Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[N:4][C:5](Br)=[CH:6][N:7]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1B(O)O.C([O-])(O)=O.[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:3]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[N:4][C:5]([C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)=[CH:6][N:7]=1
Reactant: OB(O)c1cccs1
Reactant: Nc1ncc(Br)nc1NCc1ccc(O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncc(-c2cccs2)nc1NCc1ccc(O)cc1

Procedure:
A mixture of 4-[(3-amino-6-bromo-pyrazin-2-ylamino)-methyl]-phenol (25 mg, 0.085 mmol), 2-thiopheneboronic acid (13 mg, 0.10 mmol), Pd(PPh3)2Cl2 (2 mg, 0.0028 mmol), and NaHCO3 (21 mg, 0.25 mmol) in DME (0.5 mL) and water (0.15 mL) was put in a microwave reaction tube and reacted in a microwave reactor at 110° C. for 7 minutes. The reaction mixture was partitioned in ethyl acetate and water, and the organic layer was evaporated. The residue was purified on a C-18 reversed phase preparative HPLC eluting with Methanol/Acetonitrile containing 0.1% trifluoroacetic acid to 4-[(3-amino-6-thiophen-2-yl-pyrazin-2-ylamino)-methyl]-phenol trifluoroacetic add salt as a white solid (12 mg).
Reaction SMILES: [OH:1][C:2]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][O:3]1.[CH3:23]O>>[CH3:23][O:1][C:2]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:6](=[O:7])[C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[CH:12][CH:13]=2)=[CH:4][O:3]1
Reactant: CO
Reactant: O=C(O)c1ccc(C2=COC(O)(c3ccccc3)C2=O)cc1
Product: COC1(c2ccccc2)OC=C(c2ccc(C(=O)O)cc2)C1=O
Reaction time: 17 h
Yield: 91.6 %

Procedure:
A solution of 1.50 g of 2-hydroxy-2-phenyl-4-(4-carboxyphenyl)-3(2H)-furanone in 100 ml of methanol was heated under reflux with stirring for 17 hrs. The reaction mixture was concentrated to a volume of 20 ml, seeded with the product and the precipitate was collected after standing at 0° C for 3 days. The precipitate was collected, washed with cold methanol and ether and dried at 0° C for 4 hrs. to give 1.42 g (91.6%) of 2-methoxy-2-phenyl-4-(4-carboxyphenyl)-3(2H)-furanone as colorless crystals, m.p. 212°-214° C.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26]([CH2:28][NH2:29])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.C1COCC1.[CH3:37][N:38]([CH3:42])[C:39](Cl)=[O:40]>C(N(CC)CC)C>[F:31][C:2]([F:30])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26]([CH2:28][NH:29][C:39]([N:38]([CH3:42])[CH3:37])=[O:40])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: NCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1
Reactant: CN(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)NCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1

Procedure:
To a solution of 5-(6-aminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (50 mg, 0.12 mmol), THF (5 mL), and dimethylcarbamyl chloride (50 mg) is added triethylamine (50 mg). After 10 min the solution is partitioned between EtOAc and water. The organic layer is separated and washed further with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:9][CH:8]=[CH:7]2)([O-])=O.[H][H]>CO.C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[N:9][CH:8]=[CH:7]2
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc([N+](=O)[O-])ccc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Yield: 94.7 %

Procedure:
di-tert-butyl (6-nitroisoquinolin-1-yl)imidodicarbonate (75.00 g, 0.193 mol) in methanol/THF (500 ml/500 ml) was hydrogenated with a hydrogen balloon in the presence of Pd/C (5%, 5 g) for 2.0 h. Filtration of the Pd/C and concentration gave a solid, which was recrystallized from methanol to give 65.72 g (94.97%) of di-tert-butyl (6-aminoisoquinolin-1-yl)imidodicarbonate as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.33 (m, 18 H) 4.18 (s, 2 H) 6.89 (d, J=2.20 Hz, 1 H) 6.99 (dd, J=9.01, 2.42 Hz, 1 H) 7.35 (d, J=6.59 Hz, 1 H) 7.75 (d, J=8.79 Hz, 1 H) 8.22 (d, J=5.71 Hz, 1 H). LC-MS: 741 (2M+Na)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:39][C:40]1[CH:41]=[CH:42][C:43]2[O:47][C:46]([S:48]([N:51]3[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]3)(=[O:50])=[O:49])=[CH:45][C:44]=2[CH:57]=1>CN(C)C=O>[Cl:39][C:40]1[CH:41]=[CH:42][C:43]2[O:47][C:46]([S:48]([N:51]3[CH2:56][CH2:55][N:54]([C:11](=[O:13])[C:10]4[CH:9]=[CH:8][C:7]([C:4]5[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=5)=[CH:15][CH:14]=4)[CH2:53][CH2:52]3)(=[O:49])=[O:50])=[CH:45][C:44]=2[CH:57]=1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Reactant: O=S(=O)(c1cc2cc(Cl)ccc2o1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2ccncc2)cc1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3o2)CC1
Reaction time: 8 h
Yield: 12.4 %

Procedure:
A stirred suspension of 4-(4-pyridyl)benzoic acid (133 mg, 0.67 mmol) in dimethylformamide (5 ml) was treated sequentially with 1-hydroxybenzotriazole hydrate (108 mg, 0.8 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (153 mg, 0.8 mmol) and 1-(5-chlorobenzofuran-2-ylsulphonyl) piperazine (201 mg,0.67 mmol). After stirring overnight the solvent was removed in vacuo and the residue chromatographed (Merck Art 9385 silica, eluting with dichloromethane containing 2% v/v of methanol) to yield 1-(5-chlorobenzofuran-2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine as a colourless solid (40 mg), 1H NMR (CDCl3) δ=3.2-3.4 ppm (broad s, 4H), δ=3.6-4.0 ppm (broad s, 4H), δ=7.35 ppm (s, 1H), δ=7.5 ppm (m, 6H), δ=7.7 ppm (m, 3H), δ=8.7 ppm (d, 2H), MS (M+H)+ 482/484.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][C:18](=O)[CH3:19])[CH:9]([C:14](=O)[CH3:15])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:25]>C(O)(=O)C.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[CH3:15][C:14]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:17]=[C:18]([CH3:19])[N:25]=1
Reactant: COC(=O)C(C(C)=O)C(CC(C)=O)c1ccc(F)cc1
Reactant: [NH4+]
Agent: Cl[Fe](Cl)Cl
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1c(-c2ccc(F)cc2)cc(C)nc1C

Procedure:
A suspension of 28.0 g (100 mmol) of methyl 3-(4-fluorophenyl)-2-(1-oxoethyl)-5-oxohexanoate (=Xa from Example 1), 120 g of ammonium acetate and 120 g of iron(III) chloride hexahydrate in 1000 ml of glacial acetic acid was refluxed, with stirring, until the precursor could no longer be detected by thin-layer chromatography (4 h). The mixture was cooled and then filtered, and the solid residue was washed with ethanol and toluene. The filtrate was evaporated and then the residue was suspended in water, the pH was adjusted to 8-9 by addition of solid sodium bicarbonate, and the mixture was extracted several times with ether. The combined extracts were washed with saturated NaCl, dried over MgSO4 and evaporated. Purification of the crude product by column chromatography (silica gel, cyclohexane/ethyl acetate 2:1) provided 23.6 g (91%) of XVa in the form of white crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C@H:3]1[C:14]([OH:16])=[O:15].[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.P(O)(O)([O-])=O.[Na+]>O1CCCC1>[CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:11])[CH3:12])[C@H:3]1[C:14]([O:16][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:15]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)OCc2ccccc2)C1(C)C
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
A solution of 25 g of (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-tert.-butoxy-1-propenyl]-cyclopropane-carboxylic acid in 250 ml of tetrahydrofuran were added at 10° C. to a mixture of 2.6 g of sodium hydride in 100 ml of tetrahydrofuran and the mixture was stirred at 15° C. for 30 minutes. A solution of 35 ml of benzyl bromide in 100 ml of tetrahydrofuran was added to the mixture which was heated at 50° C. for 48 hours and then was cooled and poured into aqueous monosodium phosphate solution. The mixture was extracted with isopropyl ether and the organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 9-1 hexane-isopropyl ether mixture to obtain 30 g of benzyl (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-tert.-butoxy-1-propenyl]-cyclopropane-carboxylate.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:16]4[C:17]=3[C:12](=[CH:13][CH:14]=[CH:15]4)[N:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.Cl.N1(CCCNC2C3C=CC=C4C=3C(=CC=C4)N=2)C=CN=C1.[C:45](Cl)(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[N:11]1[C:12]2[C:17]3[C:16](=[CH:21][CH:20]=[CH:19][C:18]=3[C:10]=1[N:9]([CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[C:45](=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH:15]=[CH:14][CH:13]=2
Reactant: O=C(Cl)c1ccccc1
Reactant: c1cc2c3c(cccc3c1)C(NCCCn1ccnc1)=N2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(c1ccccc1)N(CCCn1ccnc1)C1=Nc2cccc3cccc1c23
Temperature: 25 °C
Reaction time: 4 h
Yield: 14.5 %

Procedure:
Five grams of N-(3-(1H-imidazol-l-yl)propyl)benz(cd)indole-2-amine (the free base of the compound of Example 1) and 100 mg of 4-dimethylaminopyridine were dissolved in 50 ml of pyridine. The solution was stirred as 2.8 grams of benzoyl chloride was slowly added. An exotherm was noted. The mixture was stirred at room temperature for 4 hours and then drowned onto 500 ml of ice. The precipitated solid was collected, washed with water, and dried. Recrystallization from chloroform-hexane gave 1.0 gram of desired compound, mp 148° C.-153° C., with decomposition.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[C:5]([O:9][C:10]([N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].OS([O-])(=O)=O.[Na+]>CCOCC>[C:5]([O:9][C:10]([N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:1][CH3:2])([OH:22])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)c2ccccc21
Reactant: CC[Mg]Br
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CCC1(O)CCN(C(=O)OC(C)(C)C)c2ccccc21
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
To a flame-dried 5-mL rb flask containing ethylmagnesium bromide (4.0 mL of a 3.0M solution in Et2O, 12.0 mmol, 3.0 equiv), at -10° C. was added dropwise a solution of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-quinolone (1.0 g, 4.0 mmol) in Et2O (4 mL). The reaction mixture was stirred at -10° C. for 15 min, then allowed to warm to rt over 10 min. A 1.0M solution of NaHSO4 (10 mL) was then rapidly added. The resulting biphasic mixture was extracted with EtOAc (3×10 mL), and the combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc, 4:1), affording 800 mg (71%) of the desired product as a clear yellow oil (Rf0.14, hexanes/EtOAc, 4:1). Data for 1-tert-butoxycarbonyl-4-ethyl-1,2,3,4-tetrahydro-4-hydroxyquinoline: 1H NMR (400 MHz, CDCl3) 7.68 (d, 1H, J=8.4, 8-H), 7.47 (dd, 1H, J=7.9, 1.7, 5-H), 7.21 (ddd, 1H, J =7.4, 7.4, 1.6, 6-H), 7.09 (ddd, 1H, J=7.8, 7.8, 1.1, 7-H), 4.03 (ddd, 1H, J=12.9, 7.1, 4.7, 2 -H), 3.47 (ddd, 1H, J=13.1, 8.6, 4.3, 2-H), 2.11 (ddd, 1H, J=13.5, 8.6, 4.8, 3-H), 1.86 (m, 3H, 3-H, CH2CH3), 1.52 [s, 9H, C(CH3)3 ], 0.89 (t, 3H, J=7.5, CH3).
Reaction SMILES: [CH3:1][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[C:14]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[CH3:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([CH3:33])[C:31]=1[OH:32].[O-]CC.[Na+]>C(O)C.C(OCC)(=O)C>[OH:5][C:4]([C:7]([F:10])([F:8])[F:9])([CH2:3][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[C:14]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:13]=1)([CH3:1])[CH3:11])[CH2:6][N:28]1[CH:29]=[C:30]([CH3:33])[C:31](=[O:32])[C:26]([CH3:25])=[CH:27]1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cc(S(C)(=O)=O)cc2c1OCC2
Reactant: Cc1cncc(C)c1O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cn(CC(O)(CC(C)(C)c2cc(S(C)(=O)=O)cc3c2OCC3)C(F)(F)F)cc(C)c1=O
Temperature: 85 °C

Procedure:
To a suspension of 7-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]-5-methanesulfonyl-2,3-dihydrobenzofuran (51.0 mg) and 3,5-dimethylpyridin-4-ol (B. Boduszek et al., Synthesis, 1979, pp. 452-453) (34 mg) in anhydrous ethanol (0.40 mL) was added sodium ethoxide (21 wt. % solution in ethanol, 52.0 μL). After heating at 85° C. for 16 hours, the reaction mixture was diluted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:8][C:7](=[O:9])[CH:6]=[CH:5][N:4]=1.[Li+].[CH3:11][Si]([N-][Si](C)(C)C)(C)C.CI>CN(C=O)C>[CH3:11][N:8]1[C:7](=[O:9])[CH:6]=[CH:5][N:4]=[C:3]1[S:2][CH3:1]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CSc1nccc(=O)[nH]1
Agent: [Li+]
Solvent: CI
Solvent: CN(C)C=O
Product: CSc1nccc(=O)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
A 0° C. suspension of 2-(methylthio)pyrimidin-4(3H)-one (2.0 g, 14.1 mmol) in DMF (40 mL) was treated with solid LiHMDS (3.06 g, 18.3 mmol), followed by methyl iodide (1.14 mL, 18.3 mmol), warmed to RT and stirred overnight. The mixture was quenched with water, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 3-methyl-2-(methylthio)pyrimidin-4(3H)-one (1.37 g, 62%). 1H NMR (400 MHz, DMSO-d6): δ 7.83 (d, J=6.5 Hz, 1H), 6.17 (d, J=6.5 Hz, 1H), 3.39 (s, 3H), 2.54 (s, 3H); MS (ESI) m/z: 157.1 (M+H+).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[Br:8][C:9]1[C:19]([OH:20])=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]=1[OH:21].I[CH2:23][CH3:24]>O>[Br:8][C:9]1[C:10]([OH:21])=[CH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:18][C:19]=1[O:20][CH2:23][CH3:24]
Reactant: CCOC(=O)c1cc(O)c(Br)c(O)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(O)c(Br)c(OCC)c1
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% oil, 3.86 g) was added to a DMF (100 mL) solution of ethyl 4-bromo-3,5-dihydroxybenzoate (12.3 g), and the mixture was stirred at 00° C. for 30 minutes in a nitrogen atmosphere. Iodoethane (4.15 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (8.87 g).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH:15]1([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[C:20]([F:26])[CH:19]=2)[CH2:17][CH2:16]1>>[CH:15]1([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][O:1][C:2]3[N:6]([C:7]4[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=4)[N:5]=[CH:4][CH:3]=3)=[C:20]([F:26])[CH:19]=2)[CH2:17][CH2:16]1
Reactant: OCc1ccc(C2CC2)cc1F
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(C3CC3)cc2F)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-cyclopropyl-2-fluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (800 MHz, CDCl3): δ 0.68-0.73 (2H, m), 0.99-1.04 (2H, m), 1.86-1.92 (1H, m), 5.24 (2H, s), 5.80 (1H, d, J=4.0 Hz), 6.78 (1H, dd, J=4.0 Hz, 23.2 Hz), 6.88 (1H, dd, J=3.2 Hz, 16.0 Hz), 7.30-7.34 (1H, m), 7.39 (1H, dd, J=1.6 Hz, 9.6 Hz), 7.57 (1H, d, J=3.2 Hz), 8.00 (1H, s), 8.69 (1H, d, J=9.6 Hz). [M+H] Calc'd for C19H15FN4O, 335. Found, 335.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:10].CO.[BH4-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[OH:10]
Reactant: O=C(c1ccc(F)cc1)c1ccc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC(c1ccc(F)cc1)c1ccc(Cl)cc1Cl
Reaction time: 8 h

Procedure:
To a stirred and cooled (10°-15° C.) mixture of 25 parts of (2,4-dichlorophenyl)(4-fluorophenyl)methanone and 80 parts of methanol are added portionwise 4.9 parts of sodium borohydride at about 10° C. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is diluted with water and the solvent is evaporated. The residue is taken up in water and the product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated, yielding 22 parts of 2,4-dichloro-α-(4-fluorophenyl)benzenemethanol as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:39])[CH:5]=[C:6]([Cl:38])[C:7]=1[CH2:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[O:10][C:11](OC1C=CC([N+]([O-])=O)=CC=1)=[O:12].[SH:40][C:41]1[CH:46]=[CH:45][C:44]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])=[CH:43][CH:42]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:38][C:6]1[CH:5]=[N+:4]([O-:39])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:31])[F:32])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[O:10][C:11]([S:40][C:41]1[CH:42]=[CH:43][C:44]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])=[CH:45][CH:46]=1)=[O:12]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: CS(=O)(=O)Nc1ccc(S)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(SC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 36.5 %

Procedure:
To a stirred solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-nitrophenoxy)carbonyloxy)ethyl)pyridine 1-oxide (prepared with an analogous procedure to that described in Scheme 3, Step 1), (200 mg, 0.342 mmol) in DCM (10 ml), DMAP (41.7 mg, 0.342 mmol), and N-(4-mercaptophenyl)methanesulfonamide (83 mg, 0.410 mmol) were sequentially added. The mixture was stirred at RT for 4 hours, then the solvent was removed and the crude purified by flash chromatography on silica gel (DCM:MeOH 10:0.2). The resulting product was further purified by flash chromatography on silica gel (EtOAc:DCM 8:2) and the desired product was obtained (81 mg, 0.125 mmol, 36.5% yield, MS/ESI+ 649.28 [MH]+, [αD]=−59.64, c=0.44 in DCM).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=O.CC(O)=O.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[N:20]1([CH2:1][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(CN2CCCCC2)CC1
Yield: 92.7 %

Procedure:
To 1,1-dimethylethyl 4-formyl-1-piperidinecarboxylate (1.02 g, 4.78 mmol) in 1,2-dichloroethane (50 mL) was added sequentially, HOAc (6.00 mL, 1M in DCM, 6.00 mmol), piperidine (1.0 mL, 10.1 mmol) and sodium triacetoxyborohydride (1.60 g, 7.55 mmol). The reaction was stirred at rt for 2 hours at which time HOAc (1.00 mL, 1M in DCM, 1.00 mmol) and sodium triacetoxyborohydride was added. When complete by TLC the reaction was quenched with saturated NaHCO3 (150 mL) and extracted with DCM. The combined organic layer was washed with H2O, dried (MgSO4) and concentrated to provide the title compound (1.25 g, 4.43 mmol, 93%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.80-0.91 (m, 2H), 1.29-1.35 (m, 11H), 1.38-1.46 (m, 4H), 1.59 (d, J=10.6 Hz, 3H), 2.00 (d, J=6.8 Hz, 2H), 2.21 (br. s., 4H), 2.62 (br. s., 2H), 3.85 (d, J=12.6 Hz, 2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C@@H:6]([N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C@H:7]([CH3:10])[CH2:8][OH:9].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([O:9][CH2:8][C@@H:7]([CH3:10])[C@H:6]([N:11]([C:12]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:18])[CH3:19])[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)(=[O:30])=[O:29]
Reactant: C[C@H](CO)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](COS(C)(=O)=O)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
To a solution of tert-butyl ((1S,2S)-1-(furan-2-yl)-3-hydroxy-2-methylpropyl)(methyl)-carbamate (108 mg, 0.40 mmol) in DCM (2 mL) at 0° C. was added triethylamine (81 mg, 0.112 ml, 0.80 mmol, 2 equiv) followed by methanesulfonylchloride (55 mg, 0.037 ml, 0.48 mmol, 1.2 equiv) and the solution was stirred at 0° C. for 1 hour. The solution was diluted with 10 mL DCM and washed with sat. NH4Cl solution, water and brine. After drying over MgSO4 the solution was concentrated in vacuo to give crude product 2.16a (140 mg, 99% yield). 1H NMR (CDCl3, 400 MHz) 7.38 (dd, J=1.76, 0.98 Hz, 1H) 6.35 (dd, J=3.13, 1.96 Hz, 1H) 6.31 (br. s., 1H) 5.29-5.32 (m, 1H) 4.16 (dd, J=9.98, 3.33 Hz, 1H) 3.90 (br. s., 1H) 2.89-2.96 (m, 3H) 2.68-2.75 (m, 3H) 2.55-2.67 (m, 1H) 1.48 (br. s., 9H) 1.11 (d, J=6.65 Hz, 3H)