Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.Cl.N([O-])=O.[Na+].[CH3:17][C:18]([C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)=[O:19]>O.C(#N)C>[CH3:17][C:18]([C:20]1[O:21][C:22]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=2)=[CH:23][CH:24]=1)=[O:19]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CC(=O)c1ccco1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)c1ccc(-c2cccc(C(F)(F)F)c2)o1
Temperature: 25 °C
Reaction time: 72 h
Yield: 22 %

Procedure:
A mixture of 322 g (2.0 moles) of 3-aminobenzotrifluoride, 690 ml of concentrated hydrochloric acid and 260 ml of water was heated with steam for 20 minutes at 80° and then cooled to 0°. An additional 200 ml of water was added to aid in stirring. A solution of 138 g (2.0 moles) of sodium nitrite in 500 ml of water was added dropwise while maintaining the temperature between 0°-5° by means of an ice bath. The reaction mixture was stirred for 30 minutes and then filtered to remove a small amount of solid which was discarded. The pH of the solution was adjusted to ca. 4 by the addition of 900 ml of saturated sodium acetate solution. A solution of 220 g (2.0 moles) of methyl-2-furyl ketone in 200 ml of acetonitrile was added followed by a solution of 40 g of CuCl2 . 2H2O in 100 ml of water. The reaction was stirred at 5°-15° for 1 hour and then warmed to room temperature becoming slightly exothermic. The reaction mixture was controlled below 33° by means of an ice bath. After 11/4 hour the reaction was no longer exothermic and was stirred at room temperature overnight. The oil mixture was extracted with 2 × 750 ml and 1 × 500 ml portions of ether. The ethereal extracts were combined and washed with 2000 ml of 5% sodium carbonate solution, with 1500 ml of water and then dried over magnesium sulfate. The ether was removed on the calab evaporator and the residue refrigerated for 72 hours. The solid which was formed was filtered, washed with pet ether and air-dried to yield 174 g. The crude product was recrystallized from 2500 ml of hexane/charcoal to yield 112 g (24%) of 5-(m-trifluoromethylphenyl)-2-furyl methyl ketone. An analytical sample was prepared by recrystallizing a sample of crude product twice from hexane/charcoal, m.p. 105°-109°.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[C:8]([OH:10])=[O:9].[OH-].[Na+].[C:13](Cl)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>O1CCOCC1>[CH2:16]([O:15][C:13]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([CH3:1])[C@@H:3]1[C:8]([OH:10])=[O:9])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[C@H]1CCCN[C@H]1C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@H]1CCCN(C(=O)OCc2ccccc2)[C@H]1C(=O)O
Reaction time: 18 h

Procedure:
(+/−)—Cis-3-methylpiperidine-2-carboxylic acid (10.4 g, 72.9 mmol) in 1,4-dioxane (200 mL) and 1 N NaOH (218 mL, 219 mmol) was treated with CBzCl (15.4 mL, 109 mmol) and stirred for 18 h. The mixture concentrated and the resulting solid was suspended in EtOAc (200 mL) and the mixture was filtered. The solids were washed with EtOAc (3 50 mL) and the solution was dried over MgSO4. The solution was concentrated to afford (+/−)-cis-1-(benzyloxycarbonyl)-3-methylpiperidine-2-carboxylic acid, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:6]=1.F[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=1>>[CH3:26][C:23]1[CH:24]=[CH:25][C:20]([N:3]2[CH:4]=[C:5]([C:7]#[C:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=3)[N:6]=[C:2]2[CH3:1])=[N:21][CH:22]=1
Reactant: Cc1ccc(F)nc1
Reactant: Cc1nc(C#Cc2cccc(C(F)(F)F)c2)c[nH]1
Product: Cc1ccc(-n2cc(C#Cc3cccc(C(F)(F)F)c3)nc2C)nc1

Procedure:
The title compound, MS: m/e=342.1 (M+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(3-trifluoromethyl-phenylethynyl)-1H-imidazole and 2-fluoro-5-methylpyridine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[C:16]([F:24])[CH:15]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[N:31]=[C:32]([Si:35]([CH3:38])([CH3:37])[CH3:36])[S:33][CH:34]=1)CCC>>[F:24][C:16]1[CH:15]=[C:14]([C:9]2[N:10]=[C:11]([CH3:13])[O:12][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([C:30]3[N:31]=[C:32]([Si:35]([CH3:38])([CH3:37])[CH3:36])[S:33][CH:34]=3)=[CH:3][CH:4]=2)[CH:19]=[CH:18][C:17]=1[S:20]([NH2:23])(=[O:22])=[O:21]
Reactant: CCCC[Sn](CCCC)(CCCC)c1csc([Si](C)(C)C)n1
Reactant: Cc1nc(-c2ccc(S(N)(=O)=O)c(F)c2)c(-c2ccc(Br)cc2)o1
Product: Cc1nc(-c2ccc(S(N)(=O)=O)c(F)c2)c(-c2ccc(-c3csc([Si](C)(C)C)n3)cc2)o1

Procedure:
The title compound was prepared according to the procedure of Example 153 (step 4) using 4-[5-(4-Bromophenyl)-2-methyl-1,3-oxazol-4-yl]-2-fluorobenzenesulfonamide instead of 2-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole and using 4-(tributylstannyl)-2-trimethylsilylthiazole instead of 4-(tributylstannyl)thiazole. The crude product was used next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH2:10]Br)[CH:7]=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH2:10][N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)[CH:7]=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13]
Reactant: COC(=O)c1cc(CBr)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(CN2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
To a solution of 5-bromomethyl-2-nitrobenzoic acid methyl ester (3.00 g, 10.9 mmol) in CH2Cl2 (100 mL) was added triethylamine (3.30 g, 33.0 mmol) and 1-methylpiperazine (3.30 g, 33.0 mmol). The mixture was heated at 50° C. under nitrogen for 16 hours, then concentrated to give crude 5-(4-methylpiperazin-1-ylmethyl)-2-nitrobenzoic acid methyl ester, which was purified by column chromatography (silica gel 230-400 mesh; 1-5% methanol in dichloromethane as eluent). Yield: 3.0 g (93%). It was further converted to its hydrochloride salt (3.7 g) by stirring in 1 M HCl in ether and was isolated by filtration.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Na+].[CH3:16][S:17][CH2:18]Cl>CN(C=O)C>[Br:1][C:2]1[C:3]([O:9][CH2:10][CH:11]2[CH2:12][CH2:13]2)=[CH:4][C:5](=[O:8])[N:6]([CH2:16][S:17][CH3:18])[CH:7]=1
Reactant: CSCCl
Reactant: Oc1cc(OCC2CC2)c(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCn1cc(Br)c(OCC2CC2)cc1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
To a solution of the title compound from Step 2 (330 mg, 1.35 mmol) in DMF (5 mL) was added NaH (40 mg, 2 mmol, 60% in mineral oil) at 0° C. The mixture was stirred at 0° C. for 30 minutes. Then, chloromethyl methyl sulfide (131 mg, 1.35 mmol) was added. The mixture was warmed to room temperature and stirred for 5 hours. The mixture was quenched with saturated aqueous NH4Cl (30 mL) and extracted with EA (10 mL×3). The combined organic layers were washed with saturated brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel (PE: EA=3:1) to afford the title compound (205 mg, 50%) as yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.60 (s, 1H), 5.86 (s, 1H), 4.96 (s, 1H), 3.84 (d, J=6.8 Hz, 2H), 2.17 (s, 3H), 1.32-1.25 (m, 1H), 0.70-0.67 (m, 2H), 0.41-0.39 (m, 2H).
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH2:10][CH2:11][C@H:12]2OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:31][CH3:32])[CH:4]=[CH:5]2.[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.[K].O>CN(C=O)C>[O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH2:10][CH2:11][C@H:12]2[N:37]2[C:33](=[O:43])[C:34]3=[CH:42][CH:41]=[CH:40][CH:39]=[C:35]3[C:36]2=[O:38])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:31][CH3:32])[CH:4]=[CH:5]2
Reactant: COc1ccc2c3c1O[C@H]1[C@H](OS(=O)(=O)c4ccc(C)cc4)CC[C@H]4[C@@H](C2)N(C)CC[C@@]341
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c3c1O[C@H]1[C@H](N4C(=O)c5ccccc5C4=O)CC[C@H]4[C@@H](C2)N(C)CC[C@@]341
Temperature: 80 °C
Reaction time: 15 h
Yield: 38.5 %

Procedure:
In 15 mL of DMF, 321 mg (0.70 mmol) of toluene-4-sulfonic acid-(4,5α-epoxy-3-methoxy-17-methyl-morphinan-6β-yl)-ester was dissolved, and 196 mg of potassium phthalimide was added thereto, followed by stirring the mixture at 80° C. for 15 hours and then at 140° C. for 20 hours. After allowing the reaction solution to cool to room temperature, water was added to the reaction mixture and the resulting mixture was extracted with chloroform. Organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated to obtain a crude product. The thus obtained crude product was purified by silica gel column chromatography to obtain 116 mg (yield: 38%) of the captioned compound.
Reaction SMILES: CN(/[CH:4]=[C:5]1\[CH2:6][C:7]([C:14]2[C:22]3[C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[O:19][C:18]=3[C:17]([O:27][CH3:28])=[CH:16][CH:15]=2)([C:12]#[N:13])[CH2:8][CH2:9][C:10]\1=O)C.Cl.[NH2:30][C:31]([NH2:33])=[NH:32].[O-]CC.[Na+]>C(O)C>[NH2:32][C:31]1[N:33]=[CH:4][C:5]2[CH2:6][C:7]([C:14]3[C:22]4[C:21]5[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=5[O:19][C:18]=4[C:17]([O:27][CH3:28])=[CH:16][CH:15]=3)([C:12]#[N:13])[CH2:8][CH2:9][C:10]=2[N:30]=1
Reactant: COc1ccc(C2(C#N)CCC(=O)/C(=C/N(C)C)C2)c2c1oc1ccccc12
Reactant: N=C(N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C2(C#N)CCc3nc(N)ncc3C2)c2c1oc1ccccc12
Temperature: 75 °C

Procedure:
A mixture of the compound obtained in example 6 (100 mg, 0.267 mmol), guanidine HCl (33.5 mg, 0.35 mmol) and sodium ethoxide (25 mg, 0.35 mmol) in 5 ml ethanol was heated at 70-80° C. for 1 hr. The mixture was cooled to room temperature and the solvent was evaporated under vacuum. The crude residue was purified by column chromatography to get 80 mg (81% yields) of a white colored solid product.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:13]=2)[CH:9]=[N:8]1.Cl[CH2:47][C:48]([NH2:50])=[O:49].C(=O)(O)[O-].[Na+]>CC(C)=O.C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:28][CH2:29][N:30]([CH2:47][C:48]([NH2:50])=[O:49])[CH2:31][CH2:32]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:34])=[O:35])[CH:13]=2)[CH:9]=[N:8]1
Reactant: NC(=O)CCl
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(CC(N)=O)CC5)cc4)cnc32)cc1
Yield: 48.9 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (50 mg. 0.077 mmol) was alkylated using 2-chloroacetamide (10 mg, 0.116 mmol) and sodium bicarbonate (20 mg, 0.231 mmol) in acetone/ethanol (5/5 mL) to get 25 mg (49.01% yield) of the titled compound. MS: m/z=663.7 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[NH:10][NH2:11].[C:12](N)(=[O:15])[CH:13]=[CH2:14].[Na]>C(O)C.C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[N:10]1[CH2:14][CH2:13][C:12](=[O:15])[NH:11]1
Reactant: NNc1cc(Cl)ccc1Cl
Reactant: C=CC(N)=O
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C1CCN(c2cc(Cl)ccc2Cl)N1

Procedure:
2,5-Dichlorophenylhydrazine hydrochloride (240 g, 1.1 mol) and acrylamide (100 g, 1.4 mol) is refluxed in a solution of sodium (56 g, 2.4 mol) in ethanol (1000 ml) and toluene (1000 ml) for 3 hours. Evaporation of the solvents, acidification with acetic acid dilution with water, filtration and drying (high vacuum, +100° C.) gives the 1-(2,5-dichlorophenyl)-3-pyrazolidone.
Reaction SMILES: [N+](C1C=CC(C([O:10][CH2:11][C@:12]2([CH3:26])[O:16][C:15](=[O:17])[N:14]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH2:13]2)=O)=CC=1)([O-])=O.[N+](C1C=CC(C(OC[C@H]2OC(=O)N(C3C=CC(OC)=CC=3)[C@H]2C)=O)=CC=1)([O-])=O>>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([N:14]2[CH2:13][C@@:12]([CH2:11][OH:10])([CH3:26])[O:16][C:15]2=[O:17])=[CH:23][CH:22]=1
Reactant: COc1ccc(N2C[C@](C)(COC(=O)c3ccc([N+](=O)[O-])cc3)OC2=O)cc1
Agent: COc1ccc(N2C(=O)O[C@H](COC(=O)c3ccc([N+](=O)[O-])cc3)[C@@H]2C)cc1
Product: COc1ccc(N2C[C@](C)(CO)OC2=O)cc1
Yield: 90 %

Procedure:
The same procedure of Reference Example 11 was repeated except that (R)-(-)-3-(4-methoxyphenyl)-5-methyl-2-oxooxazolidin-5-ylmethyl p-nitrobenzoate obtained in Reference Example 9 was used in lieu of (4S, 5S)-(-)-3-(4-methoxyphenyl)-4-methyl-2-oxooxazolidin-5-ylmethyl p-nitrobenzoate to give the title compound (yield 90% ).
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[C:4]([C:12]#N)=[C:5]([C:10]#N)[C:6](=O)[C:7]=1Cl.[OH:15][C:16]1C=C2C(=C[C:25]=1[O:26][CH3:27])CCCC2>O1CCOCC1>[OH:15][C:16]1[CH:10]=[C:5]2[C:4](=[CH:12][C:25]=1[O:26][CH3:27])[C:3](=[O:14])[CH2:2][CH2:7][CH2:6]2
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: COc1cc2c(cc1O)CCCC2
Solvent: C1COCCO1
Product: COc1cc2c(cc1O)CCCC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.8 %

Procedure:
A solution of 231 mg of 2,3-dichloro-5,6-dicyanobenzoquinone in 2 mL of dioxane was added dropwise over a period of 3 minutes to a stirred solution of 89 mg of 6-hydroxy-7-methoxytetralin dissolved in 5% aqueous dioxane under an atmosphere of nitrogen. The resulting solution was stirred at 25° C. under nitrogen for 3 hours. Thereafter the reaction mixture was filtered through a sintered glass funnel and the solid residue of 2,3-dichloro-5,6-dicyanodihydrobenzoquinone was washed with 2 mL of dioxane. The residue wash solution was combined with the filtrate. Thereafter the dioxane was evaporated from the combined filtrate at reduced atmospheric pressure. The resulting residue was chromatographed on a column of silica gel eluted with a solution of ethyl acetate and hexane in ratio of 1 to 1 to obtain 68 mg of known 6-hydroxy-7-methoxytetralin-1-one having m.p. 117-119° C. (lit. 117-119° C. Grethe, G. et al J Org. Chem, 1968, 33 504-508.)
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.[CH3:15][C:16](=[CH2:20])[C:17](Cl)=[O:18]>ClCCl>[CH3:15][CH:16]1[C:17](=[O:18])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH:8]=[CH:7][C:6]=2[CH2:20]1
Reactant: c1ccc2ccccc2c1
Reactant: C=C(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1Cc2ccc3ccccc3c2C1=O
Temperature: -30 °C
Yield: 84 %

Procedure:
Aluminum chloride powder (240 g) was added to a dry round-bottomed flask under nitrogen, after which 1 l of dichloromethane was added. The suspension was cooled to -30° C., and 100 g of naphthalene and 90.5 g of freshly distilled 2-methyl-2-propenoyl chloride in 950 ml of dichloromethane were added dropwise under nitrogen in 1.5 h. The reaction mixture was stirred for another hour at -30° C., after which the cold reaction mixture was poured into 10 l of ice water. The organic layer was separated, the water layer was extracted with dichloromethane, and the combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated to dryness. The crude product was distilled at 200° C./33 Pa, after which 127 g (84%) of 2,3-dihydro-2-methyl-1H-benz[e]indene-1-one were obtained with a purity >95% (GLC).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([OH:29])[CH:27]=3)[NH:22][CH:21]=2)[CH2:16][CH2:15]1.[OH-].[Na+]>C1COCC1>[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:29][S:9]([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])(=[O:11])=[O:10])[CH:27]=3)[NH:22][CH:21]=2)[CH2:16][CH2:15]1
Reactant: CN1CCC(c2c[nH]c3ccc(O)cc23)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)c4ccc(F)cc4F)cc23)CC1
Yield: 100.5 %

Procedure:
By a method similar to Example 31, using 2,4-difluorobenzenesulfonyl chloride (463 mg, 2.2 mmol) was added to a solution of 3-(1-methylpiperidin-4-yl)-5-hydroxy-1H-indole (418 mg, 1.8 mmol) in 0.2 N sodium hydroxide (10 mL, 2.0 mmol) and THF (5 mL) gave 735 mg of product. The crude product was recrystallized from ethyl acetate/hexanes to give 680 mg (92%) of white crystals: mp=163-164° C.; MS(m/e): 406 (M+); Calculated for C20H20F2N2O3S: C, 59.10; H, 4.96; N, 6.89. Found: C, 58.86; H, 4.94; N, 6.95.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:28][C:29]([C:32]1[CH:37]=[CH:36][C:35]([CH2:38][O:39][CH2:40][CH2:41]O)=[CH:34][CH:33]=1)([CH3:31])[CH3:30]>C(Cl)Cl.[Al]>[Br:1][CH2:41][CH2:40][O:39][CH2:38][C:35]1[CH:36]=[CH:37][C:32]([C:29]([CH3:31])([CH3:30])[CH3:28])=[CH:33][CH:34]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1ccc(COCCO)cc1
Agent: [Al]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(COCCBr)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12 %

Procedure:
A solution of N-bromosuccinimide (272 mg, 1.53 mmol) in DCM (2.5 mL) was added to resin-bound triphenylphosphine (510 mg, 1.53 mEquiv, Fluka) in DCM (2.5 mL), and the reaction was stirred at rt for 10 min. A solution of 2-({[4-(1,1-dimethylethyl)phenyl]methyl}oxy)ethanol (160 mg, 0.768 mmol) in DCM (1.5 mL) was added to the reaction, and the residual alcohol was transferred with additional DCM (1.5 mL). The reaction vial was capped, wrapped in aluminum foil, and stirred at rt for 20 h. The reaction was filtered through a SPE cartridge (5 g silica) eluting with the following 10 mL fractions: DCM (fraction 1), 30% EtOAc/hexanes (fraction 2), and 50% EtOAc/hexanes (fraction 3) to give the title compound (25 mg, 12%). The product was characterized by 1H NMR (400 MHz) in CDCl3.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C@@H:8]([NH:18][C:19](=[O:31])[CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[NH:23][CH:22]=2)[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[C:5]([C:32]2[CH:33]=[CH:34][C:35](F)=[C:36]([CH:40]=2)C(N)=O)=[CH:4][CH:3]=1.NC1N=C(C(NC(=O)CC2C3C(=CC=C(F)C=3)NC=2)CC2C=C(F)C=C(F)C=2)C(Br)=CC=1.[O:74](C1C=CC(B(O)O)=CC=1)[C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1>>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]([NH:18][C:19](=[O:31])[CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[NH:23][CH:22]=2)[CH2:9][C:10]2[CH:11]=[C:12]([F:17])[CH:13]=[C:14]([F:16])[CH:15]=2)[C:5]([C:32]2[CH:33]=[CH:34][C:35]([O:74][C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=3)=[CH:36][CH:40]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)c1cc(-c2ccc(N)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)ccc1F
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: Nc1ccc(Br)c(C(Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)n1
Product: Nc1ccc(-c2ccc(Oc3ccccc3)cc2)c(C(Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)n1

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 1H of Example 1 utilizing 1G and (4-phenoxyphenyl)boronic acid. 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.49 (d, J=9.0 Hz, 1H), 7.32 (t, J=7.8 Hz, 2H), 7.29-7.18 (m, 1H), 7.10 (m, 2H), 7.01 (m, 5H), 6.82 (t, J=9.1 Hz, 4H), 6.56 (d, J=8.9 Hz, 1H), 6.43 (s, 1H), 6.19 (d, J=6.4 Hz, 2H), 5.30 (d, J=8.0 Hz, 1H), 3.52 (s, 2H), 2.97-2.85 (m, 1H), 2.75 (dd, J=14.0, 6.9 Hz, 1H). MS (m/z) 592.8 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:23]=2[C@H:24]2[CH2:29][C@@H:28]([NH:30]C(=O)OC(C)(C)C)[C@@H:27]([OH:38])[C@@H:26]([CH3:39])[CH2:25]2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:40].[CH3:41][S:42](Cl)(=[O:44])=[O:43]>N1C=CC=CC=1>[CH3:41][S:42]([O:38][C@H:27]1[C@@H:26]([CH3:39])[CH2:25][C@@H:24]([C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[NH:17][C:15](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([F:40])=[C:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[N:14]=2)[CH2:29][C@H:28]1[NH2:30])(=[O:44])=[O:43]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1O
Solvent: c1ccncc1
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](N)[C@H]1OS(C)(=O)=O
Reaction time: 0.08 h
Yield: 45 %

Procedure:
To a solution of tert-butyl (1R,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-2-hydroxy-3-methylcyclohexylcarbamate (1.0 equiv.) in pyridine (0.12 M) was added MsCl (7.0 equiv.). The capped solution was stirred for 5 minutes and then the homogeneous solution was left standing at rt for 16 hrs. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and H2O. The organic layer was washed with H2O, 10% CuSO4, H2O, Na2CO3(sat.), NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by ISCO chromatography. The Boc protected product was treated with 25% TFA/CH2Cl2 for 20 minutes at which time the volatiles were removed in vacuo and the residue was dissolved in DMSO and purified by RP-HPLC. The product fractions were lyophilized directly to yield (1S,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-6-methylcyclohexyl methanesulfonate in 45% yield. LC/MS (m/z)=535.2 (MH+), Rt=0.60 min.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K].[OH-].[Na+]>CN(C=O)C.C(Cl)Cl>[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][N:15]1[C:11](=[O:21])[C:12]2[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14]1=[O:16]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(CCl)c1ccccc1
Agent: [K]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccccc2C1=O)c1ccccc1
Reaction time: 4 h
Yield: 82.8 %

Procedure:
A 250 ml round-bottomed flask equipped with a magnetic stirrer is charged with 30 g of 2-chloroacetophenone and 36.3 g of potassium phthalimide in 120 ml of DMF. After 4 h at RT, the mixture is concentrated under vacuum. The solid obtained is taken up in 120 ml of DCM and 100 ml of 1 sodium hydroxide solution. The organic phase is washed with saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated under vacuum. The solid obtained is triturated in diisopropyl ether. The insolubles are filtered off and dried under vacuum to give 42.6 g of 2-(2-oxo-2-phenylethyl)-1H-isoindole-1,3(2H)-dione in the form of a beige solid, which is used as it is in the following step.