(F)COCCn1c(NC2CCNCC2)nc2ccccc21

Procedure:
Prepare by the method of Preparation 14 using 2-methanesulfonyloxyethyl 2,2,2-trifluoroethyl ether and (1H-benzimidazol-2-yl)(1-ethoxycarbonylpiperidin-4-yl)amine to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:10])[C:7]=1[CH:8]=[O:9].Cl.[F:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.CN1C(=O)CCC1.[OH-].[K+:29]>O>[OH-:9].[K+:29].[Br:10][C:6]1[CH:5]=[N:4][CH:3]=[C:2]2[N:19]([C:16]3[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=3)[N:20]=[CH:8][C:7]=12
Reactant: NNc1ccc(F)cc1
Reactant: O=Cc1c(Br)cncc1Br
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Fc1ccc(-n2ncc3c(Br)cncc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 1 L flask was charged 3,5-dibromopyridine-4-carboxaldehyde (50.0 g, 188.7 mmol, 1.0 eq) and 4-fluorophenylhydrazine hydrochloride (31.0 g, 190.7 mmol, 1.01 eq). NMP (250 mL) was charged, and the resulting slurry was stirred at ambient temperature for 2 hours. A solution of aqueous KOH was prepared from 85% KOH pellets (27.4 g, 415.2 mmol, 2.2 eq) and water (27.4 mL), and this KOH solution was charged to the reaction mixture. The batch was heated to 80° C. and held at this temperature for 30-60 minutes. Water (250 mL) was then charged at 80° C., and the resulting slurry was cooled to ambient temperature over 4-16 hours. The slurry was filtered, the solid was washed with water, and oven dried under vacuum to afford 4-bromo-1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine as a tan colored solid, 51.5 g, 99.3 area % purity by HPLC, 93% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([O:13][CH3:14])[C:4]=1[O-:5].[K+].C([O-])([O-])=O.[K+].[K+].[Na+].[I-].Br[CH2:25][CH2:26][Cl:27]>CC#N>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([O:13][CH3:14])[C:4]=1[O:5][CH2:25][CH2:26][Cl:27]
Reactant: COc1cc([N+](=O)[O-])cc(OC)c1[O-]
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc([N+](=O)[O-])cc(OC)c1OCCCl

Procedure:
A mixture of potassium 2,6-dimethoxy-4-nitrophenoxide (Step B, 3.3 g, 13.9 mmol), K2CO3 (5.8 g, 41.8 mmol), NaI (0.21 g, 1.39 mmol), and 1-bromo-2-chloroethane (11.6 mL, 139 mmol) in CH3CN (50 mL) was stirred and heated under reflux under N2 for 40 h when the color had turned pale brown. Filtration, washing the solids well with CH3CN and evaporating the filtrate gave 3,5-dimethoxy-4-(2-chloroethoxy)nitrobenzene as a pale brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([I:19])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[C:8]([C:13]([O:15]CC)=[O:14])=[C:7]2O.C1COCC1.[Li+].[OH-]>CO.C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([I:19])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:13]([OH:15])=[O:14])=[CH:7]2
Reactant: CCOC(=O)c1c(O)c2cc(I)cc(F)c2[nH]c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(O)c1cnc2c(F)cc(I)cc2c1
Temperature: 40 °C
Yield: 70.6 %

Procedure:
To a solution of ethyl 8-fluoro-4-hydroxy-6-iodoquinolone-3-carboxylate (1.5 g) in 60 mL of 1:1 MeOH:THF is added 16 mL of 1M LiOH. The reaction is maintained at 40° C. overnight. The reaction mixture is cooled to room temperature, then diluted with 40 mL glacial acetic acid. The resulting precipitate is collected, washed with H2O, and dried to yield 0.890 g of 8-fluoro-6-iodoquinoline-3-carboxylic acid as a white solid. This acid (0.25 g) and 1,1'-carbonyldiimidazole (0.146 g) are dissolved in mL anhydrous THF and heated at 65° C. for 3 days. After the reaction mixture is cooled to room temperature, 4-chlorophenylhydrazine (0.161 g) and diisopropylethylamine (0.16 mL) are added. The reaction mixture is heated at 65° C. overnight to solubilize the reactants. The mixture is cooled to room temperature and partitioned between EtOAc and H2O. The aqueous layer is extracted with EtOAc (2×). The combined organic layers are washed with brine (1×), dried over Na2SO4, and condensed. The crude product is recrystallized with EtOAc/hexanes to yield 0.13g of the desired product as an off-white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH:13]1([N:16]=[C:17]=S)[CH2:15][CH2:14]1>>[Cl:8][C:6]1[S:5][C:4]2[S:9](=[O:10])(=[O:11])[N:12]=[C:17]([NH:16][CH:13]3[CH2:15][CH2:14]3)[NH:2][C:3]=2[CH:7]=1
Reactant: S=C=NC1CC1
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Agent: Cl
Product: O=S1(=O)N=C(NC2CC2)Nc2cc(Cl)sc21

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and cyclopropyl isothiocyanate by a procedure analogous to the procedure described in example 3Bc-d; mp 272°-273° C.; 1H-NMR (DMSO-d6 ): δ 0.55 (m, 2H), 0.78 (m, 2H), 2.6 (m, 1H), 7.10 (s, 1H), 7.88 (br. s, 1H), 10.95 (br. s, 1H).
Reaction SMILES: C([O:3][C:4](=O)[C@H:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)[NH:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([Br:14])[CH:9]=1)C.[BH4-].[Na+].CO.O>O1CCCC1>[Br:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][N:11]=1)[C:7]([NH:6][CH:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)[CH2:4][OH:3])=[O:15]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC)c(OC)c1)NC(=O)c1ccnc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CC(CO)NC(=O)c2ccnc(Br)c2)cc1OC
Yield: 88.2 %

Procedure:
To a solution of N-(2-bromoisonicotinoyl)-3-(3,4-dimethoxyphenyl)alanine ethyl ester (12.8 g) in tetrahydrofuran (100 ml) is added sodium borohydride (3.3 g), and thereto is added dropwise methanol (15 ml) with heating under reflux over a period of three hours. The reaction mixture is cooled with ice, and thereto is added water. The mixture is extracted with chloroform, and the extract is washed, dried, and concentrated to give 2-(2-bromoisonicotinoylamino)-3-(3,4-dimethoxyphenyl)-1-propanol (10.2 g).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]1)=[O:5])C>CO.[OH-].[Na+]>[CH2:12]([N:9]1[CH2:8][CH2:7][C:6]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN1CCC(C(=O)OCC)(S(=O)(=O)c2ccc(OC)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCN1CCC(C(=O)O)(S(=O)(=O)c2ccc(OC)cc2)CC1

Procedure:
1-Butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (6.42 g 16.8 mmol) dissolved in methanol (200 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.6 g (27%); white powder; mp 206 ° C.; MS: 356.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:35][CH:36]([CH3:38])[CH3:37])[C@H:19]1[CH2:24][C@@H:23]([CH:25]2[CH2:27][O:26]2)[CH2:22][N:21]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20]1)=[O:17].[CH3:39][O-:40].[Na+].CO>CO>[OH:26][CH:25]([C@@H:23]1[CH2:24][C@H:19]([N:18]([C:16]([C:8]2[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)=[O:17])[CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:20][N:21]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:22]1)[CH2:27][O:40][CH3:39]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C3CO3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(O)COC)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 70 °C
Reaction time: 6 h

Procedure:
tert-Butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-oxirane-2-ylpiperidine-1-carboxylate (200 mg) was dissolved in methanol (5 ml), 28% sodium methylate-methanol solution was added, and the mixture was stirred at 70° C. for 6 hr. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object product (157 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH2:9][N:10]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=2[C:32]2[CH:37]=[C:36]([CH:38]([CH3:40])[CH3:39])[CH:35]=[CH:34][C:33]=2[O:41][CH3:42])[C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.C([O-])(O)=O.[Na+].[N-:63]=[N+:64]=[N-:65].[Na+]>C(Cl)Cl.O>[N:63]([CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:9][N:10]([CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:25]=[CH:24][C:23]=1[C:32]1[CH:37]=[C:36]([CH:38]([CH3:40])[CH3:39])[CH:35]=[CH:34][C:33]=1[O:41][CH3:42])[C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[N+:64]=[N-:65]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(CC(O)c1ccc(Cl)cc1)C(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(CC(N=[N+]=[N-])c1ccc(Cl)cc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of benzyl [2-(4-chlorophenyl)-2-hydroxyethyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. (44 mg, 0.07 mmol) in CH2Cl2 (6 mL) was cooled to 0° C. and N,N diisopropylethylamine (63 lit, 0.36 mmol) was added followed by methanesulfonyl chloride (14 μL, 0.18 mmol). The reaction was stirred at 0° C. for 30 minutes and then poured into saturated NaHCO3 (15 mL). The resultant mixture was extracted with EtOAc (50 mL) and the organic layer was washed with brine (15 mL), dried over Na2SO4, filtered through a short plug of silica gel, and concentrated. The residue was redissolved in DMPU (6 mL) and sodium azide (12 mg, 0.18 mmol) was added. The reaction was stirred at room temperature for 24 hours and then poured into H2O (15 mL). The resultant mixture was extracted with EtOAc (50 mL) and the organic layer was washed with H2O (2×15 mL) and brine (15 mL), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography with 25% EtOAc/hexanes afforded benzyl [2-azido-2-(4-chlorophenyl)ethyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. Rf=0.66 (25% EtOAc/hexanes). LCMS=637.3 (M+1)+. 1H NMR (C6D6, 600 MHz, peaks doubled; rotamers and/or atropisomers present) δ 8.03-6.52 (m, 15 H), 5.00-5.08 (m, 2H), 4.76-4.12 (m, 3H), 3.28-2.86 (m, 5H), 2.77 (m, 1H), 1.23-1.18 (m, 6H).