Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[CH3:10][O:11][C:12](=[O:22])[C:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][C:14]=1[CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH3:10][O:11][C:12](=[O:22])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH:1][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=2[F:9])=[CH:15][C:14]=1[CH3:21]
Reactant: COC(=O)c1ccc(C=O)cc1C
Reactant: Nc1ccc(O)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNc2ccc(O)cc2F)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
A mixture of 4-amino-3-fluoro-phenol (900 mg, 7.08 mmol) and 4-formyl-2-methyl-benzoic acid methyl ester (1.23 g, 6.90 mmol) in 35 mL acetic acid is stirred for two hours at room temperature. Sodium triacetoxyborohydride (3.20 g, 15.1 mmol) is added and stirred at room temperature. Upon completion, the mixture is concentrated under reduced pressure and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer is separated and extracted with ethyl acetate (3×). The combined ethyl acetate layers are dried (MgSO4) and concentrated under reduced pressure. The residue is purified on 120 g silica eluting with a gradient of ethyl acetate in heptane (10% to 60%) to provide the title compound (1.9 g, 93%) as a yellow oil. ES/MS m/e 290.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[N:3]=1.[O-]CC.[Na+].[Na].Br[CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CS(C)=O.C(O)C>[CH2:28]([O:27][C:25]([CH:24]([O:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]([F:17])([F:15])[F:16])=[CH:11][CH:12]=2)[N:3]=1)[CH3:30])=[O:26])[CH3:29]
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ncn(-c2ccc(OC(F)(F)F)cc2)n1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CS(C)=O
Solvent: CCO
Product: CCOC(=O)C(C)Oc1ncn(-c2ccc(OC(F)(F)F)cc2)n1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Eleven g of 3-hydroxy-1-(4-trifluoromethoxyphenyl)-1,2,4-1H-triazole was dissolved in 100 ml of dimethylsulfoxide, and to it was added a solution of sodium ethoxide prepared from 1.2 g of sodium and 20 ml of absolute ethanol. An additional 100 ml of dimethylsulfoxide was added, and the solution was heated on the steam bath for 90 minutes. Then 8.3 g of ethyl 2-bromopropionate was added, and heating was continued for 90 minutes more. The solution was cooled and poured over ice water, and the solid was collected and dried to obtain 15 g of the desired product, m.p. 52°-53°.
Reaction SMILES: O[CH:2]([C:4]1[O:5][C:6](=[O:29])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].P(Br)(Br)[Br:31].CN(C=O)C>C(Cl)Cl>[Br:31][CH:2]([C:4]1[O:5][C:6](=[O:29])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3]
Reactant: BrP(Br)Br
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1cccc(S(=O)(=O)N2CCOCC2)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(Br)c1oc(=O)c2ccccc2c1-c1cccc(S(=O)(=O)N2CCOCC2)c1
Yield: 49.6 %

Procedure:
The title compound was made in a similar way as that of the intermediate C6, using 3-(1-hydroxyethyl)-4-(3-(morpholinosulfonyl)phenyl)-1H-isochromen-1-one (intermediate B9, 163 mg, 0.392 mmol), 1M PBr3 (0.68 ml, 0.667 mmol) in DCM (3.2 ml) at RT. The crude was tritured with DMF to give the title compound (93 mg, 49%). The solution was purified via reverse phase chromatography with a Biotage C18 SNAP 30 g column (Phase A, water 95%, ACN 4.9%, formic acid 0.1%); Phase B ACN 99.9%, formic acid 0.1%) to give further compound (68 mg, 36.2%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+]([O-])=O)=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1.P(Cl)(Cl)([Cl:15])=O.[OH-].[Na+]>ClCCl>[Cl:15][C:3]1[C:2]([Cl:1])=[CH:7][N+:6]([O-:8])=[C:5]([CH3:9])[CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cc(Cl)c(Cl)c[n+]1[O-]

Procedure:
To a stirred and cooled solution of 5-chloro-4-nitro-2-methyl-pyridine-N-oxide (9.7 g) in dichloromethane (100 ml) at 5°-10°, a solution of phosphoryl chloride (14.7 ml) in dichloromethane (100 ml) was added. The solution was heated under reflux for 4.5 hours, poured on ice-water and basified (NaOH) to pH 8-9. The dichloromethane was separated, dried (K2CO3), stripped and the residue triturated with ether filtered, washed and dried to give 4,5-dichloro-2-methylpyridine-N-oxide, (7.69 g). m.p.120°-123°
Reaction SMILES: O.[OH-].[Li+].[C:4]1(/[C:10](=[N:17]/[O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[O:32][N:31]=[C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:29]=3)=[CH:22][CH:21]=2)/[CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.Cl>O1CCCC1>[C:4]1(/[C:10](=[N:17]/[O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[O:32][N:31]=[C:30]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:29]=3)=[CH:22][CH:21]=2)/[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCc2cc(-c3ccccc3)no2)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC/C(=N\OCc1ccc(OCc2cc(-c3ccccc3)no2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
Lithium hydroxide monohydrate (58.3 mg) was added to a solution of methyl E-4-phenyl-4-[4-(3-phenyl-5-isoxazolylmethoxy)benzyloxyimino]butyrate (326 mg) in tetrahydrofuran (6 ml)-water (4 ml) and stirred at room temperature for 2 hours. 1N hydrochloric acid (1.4 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-phenyl-4-[4-(3-phenyl-5-isoxazolylmethoxy)benzyloxyimino]butyric acid (306 mg, yield 97%) as colorless crystals. m.p. 96-97° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.NC1SC=CN=1.[C:17]([N:25]=[C:26]=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:17]([NH:25][C:26]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NCCCNc1nccs1
Agent: Nc1nccs1
Product: O=C(NC(=S)NCCCNc1nccs1)c1ccccc1

Procedure:
By the procedure of Example 46, reacting 2-(3-aminopropylamino)thiazole (prepared from 2-aminothiazole by the method of Example 53) with benzoyl isothiocyanate gives N-benzoyl-N'-[3-(2-thiazolylamino)propyl]thiourea. Removing the benzoyl group by the procedure of Example 46 gives N-[3-(2-thiazolylamino)propyl]thiourea.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH2:9]([S:13][C:14]1[C:22]([S:23](=[O:26])(=[O:25])[NH2:24])=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[N+:27]([O-])=O)[CH2:10][CH2:11][CH3:12].Cl.[OH-].[Na+]>N.C(O)(C)C>[NH2:27][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([S:23](=[O:25])(=[O:26])[NH2:24])[C:14]=1[S:13][CH2:9][CH2:10][CH2:11][CH3:12])[C:18]([OH:20])=[O:19]
Reactant: CCCCSc1c([N+](=O)[O-])cc(C(=O)O)cc1S(N)(=O)=O
Agent: Cl
Agent: N
Agent: O=S([O-])S(=O)[O-]
Solvent: CC(C)O
Product: CCCCSc1c(N)cc(C(=O)O)cc1S(N)(=O)=O
Reaction time: 1 h

Procedure:
To a solution of sodium dithionite (15.9 g) in aqueous ammonia (13 g NH3 in 150 ml water) 4-n-butylthio-3-nitro-5-sulphamyl-benzoic acid (8.35 g) was added in portions during 1 hour, while stirring. The reaction mixture was then heated on a steam bath for 30 minutes. Hydrochloric acid was added until the pH was 1, and heating was continued for 1 hour. After cooling, the pH was adjusted to 3 by the addition of 2N sodium hydroxide, and isopropanol (25 ml) was added. The precipitated 3-amino-4-n-butylthio-5-sulphamyl-benzoic acid was filtered off and recrystallized from aqueous ethanol. The melting point was 223°-224° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:24]I>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:24])[C@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(c1)[C@H](NC(=O)OC(C)(C)C)CC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)[C@H](N(C)C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A solution of (R)-methyl 3-(tert-butoxycarbonylamino)-2,3-dihydro-1H-indene-5-carboxylate (600 mg, 2.062 mmol, 1.0 eq.) in dry DMF (2 ml) was added to a stirred suspension of NaH (118 mg, 2.474 mmol, 1.2 eq., 50% in mineral oil) in DMF (3 ml) at 0° C. MeI (322 μl, 5.15 mmol, 2.5 eq.) was added to the reaction mixture at same temperature and it was stirred at RT for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture diluted with ice-cold water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with water (50 ml) and brine (50 ml), and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the crude product as a brown sticky solid which was used in the next step without further purification. Yield: 90% (566 mg, 1.855 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17]/[C:18](=[C:37]2\[C:38](=[O:52])[N:39](C(=O)C)[C:40]3[C:45]\2=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)/[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:26]3C(=O)C4=CC=CC=C4C3=O)=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17]/[C:18](=[C:37]2\[C:38](=[O:52])[NH:39][C:40]3[C:45]\2=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)/[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][CH:20]=2)=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)N1C(=O)/C(=C(\Nc2ccc(CCNC(=O)OC(C)(C)C)cc2)c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)c2cc([N+](=O)[O-])ccc21
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccc(CN)cc2)cc1

Procedure:
Prepared analogously to Example 140 from (Z)-3-{1-[4-(2-tert.butoxycarbonylamino-ethyl)-phenylamino]-1-(4-phthalimidomethyl-phenyl)-methylidene}-1-acetyl-5-nitro-2-indolinone and hydrazine hydrate solution in ethanol.
Reaction SMILES: [C:1]([C:3]([CH3:13])([CH3:12])[CH2:4][CH2:5][Si:6]([CH3:11])([O:9][CH3:10])[O:7][CH3:8])#[N:2].N.[H][H]>[Ni]>[NH2:2][CH2:1][C:3]([CH3:13])([CH3:12])[CH2:4][CH2:5][Si:6]([CH3:11])([O:9][CH3:10])[O:7][CH3:8]
Reactant: CO[Si](C)(CCC(C)(C)C#N)OC
Reactant: [H][H]
Agent: [Ni]
Agent: N
Product: CO[Si](C)(CCC(C)(C)CN)OC
Yield: 95.8 %

Procedure:
To a 1-liter, high-pressure, stirred autoclave was added a mixture of 3-cyano-3-methylbutylmethyldimethoxysilane (631 grams, 3.13 moles) containing 12.0 grams of dissolved ammonia and 8.5 grams of nickel (5%) on kieselguhr. The autoclave was sealed, pressurized to 800 psi with hydrogen and heated for 10 hours. The contents were cooled and the product was collected, filtered, and distilled. The yield was 615.9 grams (95.9% yield after distillation) of 4-amino-3,3-dimethylbutylmethyldimethoxysilane, as characterized by 1H and 13C NMR spectroscopy.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[N:5]=[C:4](O)[N:3]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(O)nc(C)c1[N+](=O)[O-]
Product: Cc1nc(Cl)nc(C)c1[N+](=O)[O-]
Reaction time: 3 h
Yield: 74.1 %

Procedure:
A mixture of Compound 1 (500 mg) and phosphorus oxychloride (3.89 g) was stirred for 3 hours under reflux. After the reaction was completed, the mixture was concentrated under reduced pressure. To the resulting residue, chloroform and water were added and the mixture was cooled and neutralized with a 2N aqueous sodium hydroxide solution to a pH of 5 to 7. The mixture was then extracted with chloroform and the organic layer was concentrated under reduced pressure to obtain 411 mg of the desired product. When necessary, some of the product was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to give a purified product.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[NH:8]1[CH2:12][CH2:11][CH:10]([P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[CH2:9]1
Reactant: CCOP(=O)(OCC)C1CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCOP(=O)(OCC)C1CCNC1
Temperature: 40 °C

Procedure:
A mixture of 3 g (10 mmol) of (R/S)-1-benzyl-pyrrolidin-3-ylphosphonic acid, diethyl ester (from Step A), 9.5 g (150 mmol) of ammonium formate and 1.0 g of 10% palladium on charcoal in 60 mL of MeOH was warmed to 40° C. for 1.5 h. The reaction was cooled, filtered through a pad of celite and concentrated. The mixture was partitioned between 75 mL of 1N NaOH and 100 mL of CH2Cl2. After separating layers, the aqueous phase was extracted with 3×100 mL of CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified on a 40M Biotage column using 90:10:1 v/v/v CH2Cl2/MeOH/NH4OH as the eluant to afford the title compound as a pale yellow oil: RF: 0.13 (95:5:0.5 v/v/v CH2Cl2MeOH/NH4OH); 1H-NMR (500 MHz) δ 1.22 (t, J=7.1, 6H), 1.81 (m, 1H), 1.95 (m, 1H), 2.25 (m, 1H), 2.73 (m, 1H), 2.89-2.99 (m, 3H), 4.06-4.16 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10][CH:9]=1.[CH2:18]([Mg]Br)[CH3:19]>C1COCC1>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:15])[CH2:12][CH2:13][CH2:8][CH2:9][CH2:10][CH2:11][CH2:18][CH3:19])=[CH:10][CH:9]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C=O)cc1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCCCCCCCC(O)c1ccc(C(=O)NCCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(4-formyl-benzoylamino)-propionic acid methyl ester (1.2 g, 5 mmol) in THF (10 mL) at 0° C. is added ethylmagnesium bromide (2M, 1.1 mL). After stirring at room temperature for 2 hours, it is quenched with saturated ammonium chloride, extracted with EtOAc. The organic is concentrated to give the titled compound as colorless oil: 270 mg (15%).
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:4]([NH:5][C:6]1=[O:7])[C:3](=[O:10])[NH:2]2.[H-].[Na+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C=O.C(OCC)C>[CH2:13]([N:2]1[C:3](=[O:10])[CH:4]2[CH2:8][CH2:9][CH:1]1[C:6](=[O:7])[N:5]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: O=C1NC2CCC1NC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: O=C1C2CCC(C(=O)N2Cc2ccccc2)N1Cc1ccccc1
Reaction time: 1 h
Yield: 91.7 %

Procedure:
A hot solution of 36.6 g (0.262 mole) of 2,5-diazabicyclo[2.2.2]octane-3,6-dione in 800 ml dry dimethylformamide was added rapidly from a dropping funnel to 12.5 g (0.52 mole) of oil-free sodium hydride. After stirring for 1 hour, the mixture was chilled and treated with 67.5 ml (0.59 mole) benzyl chloride during a period of a few minutes. After stirring at room temperature for 18 hours, 1 liter of water was added cautiously, and the mixture was extracted with chloroform. The extracts were washed with water, dried with sodium sulfate, and evaporated to dryness to yield a crystalline residue. Trituration in diethyl ether provided 77.0 g (91%) of product as colorless needles, melting point 168°-170°C.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][S:5][CH:6]=1.Cl.Cl.[F:13][C:14]([F:34])([F:33])[C:15]([C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1)([OH:20])[C:16]([F:19])([F:18])[F:17].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:3]([S:7]([N:30]2[CH2:31][CH2:32][N:27]([C:24]3[CH:23]=[CH:22][C:21]([C:15]([OH:20])([C:14]([F:13])([F:34])[F:33])[C:16]([F:19])([F:17])[F:18])=[CH:26][CH:25]=3)[CH2:28][CH2:29]2)(=[O:9])=[O:8])=[CH:4][S:5][CH:6]=1
Reactant: O=S(=O)(Cl)c1cscc1Br
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cscc1Br)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
To a 20 mL vial containing 4-bromothiophene-3-sulfonyl chloride (0.20 g, 0.77 mmol, ASDI, Newark, Del.) was added a solution of 1,1,1,3,3,3-hexafluoro-2-(4-(piperazin-1-yl)phenyl)-2-propanol dihydrochloride (0.31 g, 0.77 mmol, Example 91) and triethylamine (0.53 mL, 3.8 mmol) in CH2Cl2 (7 mL). The solution was stirred at room temperature for 16 h. To the vial was added saturated aqueous sodium bicarbonate (4 mL) and the solution was stirred for 15 min. The solution was transferred onto a phase separation cartridge (Radleys Discovery Technologies, Essex, UK) with the organic phase being collected and passed through a plug of Na2SO4. The resulting solution was concentrated and purified by Prep-HPLC (Instrumentation: MS—Waters SQ; UV—Waters 2487 or Waters PD, Waters, Milford, Mass. Solvents: A: Water w/0.1% NH4OH B: Acetonitrile w/0.1% NH4OH. Column: Phenomenex Gemini-NX C18 110 Å 5 μm 21×100. Flow Rate: 44 mL/min. 10 min Method, variable gradient over 8 min. Mass spectral data were acquired from 100-850 amu in electrospray positive mode) to afford 2-(4-(4-(4-bromothiophen-3-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (81 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.43 (br s, 1H), 8.08 (d, J=5.1 Hz, 1H), 7.47 (d, J=9.0 Hz, 2H), 7.37 (d, J=5.1 Hz, 1H), 7.02 (d, J=9.0 Hz, 2H), 3.31-3.35 (m, 4H), 3.26-3.29 (m, 4H). m/z (ESI, +ve ion) 552.8 (M+H)+. GK-GKRP IC50 (Binding)=0.816 μM.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=O.[N:20]([O-])=O.[Na+].[OH-].[Na+]>Cl.O>[N+:17]([C:14]1[CH:13]=[C:3]2[C:2](=[CH:16][CH:15]=1)[NH:1][N:20]=[C:4]2[CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)([O-:19])=[O:18]
Reactant: O=N[O-]
Reactant: CN1CCC(C(=O)c2cc([N+](=O)[O-])ccc2N)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCC(c2n[nH]c3ccc([N+](=O)[O-])cc23)CC1
Temperature: -3 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
To a -5° C. solution of 4-(2-amino-5-nitrobenzoyl)-1-methylpiperidine (570 mg, 2.2 mmol) in 9.6N aqueous hydrochloric acid (10 mL) was added dropwise a solution of sodium nitrite (164 mg, 2.4 mmol) in water (3 mL). This resulting diazonium salt solution was stirred 10 minutes at -5° C. then added dropwise to a -5° C. solution of stannous chloride dihydrate (1.95 g, 8.6 mmol) in 12N aqueous hydrochloric acid (6 mL). The resulting solution was stirred 2 hours at -3° C., basified with 1N aqueous sodium hydroxide (190 mL) and extracted exhaustively with ethyl acetate and methylene chloride. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give 420 mg of a brown residue. Purification by radial chromatography (silica gel, 2000 micron rotor, methylene chloride:methanol:ammonium hydroxide, 100:10:1) gave 177 mg (31.4%) of the title compound. The product was crystallized as the hydrochloride salt. EA calculated for C13H17ClN4O2 : C, 52.62; H, 5.77; N, 18.88. Found: C, 52.39; H, 5.96; N, 18.77.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CCCCCC.[CH2:26]([O:33][CH2:34][N:35]1[C:39](=[O:40])[C:38]([C:41]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[N:43]([S:50]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)(=[O:52])=[O:51])[CH:42]=2)=[C:37](Br)[C:36]1=[O:60])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH2:26]([O:33][CH2:34][N:35]1[C:36](=[O:60])[C:37]([C:3]2[C:4]3[C:9](=[N:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[C:38]([C:41]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[N:43]([S:50]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)(=[O:52])=[O:51])[CH:42]=2)[C:39]1=[O:40])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1C(Br)=C(c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)C(=O)N1COCc1ccccc1
Reactant: c1cnc2[nH]ccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C1C(c2c[nH]c3ncccc23)=C(c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)C(=O)N1COCc1ccccc1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a solution, held at −15° C., of 7-azaindole (1.542 mmol), dissolved in 10 ml of dry toluene, there is added, dropwise, a 1M solution of LiHMDS in hexane (1.78 mmol). After stirring for 1 hour at −15° C., a solution of the compound of Step B (0.637 mmol), dissolved in 10 ml of dry toluene, is added, dropwise, at −20° C. After 24 hours at ambient temperature, the reaction mixture is hydrolysed with saturated aqueous ammonium chloride solution and the pH is then adjusted to 7. The mixture is extracted with ethyl acetate. The organic phases are combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered. After purifying by chromatography on silica gel (cyclohexane/ethyl acetate: 3/2), the expected product is isolated.
Reaction SMILES: I[C:2]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([Sn](CCCC)(CCCC)[C:19]1[O:20][CH:21]=[CH:22][N:23]=1)CCC>COCCOC.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][C:12]1[C:2]([C:19]2[O:20][CH:21]=[CH:22][N:23]=2)=[C:3]([CH:9]=[CH:10][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: CCOC(=O)c1cccc(C)c1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCOC(=O)c1cccc(C)c1-c1ncco1
Temperature: 150 °C
Yield: 2057.2 %

Procedure:
In a microwave vial was dissolved ethyl 2-iodo-3-methylbenzoate (627 mg, 2.16 mmol) and 2-(tributylstannyl)oxazole (0.54 mL, 0.07 mmol) in DME (2.59 mL). The solution was degassed with N2 for 5 minutes then CuI (21 mg, 0.11 mmol) and Pd(PPh3)4 (125 mg, 0.11 mmol) were added. The reaction was purged with N2 and heated at 150° C. for 1 h. The reaction was cooled to rt, filtered through a pad of celite and purified via silica gel chromatography (0-40% EtOAc in hexanes) to give the title compound of step A (333 mg, 67%). MS (ESI) mass calcd. for C13H13NO3, 231.1; m/z found 232.1 [M+H]+. 1H NMR (500 MHz, Chloroform-d) 7.89-7.82 (m, 1H), 7.79 (d, J=0.8 Hz, 1H), 7.48-7.43 (m, 2H), 7.30 (d, J=0.9 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 2.27 (s, 3H), 1.18 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:22]=[C:21]3[C:17]([N:18]([CH3:24])[C:19](=[O:23])[NH:20]3)=[C:16](I)[N:15]=2)=[N:6]1.[NH2:30][CH2:31][CH2:32][OH:33]>CN1CCCC1=O>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:22]=[C:21]3[C:17]([N:18]([CH3:24])[C:19](=[O:23])[NH:20]3)=[C:16]([NH:30][CH2:31][CH2:32][OH:33])[N:15]=2)=[N:6]1
Reactant: NCCO
Reactant: Cn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Solvent: CN1CCCC1=O
Product: Cn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(NCCO)c21
Temperature: 150 °C

Procedure:
200 mg (0.399 mmol) of the compound obtained in example 107 were dissolved in N-methylpyrrolidone (4 ml) and admixed with 2-aminoethanol (1.5 ml), and then heated in a microwavable flask with septum in a microwave at 150° C. for 5 h. The reaction mixture was purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 31 mg of the title compound were obtained (18% of theory).