Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=O)=[CH:4][N:3]=[CH:2]1.[CH2:15]([C:22]1([OH:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O.C(N(CC)CC)C>[CH2:15]([C:22]1([OH:28])[CH2:27][CH2:26][N:25]([C:8]([C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5]2[O:1][CH:2]=[N:3][CH:4]=2)=[O:10])[CH2:24][CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccccc1-c1cnco1
Reactant: OC1(Cc2ccccc2)CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1-c1cnco1)N1CCC(O)(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.7 %

Procedure:
A suspension of 2-(1,3-oxazol-5-yl)benzoic acid (0.30 g), 4-benzyl-4-hydroxypiperidine (0.36 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.46 g), 1-hydroxybenzotriazole (0.40 g) and triethylamine (0.40 g) in DMF (3 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (0.28 g).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH:9]=O)[CH3:8].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](O)=[O:20])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[CH:9][N:7]([CH3:6])[CH3:8])[CH:19]=[O:20])=[CH:14][CH:13]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CN(C)C=C(C=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phosphorus oxychloride (92 g) was added dropwise to stirred DMF (78 ml) between 10°-15° C. To the resulting slurry was added 4-chlorophenylacetic acid (34.12 g). The resulting mixture was stirred at room temperature for one half hour and then heated to 70°-80° C. during 5.5 hours, during which time the mixture became effervescent. The reaction mixture was cooled and poured slowly onto cracked ice. The resulting suspension was brought to pH 10 with solid potassium carbonate. Ice was added intermittently during this addition to maintain the temperature below 15° C. Toluene (150 ml) was added and the resulting mixture heated at 100° C. for one hour. The mixture was cooled and allowed to stand overnight. The two resulting layers were separated and the aqueous layer extracted with toluene (2×100 ml). The combined organic layers were washed with water (5×200 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo and the resulting yellow solid was triturated with hexane to yield 26 g of 2-(4-chlorophenyl)-3-dimethylaminopropenal as a tan solid mp. 120°-125° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH:7]=[CH:6][C@@H:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:4]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:3]1=[O:21].[OH:22][C@@H:23]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:24]([NH:26][C@H:27]([C:32](O)=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:25].CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl>[CH:18]1([CH2:17][N:4]2[C@H:5]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[CH:6]=[CH:7][CH2:8][C@H:2]([NH:1][C:32](=[O:33])[C@H:27]([CH2:28][CH:29]([CH3:31])[CH3:30])[NH:26][C:24](=[O:25])[C@@H:23]([OH:22])[CH2:35][CH:36]([CH3:37])[CH3:38])[C:3]2=[O:21])[CH2:19][CH2:20]1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](O)CC(C)C)C(=O)O
Reactant: COc1ccc([C@@H]2C=CC[C@H](N)C(=O)N2CC2CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc([C@@H]2C=CC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](O)CC(C)C)C(=O)N2CC2CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a solution of (3S,7S)-3-amino-1-(cyclopylmethyl)-7-(4-methoxyphenyl)-1,3,4,7-tetrahydro-2H-azepin-2-one (11e) (35 mg) in DCM (3 mL) at 0° C. under N2 was added N-[(2S)-2-hydroxy-4-methylpentanoyl]-L-leucine (7b) (30 mg), HOBt-hydrate (41 mg), EDAC.HCl (35 mg) and N-methyl morpholine (25 mg). The reaction mixture was stirred 1 h at 0° C. and 3H at room temperature, then diluted with 30% Hexanes/EtOAc (100 mL). The organic phase was consecutively washed with H2O, 0.2 N HCl, saturated NaHCO3, and brine, dried (Na2SO4), filtered and evaporated. The crude product was purified by flash chromatography (2% MeOH/DCM) to afford the title compound as an off-white solid (60 mg, 95%). 1H NMR (300 MHz, CDCl3) δ 0.40 (m, 2H), 0.58 (m, 2H), 0.74 (m, 1H), 0.87 (d, 6H), 1.26 (m, 1H), 1.53, (m, 2H), 1.59 (m, 1H), 1.67 (m, 2H), 2.00 (m, 2H), 3.20 (m, 2H), 3.66 (s, 1H), 3.89 (m, 1H), 4.28 (m, 1H), 4.96 (m, 1H), 5.32 (m, 1H), 6.13 (bd, 1H), 6.48 (m, 1H), 6.85-6.94 (m, 4H). MS APCI, m/z=514 (M+1). LC/MS 2.47 min., Method A.
Reaction SMILES: [F:1][C:2]1[C:7](I)=[CH:6][C:5]([CH:9]([CH3:11])[CH3:10])=[CH:4][N:3]=1.[CH3:12][N:13](C=O)C>CCOC(C)=O.[C-]#N.[C-]#N.[Zn+2].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>[F:1][C:2]1[N:3]=[CH:4][C:5]([CH:9]([CH3:11])[CH3:10])=[CH:6][C:7]=1[C:12]#[N:13]
Reactant: CN(C)C=O
Reactant: CC(C)c1cnc(F)c(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)c1cnc(F)c(C#N)c1
Temperature: 80 °C

Procedure:
To a mixture of 2-fluoro-3-iodo-5-isopropylpyridine and 485 mg (4.13 mmol) of Zn(CN)2 in 15 mL of DMF (degassed) was added 360 mg (0.312 mmol) of Pd(PPh3)4. The mixture was heated at 80° C. under Ar for 19 h. The mixture was diluted with EtOAc, and the organic layer was washed with 10% NH4OH (2×10 mL), H2O (3×), and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (5% Et2O/hexanes) provided 384 mg of pure 2-fluoro-5-isopropylnicotinonitrile as a yellow liquid.
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.C[Si](Cl)(C)C.[CH2:15]([O:17][C:18](=[O:47])[CH2:19][CH2:20][N:21]([C:39]1([C:44](Cl)=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40]1)[S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH3:16]>Cl>[CH2:15]([O:17][C:18](=[O:47])[CH2:19][CH2:20][N:21]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:39]1([C:44](=[O:45])[NH:2][OH:3])[CH2:43][CH2:42][CH2:41][CH2:40]1)[CH3:16]
Reactant: NO
Reactant: CCOC(=O)CCN(C1(C(=O)Cl)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)CCN(C1(C(=O)NO)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.37 g (19.7 mmol, 1.3 equivalents) of hydroxylamine hydrochloride in 9.2 mL (114 mmol, 7.5 equivalents) of dry pyridine at 0° C. was treated with 5.8 mL (45 mmol, 3.0 equivalents) of trimethylsilyl chloride, causing white solids to precipitate, and allowedc to warm to ambient temperature overnight. This mixture was cooled to 0° C. and treated with a solution of 7.54 g (15.1 mmol) of 3-{(1-chlorocarbonylcyclopentyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}propionic acid ethyl ester in 73 mL of dichloromethene, prepared as described above without isolation, causing an exotherm to 8° C. This mixture was stirred at 0° C. for 30 minutes and at ambient temperature for one hour before treating with 50 mL of 2N aqueous hydrochloric acid and stirring at ambient temperature for one hour. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with 2N aqueous hydrochloric acid (2×50 mL) and water (50 mL). This solution of 3-[[4-(4-fluorophenoxy)benzenesufonyl]-(1-hydroxycarbamoylcyclopentyl)amino]propionic acid ethyl ester in dichloromethane was used for the preparation of 3-[[4-(4-fluoro-phenoxy)benzenesulfonyl]-1-hydroxycarbamoylcyclopentyl)amino]propionic acid without isolation. An aliquot was concentrated to a foam.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1)=[O:14]>>[Br:21][C:17]1[CH:16]=[C:15]([C:13](=[O:14])[CH2:12][O:10][C:3]2[CH:4]=[C:5]([CH3:9])[CH:6]=[C:7]([CH3:8])[C:2]=2[CH3:1])[CH:20]=[CH:19][CH:18]=1
Reactant: O=C(CBr)c1cccc(Br)c1
Reactant: Cc1cc(C)c(C)c(O)c1
Product: Cc1cc(C)c(C)c(OCC(=O)c2cccc(Br)c2)c1
Yield: 52 %

Procedure:
Using 2,3,5-trimethylphenol and 2-bromo-1-(3-bromophenyl)ethanone, the title compound was synthesized in the same manner as in Reference Example 159. Yield 52%. Oily matter.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[C:9]([CH3:11])[N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[NH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=1[C:26]([OH:28])=[O:27].C(N(C(C)C)CC)(C)C>C(O)(C)C.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=2[C:26]([OH:28])=[O:27])[C:5]2[CH:10]=[C:9]([CH3:11])[N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(C)cc3c(Cl)nc(Cl)nc32)cc1
Reactant: Nc1cccc(F)c1C(=O)O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2c(C)cc3c(Nc4cccc(F)c4C(=O)O)nc(Cl)nc32)cc1
Temperature: 85 °C
Yield: 66 %

Procedure:
To a suspension of 2,4-dichloro-6-methyl-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 1.40 mmol) and 2-amino-6-fluorobenzoic acid (218 mg, 1.40 mmol) in isopropanol (15 mL) was added diisopropylethylamine (907 mg, 7.02 mmol) and the mixture was heated at 85° C. for ˜72 h. The reaction was diluted with EtOAc (100 ml) and washed with a solution of 1N HCl, a saturated solution of sodium bicarbonate and a saturated solution of NaCl. Solid began to crash out on addition of brine. Ether was added to force everything out of solution and also water was added to ensure NaCl was all in solution. The solids were filtered and dried under reduced pressure to afford 2-({2-chloro-6-methyl-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzoic acid (439 mg, 0.924 mmol) as a pale yellow solid. ESIMS (M+H)+=475.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[NH2:12])(=[O:5])=[O:4].[C:13](N1C=CN=C1)(N1C=CN=C1)=[S:14]>O1CCOCC1.CN(C=O)C>[CH3:1][N:2]1[C:13](=[S:14])[NH:12][C:11]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[S:3]1(=[O:5])=[O:4]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CNS(=O)(=O)c1cnccc1N
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CN1C(=S)Nc2ccncc2S1(=O)=O
Reaction time: 0.5 h

Procedure:
A solution of N-methyl-4-aminopyridine-3-sulfonamide (de Tullio et al., Tetrahedron 1995, 3221-3234) (5.0 g) and thiocarbonyidiimidazole (7.5 g) in dioxane (30 mL) and DMF (15 mL) was heated at 90° C. for 2 h. The solvents were removed by distillation under reduced pressure. The residue was dispersed in 0.6N NaOH (20 mL) and stirred for 30 min. The alkaline solution was treated with charcoal, filtered, and the filtrate was adjusted to pH 4-5. The precipitate was collected by filtration, washed with water and dried (yield: 4 g); m.p. 195°-198° C. (Compound IV).
Reaction SMILES: [CH:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].[C:12]12[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:17]C(=O)O[C:13]2=[O:14].O>CN(C=O)C>[NH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=1[C:13]([NH:9][C:8]1[CH:7]=[CH:6][C:5]([CH:1]([CH2:3][CH3:4])[CH3:2])=[CH:11][CH:10]=1)=[O:14]
Reactant: CCC(C)c1ccc(N)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)c1ccc(NC(=O)c2ccccc2N)cc1
Temperature: 115 °C
Reaction time: 16 h

Procedure:
4-sec-butyl aniline (B) (1.49 g, 10.0 mmol) was added to a solution of isatoic anhydride (A) (1.63 g, 10.0 mmol) in anhydrous DMF (40 mL) and the reaction mixture was stirred at 115° C. for 16 hours under nitrogen. It was then cooled to room temperature and poured into water (200 mL), and extracted with ethyl acetate (200 mL). The organic phase was washed with water (100 mL), 10% aqueous NaOH solution (100 mL), water (100 mL) and dried over anhydrous Na2SO4. Removal of solvent gave 2-amino-N-(4-sec-butylphenyl)benzamide (C) as a brown solid. Yield: 1.27 g (47%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:15]([N:17]2[CH2:20][C:19]([CH2:22][OH:23])([OH:21])[CH2:18]2)=[O:16])=[CH:12][S:13][CH:14]=1.[CH:24]([C:27]1[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:30]=[C:29]([CH:36]([CH3:38])[CH3:37])[C:28]=1[S:39](Cl)(=[O:41])=[O:40])([CH3:26])[CH3:25]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:26][CH:24]([C:27]1[CH:32]=[C:31]([CH:33]([CH3:34])[CH3:35])[CH:30]=[C:29]([CH:36]([CH3:38])[CH3:37])[C:28]=1[S:39]([O:23][CH2:22][C:19]1([OH:21])[CH2:18][N:17]([C:15]([C:11]2[C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=3[F:1])=[CH:14][S:13][CH:12]=2)=[O:16])[CH2:20]1)(=[O:40])=[O:41])[CH3:25]
Reactant: O=C(c1cscc1Nc1ccc(I)cc1F)N1CC(O)(CO)C1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)OCC2(O)CN(C(=O)c3cscc3Nc3ccc(I)cc3F)C2)c(C(C)C)c1
Yield: 25.6 %

Procedure:
1-({4-[(2-Fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)-3-(hydroxymethyl)azetidin-3-ol (247 mg, 0.551 mmol), was suspended in dichloromethane (10 mL) and treated with 4-(dimethylamino)pyridine (80 mg, 0.661 mmol), and 2,4,6-triisopropylbenzenesulfonyl chloride (183 mg, 0.604 mmol) at ambient for 15 h. The mixture was adsorbed on to silica and purified by column chromatography (silica gel, 30% ethyl acetate in hexanes) to give [1-({4-[(2-fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl 2,4,6-tris(1-methylethyl)benzenesulfonate (101 mg, 0.141 mmol, 26% yield): MS (EI) for C30H36FIN2O5S2: 715 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([F:11])[CH:3]=1.Br[C:13]1[N:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[N:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]3)=[CH:15][CH:14]=2)=[C:4]([F:11])[CH:3]=1
Reactant: OB(O)c1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(Br)cc3F)nc2)CC1
Temperature: 80 °C
Yield: 62.5 %

Procedure:
4-Bromo-2-fluorobenzeneboronic acid (0.69 g, 3.10 mmol) was added to a solution of 1,1-dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (1.0 g, 2.70 mmol) in DME (30 mL), followed by addition of 2M Na2CO3 (8 mL) and Pd(PPh3)4 (0.16 g, 0.13 mmol). The reaction mixture was degassed with N2 and heated at 80° C. for 4 h, then cooled to ambient temperature. Water was added and the mixture was extracted with EtOAc (70 mL×2). The combined organic extract was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by chromatography on a silica gel column eluted with 1:5 EtOAc/hexanes to give 0.785 g (63%) of 1,1-dimethylethyl 4-({[6-(4-bromo-2-fluorophenyl)-3-pyridinyl]oxy}methyl)-1-piperidinecarboxylate as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.38 (d, 1H, J=2.6 Hz), 7.90-7.85 (m, 1H), 7.75-7.65 (m, 1H), 7.40-7.30 (m, 2H), 7.30-7.20 (m, 1H), 4.18 (bs, 2H), 3.89 (d, 2H, J=6.3 Hz), 2.85-2.70 (m, 2H), 2.05-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.46 (s, 9H), 1.35-1.25 (m, 2H); LRMS m/z 465/467 (M+H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]1[C:18]2[N:17]([CH2:19][CH:20]([OH:29])[CH2:21][NH:22][CH2:23][C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:15]1[C:16]2[N:17]([CH2:19][CH:20]([OH:29])[CH2:21][N:22]([CH2:23][C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)[S:2]([CH3:1])(=[O:4])=[O:3])[C:18]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: OC(CNCc1ccco1)Cn1c2ccccc2c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(Cc1ccco1)CC(O)Cn1c2ccccc2c2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
Methanesulfonyl chloride (0.650 mL, 8.4 mmol) was added dropwise to a cold stirring solution of 1-(9H-carbazol-9-yl)-3-((furan-2-ylmethyl)amino)propan-2-ol (2.7 g, 8.4 mmol) and triethylamine (1.3 mL, 9.2 mmol) in anhydrous methylene chloride (55 mL), which was kept at 0-5° C. with an external ice bath. The solution was stirred at 0° C. for 2 hours and then diluted with methylene chloride and successively washed with 0.25N aqueous hydrochloric acid twice, water, and saturated aqueous sodium chloride. The organics were dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (0-10% ethyl acetate in methylene chloride) to give the desired product as a white solid (1.5 g, 45%). 1H NMR (d6-DMSO, 300 MHz) δ 8.09-8.06 (d, 2H, J=8.1 Hz), 7.42-7.37 (m, 5H), 7.18-7.14 (m, 2H), 6.37-6.35 (dd, 1H, J=1.8, 3 Hz), 6.31-6.30 (d, 1H, J=3 Hz), 4.52-4.39 (dd, 2H, J=15.9, 24.6 Hz), 4.39-4.30 (dd, 1H, J=3.3, 14.4 Hz), 4.22-4.10 (m, 1H), 4.20-4.05 (br m, 1H), 3.40-3.33 (m, 1H) 3.26-3.17 (m, 1H), 2.90 (s, 3H). ESI (m/z): 398.9 (M+H). HPLC analysis: (C18, 10-90% acetonitrile in water+0.1% trifluoroacetic acid over 10 min: retention time, % area at 254 nm): 8.6 min, 97.9%.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[N:33]=[CH:32][C:31]([CH2:34][CH2:35][CH3:36])=[CH:30][N:29]=4)[CH2:24][CH2:23]3)=[CH:17][C:16]2=[O:37])=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[O:37]=[C:16]1[CH:17]=[C:18]([O:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[CH:32][C:31]([CH2:34][CH2:35][CH3:36])=[CH:30][N:29]=3)[CH2:24][CH2:23]2)[CH:19]=[CH:20][N:15]1[C:12]1[CH:11]=[CH:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:14][CH:13]=1
Reactant: CCCc1cnc(N2CCC(Oc3ccn(-c4ccc(S(=O)(=O)NC(C)(C)C)cc4)c(=O)c3)CC2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cnc(N2CCC(Oc3ccn(-c4ccc(S(N)(=O)=O)cc4)c(=O)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.2 %

Procedure:
To a stirring solution of N-tert-butyl-4-(2-oxo-4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)pyridin-1(2H)-yl)benzenesulfonamide (23 mg, 0.044 mmol) in CH2Cl2 (1 mL) was added trifluoroaceticacid (0.4 mL, 5 mmol, Aldrich). The reaction was stirred at room temperature for 2 days and then concentrated in vacuo to a yellow oil. The oil was purified by flash chromatography (SiO2, 0 to 5% MeOH in CH2Cl2) to yield 11 mg of the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.18 (s, 2H), 8.03 (d, J=8.53 Hz, 2H), 7.54 (d, J=8.28 Hz, 2H), 7.23 (d, J=7.78 Hz, 1H), 6.07 (dd, J=7.65, 2.63 Hz, 1H), 6.03 (d, J=2.51 Hz, 1H), 4.56-4.65 (m, 1H), 4.16-4.25 (m, 2H), 3.60-3.71 (m, 2H), 2.42 (t, J=7.53 Hz, 2H), 2.04-2.14 (m, 2H), 1.80-1.90 (m, 2H), 1.53-1.64 (m, 2H), 0.95 (t, J=7.28 Hz, 3 H). MS (ESI) 470 (M+H).
Reaction SMILES: C([Li])CCC.[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>CCOCC>[CH2:24]([Sn:19]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:20][CH2:21][CH2:22][CH3:23])[C:7]1[S:6][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=1)[CH2:25][CH2:26][CH3:27]
Reactant: c1ccc2scnc2c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2s1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
n-Butyllithium (1.6M, 10 mL, 15.98 mmol) was added to a solution of benzothiazole (1.80 g, 13.3 mmol) in anhydrous ether (30 ml) stirred at −78° C. under nitrogen. After 10 min, tri-n-butylstannyl chloride (4.33 g, 13.31 mmol) was added, then the solution was allowed to warm to room temperature, and stirred for another 1 h. The mixture was quenched and washed with 1N sodium hydroxide, dried through MgSO4, filtered, and evaporated to give the sub-title compound as a brown oily residue (5.0 g), which was used without further purification in the next step.
Reaction SMILES: [CH2:1]([Si:9](Cl)(Cl)Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20].Cl>CCCCCCC>[CH2:1]([Si:9]([O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH3:13])([O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH3:13])[O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: COCCOCCO
Reactant: CCCCCCCC[Si](Cl)(Cl)Cl
Agent: Cl
Solvent: CCCCCCC
Product: CCCCCCCC[Si](OCCOCCOC)(OCCOCCOC)OCCOCCOC
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a dry flask fitted with an agitator, thermometer, additional funnel and reflux condenser was charged 222.8 g (0.90 mole) of octyltrichlorosilane and 225 g of heptane. The mixture was blanketed with nitrogen, heated to 80° C. and 333.7 g (2.78 mole) of 2-(2-methoxyethoxy)ethanol was added slowly over a 2 hour period. Hydrogen chloride was evolved from the mixture. After the addition was complete heating of the reaction was continued for 24 hours at 80° C. Then the solvent and all volatile components of the mixture were removed under vacuum, producing 451 g of the clear, colorless liquid product.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:13]=[C:12](S(C)(=O)=O)[N:11]=1)=[O:9].[CH3:36][OH:37].O>C(Cl)Cl>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:13]=[C:12]([O:37][CH3:36])[N:11]=1)=[O:9]
Reactant: CO
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1nc(S(C)(=O)=O)ncc1-c1ccccc1
Solvent: ClCCl
Solvent: O
Product: COc1ncc(-c2ccccc2)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reaction time: 12 h
Yield: 73.5 %

Procedure:
To a solution of 0.45 g (0.87 mmol) 2-methanesulfonyl-5-phenyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide in 15 ml methanol 0.123 g (2.17 mmol) sodiummethanolate (95%) were added at RT and the reaction solution stirred for 12 hrs. The reaction mixture was distibuted between 100 ml H2O and 100 ml CH2Cl2. The aqueous layer was extracted three times with 50 ml CH2Cl2, the combined organic layers dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/methanol 40:1) to give 0.30 g (73%) 2-methoxy-5-phenyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a off-white solid, m.p. 97.5-98.5°.