Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:10])=[O:9])=[C:6]([OH:15])[C:5]([NH:16][C:17]2[C:20](=O)[C:19](=[O:22])[C:18]=2[O:23]CC)=[CH:4][CH:3]=1.[NH2:26][C@@H:27]([CH2:29][CH3:30])[CH3:28]>C1COCC1>[C@H:27]([NH:26][C:20]1[C:19](=[O:22])[C:18](=[O:23])[C:17]=1[NH:16][C:5]1[C:6]([OH:15])=[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:10])=[O:9])[C:2]([Cl:1])=[CH:3][CH:4]=1)([CH2:29][CH3:30])[CH3:28]
Reactant: CC[C@@H](C)N
Reactant: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O
Solvent: C1CCOC1
Product: CC[C@@H](C)Nc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O
Temperature: 50 °C

Procedure:
To a stirred solution of 6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide (Intermediate A) (1 g, 2.56 mmol) in THF (20 ml) was added (R)-(−)-2-aminobutane (0.52 ml, 5.12 mmol). The reaction mixture was heated at 50° C. for 7 hours. The reaction mixture was concentrated in vacuo and dissolved in EtOAc. The EtOAc solution was washed with 1M HCl (aq) and brine. The EtOAc solution was dried (MgSO4) and concentrated in vacuo. The residue was crystallized from toluene to give a solid; [M+H]+ 418.2. 1H NMR (DMSO) 0.9 (3H, t, CH3), 1.2 (3H, d, CH3), 1.5 (2H, m), 3.0 (3H, s, CH3), 3.6 (3H, s, CH3), 4.0 (1H, m), 7.2 (1H, d), 8.1 (1H, d), 8.3 (1H, d), 9.4 (1H, s), 10.1 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.CC(O)C>O>[Cl:22][C:16]1[N:15]=[C:14]2[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)=[N:13]2)=[CH:18][CH:17]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: O=C(O)c1ccc(F)cc1
Solvent: O
Solvent: CC(C)O
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1ccc(F)cc1
Temperature: 4 °C
Yield: 68.9 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-fluorobenzoic acid (11.2 g), N,N'-carbonyldiimidazole (12.9 g) and 2-amino-7-chloro-1,8-naphthyridine (8.9 g). The product produced by precipitation in water (14.3 g; m.p. 230° C.) is dissolved in boiling 2-propanol (800 cc). After 4 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with 2-propanol (3×10 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-chloro-1,8-naphthyridin-2-yl)-4-fluorobenzamide (10.3 g) is produced, m.p. 236° C. EXAMPLE 16
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16]CC4C=CC5N(C6CCCCO6)C=NC=5C=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO.O>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: c1cc(Nc2cc(C3CC3)[nH]n2)nc(NCc2ccc3c(c2)ncn3C2CCCCO2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: Nc1nccc(Nc2cc(C3CC3)[nH]n2)n1

Procedure:
To a solution of 32 (406 mg, 0.94 mmol) in MeOH (5 mL) and water (1 mL) was added p-TsOH.H2O (178 mg, 0.94 mmol). The reaction mixture was heated at reflux for 18 h. The solvent was evaporated under reduced pressure and the residue was purified by preparative HPLC to afford 180 mg (55%) of N2-41H-benzo[d]imidazol-5-yl)-methyl)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (I-13) as white solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].F[C:11]1[C:12]([C:18]#[N:19])=[N:13][CH:14]=[C:15]([F:17])[CH:16]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1.C(OCC)(=O)C>[F:17][C:15]1[CH:16]=[C:11]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=2[F:1])[C:12]([C:18]#[N:19])=[N:13][CH:14]=1
Reactant: Nc1ccc(I)cc1F
Reactant: N#Cc1ncc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ncc(F)cc1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution of 2-fluoro-4-iodoaniline (930.5 mg, 3.93 mmol) and 3,5-difluoropyridine-2-carbonitrile (500 mg, 3.57 mmol) in THF (8 mL) at −78° C., was added LiHMDS (6.1 ml, 7.50 mmol). The mixture was allowed to warm to room temperature and stirred for 12 h. The mixture as diluted with ethyl acetate and washed with H2O and brine. The organic layer was dried with solid Na2SO4 and was concentrated. The resulting residue was purified by flash chromatography in silica (25% ethyl acetate-hexane) to give pure product. LC/MS [7.72 min; 358 (M+1)].
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:15]1([C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Br:26][C:27]1[CH:28]=[C:29]([CH2:33][C:34](O)=[O:35])[CH:30]=[CH:31][CH:32]=1.C(Cl)Cl>ClC1C=CC=CC=1Cl>[Br:26][C:27]1[CH:28]=[C:29]([CH2:33][C:34]([C:23]2[O:22][C:21]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:25][CH:24]=2)=[O:35])[CH:30]=[CH:31][CH:32]=1
Reactant: c1ccc(-c2ccco2)cc1
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Solvent: Clc1ccccc1Cl
Product: O=C(Cc1cccc(Br)c1)c1ccc(-c2ccccc2)o1
Temperature: 80 °C

Procedure:
Phosphorous pentoxide (2.02 g, 14.20 mmol) suspended in 1,2-dichlorobenzene (60 mL) was added to a mixture of 2-phenyl-furan (23) (500 mg, 2.84 mmol) and 3-bromophenylacetic acid (24) (1.34 g, 6.25 mmol). The reaction mixture was heated to 80° C. for 2 hours and then cooled to ambient temperature. DCM was added, the organic layer washed with water and partially reduced in vacuo. The crude product was purified by Flash Master Jones Chromatography using a 50 g silica cartridge and first eluting with heptane to remove excess 1,2-dichlorobenzene, then 5-10% EtOAc in heptane to give the title compound. Yield: 278 mg, 38%; LC-MS tr 1.73 min; HPLC Purity: 100%; MS (ES+) m/z 341, 343 (M+H)
Reaction SMILES: [CH3:1][CH:2]([Mg]Cl)[CH2:3][CH3:4].[P:7]([Cl:10])(Cl)Cl>C(OCC)C>[CH3:1][CH:2]([P:7]([CH:2]([CH2:3][CH3:4])[CH3:1])[Cl:10])[CH2:3][CH3:4]
Reactant: CCC(C)[Mg]Cl
Reactant: ClP(Cl)Cl
Solvent: CCOCC
Product: CCC(C)P(Cl)C(C)CC

Procedure:
In the manner of Examples 6 and 7, 2-butyl magnesium chloride (800 cm3 of a 2M solution in diethyl ether supplied by Aldrich Chemical Co.) was reacted with phosphorus trichloride (110 g) in diethyl ether (450 cm3) to give di-2-butylchlorophosphine (77.8 g, b.p. 84° C. at a pressure of 15 mm of mercury), and this compound was further reacted with hexamethyldisilazane and sulphur to give N-(di-2-butylphosphinothioyl)-P,P-di-2-butylphosphinothioic amide (m.p. 110°-114° C. 31P NMR in CDCl3, multiplet 87.9 ppm downfield of H3PO4). In this compound of Formula I, R1 =R2 =R3 =R4 =2-butyl.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:21](O)(=[O:23])[CH3:22].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[C:21]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)(=[O:23])[CH3:22]
Reactant: CC(=O)O
Reactant: C=Cc1ccc2ncn(-c3ccc4c(c3)CCN4)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=Cc1ccc2ncn(-c3ccc4c(c3)CCN4C(C)=O)c2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3-(2,3-dihydro-1H-indol-5-yl)-5-vinyl-3H-imidazo[4,5-b]pyridine (Intermediate 10.1) (150.0 mg, 0.57 mmol), glacial acetic acid (39.3 μl, 0.69 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (175.4 mg, 0.91 mmol), 4-dimethylaminopyridine (419.2 mg, 3.43 mmol), and dichloromethane (10 ml) is stirred for 24 h at ambient temperature. The mixture is successively extracted with saturated aqueous ammonium chloride and saturated aqueous sodium bicarbonate. The organic layer is dried over sodium sulfate and concentrated in vacuo to render 139.1 mg (80%) of the respective amide. HPLC (over 10 min 10-85% MeCN/100 mM aq. NaOAc): 99% purity, tR 6.43 min (tR(SM) 6.64 min). GC/MS: 96% purity, tR 13.98 min, m/z 304 (M, 58), 262 (100), 207 (62) Finnegan LCQ.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[N:10]([C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:9]1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[N:10]([C:21](=[O:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:9]1
Reactant: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CN(C(=O)c2ccccc2)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)[C@@H](N)CN(C(=O)c2ccccc2)c2ccccc21

Procedure:
(S)-(5-Benzoyl-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester (260 mg, 0.66 mmol) was dissolved in a mixture of trifluoroacetic acid and dichloromethane (1:1, 2 ml) for 2.5 h. Upon evaporation of the volatile parts, (S)-3-amino-5-benzoyl-1-methyl-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one was obtained in sufficient purity for the next step.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.Br[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([O:1][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:18][CH:17]=2)[CH:8]=1
Reactant: Oc1ccc(Oc2cnc3ccccc3c2)cc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)Oc1ccc(Oc2cnc3ccccc3c2)cc1
Temperature: 80 °C

Procedure:
A mixture of 3-(4-hydroxyphenoxy)quinoline (2.4 g), ethyl 2-bromopropionate (2.1 g), anhydrous potassium carbonate (3.3 g) and dimethylformamide (50 ml) was stirred and heated at 80° C. for 4 hours. The mixture was poured into water (500 ml) and extracted with diethyl ether (2×100 ml). The ether extracts were dried, evaporated to dryness and then chromatographed on silica gel (100 g) with dichloromethane elution. Ethyl 2-[4-(3-quinolinyloxy)phenoxy]propionate was obtained as a pale yellow oil (1.9 g). Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 8.75 (1H, d); 8.1 (1H, bd); 7.7-7.3 (4H, m); 7.0 (4H, s, phenoxy protons); 4.75 (1H, q, CH-CH3); 4.25 (2H, q, OCH2 -CH3); 1.65 (3H, d, CH-CH3); 1.25 (3H, t, OCH2 -CH3).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][OH:5].N12CCCN=C1CCCCC2.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(#N)C>[Si:20]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][OH:5])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N[C@@H](CCO)C(=O)O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)[Si](C)(C)N[C@@H](CCO)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of L-homoserine (1 g, 8.4 mmol) in acetonitrile (10 ml) at 0° C. was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.32 ml, 8.8 mmol, 1.05 eq). tert-butyldimethylsilyl chloride (1.33 g, 8.8 mmol, 1.05 eq) was then added portionwise over 5 minutes and the reaction mixture allowed to warm to room temperature and stirred for 16 hours. A white precipitate formed, which was filtered off and washed with acetonitrile before drying under reduced pressure. The title compound was isolated as a white solid (1.8 g, 92% yield). 1H NMR (500 MHz, DMSO-d6), δ: 7.5 (1H, br s), 3.7 (1H, m), 3.35 (4H, br m), 1.95 (1H, m), 1.70 (1H, m), 0.9 (9H, s), 0.1 (6H, s).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH2:19][CH2:20][CH2:21]O)[NH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.C1(C)C=CC(S([Cl:38])(=O)=O)=CC=1>C(#N)C>[C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH2:19][CH2:20][CH2:21][Cl:38])[NH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=S(=O)(c1ccccc1)c1c[nH]c2cccc(CCCO)c12
Solvent: c1ccncc1
Solvent: CC#N
Product: O=S(=O)(c1ccccc1)c1c[nH]c2cccc(CCCCl)c12
Reaction time: 264 h
Yield: 48 %

Procedure:
To a solution of 3-[3-(phenylsulfonyl)-1H-indol-4-yl]propan-1-ol (1.006 g, 3.19 mmol) in anhydrous acetonitrile (25 mL) at room temperature under nitrogen was added pyridine (0.65 mL, 7.97 mmol) followed by p-toluenesulfonyl chloride, and the reaction mixture stirred for 11 days. The reaction mixture was then concentrated to a small volume in vacuo, and the mixture partitioned between ethyl acetate (100 mL) and 1 N aqueous HCl (100 mL). The organic phase was separated, washed with water (2×100 mL) and brine (200 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford a yellow syrup. Purification by flash chromatography (0 to 40% ethyl acetate/hexane) afforded 3-phenylsulfonyl-4-(3-chloro-propyl)-1H-indole as a colorless foam (0.51 g, 48%). MS (ES+) m/z 334 (M+H). Further elution afforded 3-[3-(phenylsulfonyl)-1H-indol-4-yl]propyl 4-methylbenzenesulfonate as a white foam (0.48 g, 32%). MS (ES+) m/z 469.7 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[C:17]3[N:24]([CH2:25][CH3:26])[C:23]([C:27]4[C:31]([NH2:32])=[N:30][O:29][N:28]=4)=[N:22][C:18]=3[CH:19]=[N:20][CH:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[C:39](Cl)(=[O:41])[CH3:40]>ClC1CC(C(C)C)CCC1(Cl)C>[NH2:32][C:31]1[C:27]([C:23]2[N:24]([CH2:25][CH3:26])[C:17]3[C:16]([CH2:15][N:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[C:39](=[O:41])[CH3:40])=[CH:21][N:20]=[CH:19][C:18]=3[N:22]=2)=[N:28][O:29][N:30]=1
Reactant: CCn1c(-c2nonc2N)nc2cncc(CNC3CCN(C(=O)OC(C)(C)C)CC3)c21
Reactant: CC(=O)Cl
Agent: CC(C)C1CCC(C)(Cl)C(Cl)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCn1c(-c2nonc2N)nc2cncc(CN(C(C)=O)C3CCNCC3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
The title compound from Example 191, Step 2 (145 mg, 0.3 mmol) in dichloromenthane at 0° C. was treated with potassium carbonate (90 mg, 0.66 mmol) followed by acetyl chloride (26 mg, 0.33 mL), and the mixture was stirred at room temperature for 1 hour. Purification of the residue by silica gel chromatography eluting with 10% methanol/dichloromethane afforded the title compound (68 mg, 10%). MS (ES+) m/e 484 [M+H]+.
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl>[F:21][C:22]([F:32])([F:33])[C:23]1[CH:24]=[C:25]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])[CH:26]=[CH:27][CH:28]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)C(=O)C(C(=O)Nc1cccc(C(F)(F)F)c1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
To an ice-cooled solution of (1S)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 3-(trifluoromethyl)phenyl isocyanate (0.37 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 7 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield a yellow oil, which was crystallized from 95% ethanol to yield the title compound as a beige solid (0.30 g, 41% yield), mp=60–62° C.; MS (−) ESI m/z=366 (M−H)−; [α]D25=−22.0° (c=1, EtOH).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[C:17]([CH3:19])([CH3:18])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[C:14](=[O:23])[CH:13]=1>O1CCCC1>[Br:1][C:2]1[S:6][C:5]([CH2:7][O:8][C:12]2[C:17]([CH3:18])([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[C:14](=[O:23])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)s1
Reactant: CC1(C)C(=O)C=C(Cl)C(C)(C)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)C(=O)C=C(OCc2ccc(Br)s2)C(C)(C)C1=O
Temperature: 25 °C
Yield: 49.8 %

Procedure:
To a solution of 5-bromothiophen-2-ylmethanol (6.76 g, 35 mmol) in tetrahydrofuran (100 ml) at 0° C. is added, carefully, sodium hydride, 60% dispersion in mineral oil, (1.2 g, 30 mmol over a period of 10 minutes. The reaction is allowed to warm to room temperature and stirred for a further hour. 5-Chloro-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione (5.02 mg, 25 mmol) is then added in one portion and the reaction mixture is allowed to stir at room temperature for 17 hours. The reaction is concentrated in vacuo and purified by flash chromatography on silica gel to give the desired compound as a white solid (4.45 g)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1F)[CH3:2].[NH:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH2:18][N:19]([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.CC(=O)OCC>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH2:18][N:19]([CH3:21])[CH3:20])[CH3:2]
Reactant: CN(C)Cc1ncc[nH]1
Reactant: CCOC(=O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccccc1-n1ccnc1CN(C)C
Temperature: 120 °C
Reaction time: 16 h
Yield: 17.8 %

Procedure:
A mixture of 2-fluoro-benzoic acid ethyl ester (200 mg; 1.19 mmol; 10 eq.), (1H-imidazol-2-ylmethyl)-dimethyl-amine (149 mg; 1.19 mmol; 1 eq.) and cesium carbonate (775 mg; 2.38 mmol; 2 eq.) in DMSO (3 mL) was stirred at 120° C. for 16 hours. The mixture was diluted with EA, washed with water (3×), dried over magnesium sulfate and concentrated in vacuo to afford the title compound (58 mg, 18%) as a white solid. HPLC (max plot) 95.7%; Rt 1.80 min.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:34][CH:35]([C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[CH:41][CH:40]=2)[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[S:51][CH:52]=[CH:53][N:54]=1>C(Cl)Cl>[CH:28]1([CH2:34][CH:35]([C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[CH:41][CH:40]=2)[C:36]([NH:49][C:50]2[S:51][CH:52]=[CH:53][N:54]=2)=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCCC2)C(=O)O)cc1
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCCC2)C(=O)Nc2nccs2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
A solution of triphenylphosphine (416 mg, 1.58 mmol) in methylene chloride (8 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (281 mg, 1.58 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of 3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-propionic acid (290 mg, 0.93 mmol) in methylene chloride (5 mL). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (233 mg, 2.32 mmol), and the resulting suspension was stirred for 20 h at 25° C. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (50 mL) and a 1N aqueous hydrochloric acid solution (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×30 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and, concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 4/1 to 1/1 hexanes/ethyl acetate) afforded 3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (337 mg, 92%) as an amorphous solid: EI-HRMS m/e calcd for C19H24N2O3S2 (M+) 392.1228, found 392.1230.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]4[N:27]=[CH:26][C:25]([CH2:28][CH2:29][CH3:30])=[CH:24][N:23]=4)[CH2:18][CH2:17]3)=[CH:11][C:10]2=[O:31])=[CH:5][CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:37]>C(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:17][CH2:18][N:19]([C:22]4[N:23]=[CH:24][C:25]([CH2:28][CH2:29][CH3:30])=[CH:26][N:27]=4)[CH2:20][CH2:21]3)=[CH:11][C:10]2=[O:31])=[CH:7][CH:8]=1)=[O:37]
Reactant: CCCc1cnc(N2CCC(Oc3ccn(-c4ccc(SC)cc4)c(=O)c3)CC2)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCc1cnc(N2CCC(Oc3ccn(-c4ccc(S(C)=O)cc4)c(=O)c3)CC2)nc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.6 %

Procedure:
To a stirring solution of 1-(4-(methylthio)phenyl)-4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)pyridin-2(1H)-one (51.4 mg, 0.118 mmol) in CH2Cl2 (15 mL) at 0° C. was added a solution of 3-Chloroperoxybenzoic acid (26.4 mg, 0.118 mmol) in 5 mL CH2Cl2. The reaction was stirred at 0° C. for 15 min and then quenched with Na2SO3 (sat. solution in H2O). The organic layer was washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo to a white solid. The solid was purified by flash chromatography (SiO2, 0 to 10% MeOH in CH2Cl2) to yield 50 mg of desired product as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.16 (s, 2H), 7.77 (d, J=8.31 Hz, 2H), 7.57 (d, J=8.31 Hz, 2H), 7.23 (d, J=7.34 Hz, 1H), 5.94-6.11 (m, 2 H), 4.44-4.64 (m, 1H), 4.07-4.31 (m, 2H), 3.50-3.74 (m, 2H), 2.77 (s, 3H), 2.40 (t, J=7.58 Hz, 2H), 1.98-2.17 (m, 2H), 1.73-1.93 (m, 2H), 1.50-1.64 (m, 2H), 0.93 (t, =7.34 Hz, 3H). MS (ESI) 453 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:31]=[C:30]([C:32](=[O:36])[NH:33][CH2:34][CH3:35])[CH:29]=[CH:28][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](O)=[O:24])=[CH:18][C:17]=1[O:26][CH3:27])(=[O:11])=[O:10].[NH2:37]C(N)=O.C(=O)([O-])[O-].[Na+].[Na+]>Cl>[C:23]([CH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:14]2[CH:28]=[CH:29][C:30]([C:32]([NH:33][CH2:34][CH3:35])=[O:36])=[CH:31][C:13]=2[NH:12][S:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])(=[O:10])=[O:11])=[C:17]([O:26][CH3:27])[CH:18]=1)(=[O:24])[NH2:37]
Reactant: CCNC(=O)c1ccc(Oc2ccc(CC(=O)O)cc2OC)c(NS(=O)(=O)c2ccc(Cl)cc2Cl)c1
Reactant: NC(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCNC(=O)c1ccc(Oc2ccc(CC(N)=O)cc2OC)c(NS(=O)(=O)c2ccc(Cl)cc2Cl)c1
Temperature: 175 °C
Yield: 67.5 %

Procedure:
A mixture of acid 12 (70 mg, 0.126 mmol) and urea (1.0 g, 16.6 mmol) was heated to 170-180° C. and maintained at this temperature for 4 h, and the mixture was allowed to cool. As soon as the temperature dropped to 110-120° C. 2 mL of 5% sodium carbonate aqueous solution was added, and the mixture was shaken vigorously. After mixture was cooled to room temperature, 20 mL of 3N HCl aqueous solution was added and the resulting mixture was extracted with ethyl acetate (4×20 mL). The combined extracts were washed with water and brine, dried and concentrated. The residue was purified by silica gel chromatography using EtOAc and 10% CH3OH/EtOAc sequentially as the eluents to give 47 mg of product. 1H NMR (Acetone-d6): δ 8.77 (s, 1H), 8.04 (d, J=2.13 Hz, 1H), 7.96 (d, J=8.57 Hz, 1H), 7.70 (, br s, 1H), 7.63 (d, J=2.13 Hz, 1H), 7.56 (dd, J=8.53, 2.13 Hz, 1H), 7.51 (dd, J=8.53, 2.13 Hz, 1H), 7.11 (d, J=1.86 Hz, 1H), 6.88 (dd, J=8.13, 1.87 Hz, 1H), 6.85 (br s, 1H), 6.75 (d, J=8.13 Hz, 1H), 6.659 (d, J=8.67 Hz, 1H), 3.67 (s, 3H), 3.51 (s, 2H), 3.38 (m, 2H), 1.17 (dd, J=7.20, 7.20 Hz, 3H). LCMS (ESI−) 551 (M−1).