Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Br:8])[CH:7]=1.Cl[C:14]1[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=1.CC1C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Br:8][C:6]1[CH:5]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[CH:3]=[C:2]([NH:1][C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:7]=1
Reactant: CC(=O)Nc1cc(N)cc(Br)c1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(Br)cc(Nc2nccc(C(F)(F)F)n2)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 50.9 %

Procedure:
To a solution of N-(3-amino-5-bromophenyl)acetamide (3.25 g, 14.19 mmol) and 2-chloro-4-(trifluoromethyl)pyrimidine (2.054 mL, 17.03 mmol) in dioxane (8.5 mL) under nitrogen, was added pTsOH (2.70 g, 14.19 mmol). The reaction was stirred at 100° C. for 18 h, cooled to at room temperature. Solvent was removed under reduced pressure and the resultant residue was diluted with sat. NaH-CO3 (aq) and DCM. The organic was dried over sodium sulfate and was concentrated to dryness. Purified by flash chromatography (1:1 to 0:100 hexanes:ethyl acetate) to yield N-(3-bromo-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)acetamide (2.71 g, 7.22 mmol, 51%) as a beige powder. MS APCI: [M+H]m/z 377.0.
Reaction SMILES: C[O-].[Na+].[CH3:4][N:5]([CH3:16])[C:6]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH2:9][CH3:10])[CH2:7][OH:8].[NH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22](OC)=[O:23])=[C:20]([O:28][CH3:29])[C:19]=1[Cl:30]>C1(C)C=CC=CC=1>[NH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:8][CH2:7][C:6]([N:5]([CH3:4])[CH3:16])([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH2:9][CH3:10])=[O:23])=[C:20]([O:28][CH3:29])[C:19]=1[Cl:30]
Reactant: COC(=O)c1ccc(N)c(Cl)c1OC
Reactant: CCC(CO)(c1cccs1)N(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC(COC(=O)c1ccc(N)c(Cl)c1OC)(c1cccs1)N(C)C
Temperature: 110 °C
Reaction time: 96 h
Yield: 25 %

Procedure:
Sodium methoxide (0.4 g) is added to a solution of 2-dimethylamino-2-(2-thienyl)-1-butanol (7.5 g) and methyl 4-amino-3-chloro-2-methoxybenzoate (16.2 g) in toluene (150 ml) and the mixture is stirred at 110° C. for 96 hours while removing methanol which is produced during the reaction. After cooling, the mixture is washed with water, dried and concentrated to remove solvent. The residue is purified by silica gel column chromatography (solvent, chloroform:ethanol=50:1), whereby 2-dimethylamino-2-(2-thienyl)butyl 4-amino-3-chloro-2-methoxybenzoate (3.6 g) is obtained as colorless crystals.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].C1C(=O)N([Br:21])C(=O)C1.O>CN(C)C=O>[Br:21][C:9]1[CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([NH2:6])=[C:7]([CH:11]([CH3:13])[CH3:12])[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1cc(Br)cc(C(C)C)c1N
Temperature: 0 °C
Yield: 99.5 %

Procedure:
To a stirred solution of 2,6-diisopropylaniline (14 g, 78.97 mmol, 1.00 equiv) in N,N-dimethylformamide (200 mL) at 0° C. was added a solution of NBS (14 g, 78.65 mmol, 1.00 equiv) in N,N-dimethylformamide (100 mL) dropwise in 60 min. The reaction was stirred for another hour at 0° C. then water (900 mL) was added. The resulting mixture was extracted with 300 mL of ethyl acetate. The combined organic layers was washed with 3×100 mL of saturated NH4Cl solution and 1×100 mL of water then dried over anhydrous sodium sulfate and concentrated under vacuum to give 20.05 g (99%) of 4-bromo-2,6-diisopropylaniline as a red oil. 1H NMR (400 MHz, DMSO-d6): δ 6.95 (s, 2H), 4.77 (s, 2H), 5.47-5.39 (m, 1H), 3.04-2.98 (m, 1H), 1.13 (d, J=6.8 Hz, 12H) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:23][CH3:24])=[CH:11][C:12]([C:21]#[N:22])=[C:13]([CH:20]=1)[C:14](N(OC)C)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1([Mg]Br)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Cl-].[NH4+].Cl>C(OCC)(=O)C.O1CCCC1>[C:14]([C:13]1[CH:20]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]([O:23][CH3:24])=[CH:11][C:12]=1[C:21]#[N:22])(=[O:15])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1cc(C#N)c(C(=O)N(C)OC)cc1OCc1ccccc1
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C#N)c(C(=O)c2ccccc2)cc1OCc1ccccc1
Reaction time: 1.5 h

Procedure:
To a mixture of 5-benzyloxy-2-cyano-4,N-dimethoxy-N-methylbenzamide (reference example 6-2) (203 mg) and tetrahydrofuran (3.1 mL) was added phenylmagnesium bromide (1.08 mol/L tetrahydrofuran solution, 0.7 mL) under ice-bath cooling. The mixture was stirred for 1.5 hours. Phenylmagnesium bromide (1.08 mol/L tetrahydrofuran solution, 0.3 mL) was added to the mixture. After stirring under ice-bath cooling for 50 minutes, the mixture was stirred at room temperature overnight. Phenylmagnesium bromide (1.08 mol/L tetrahydrofuran solution, 0.35 mL) was added to the mixture. After stirring at 0° C. for 1.5 hours, to the mixture were added a saturated aqueous solution of ammonium chloride, 1 mol/L hydrochloric acid and ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid, water and brine successively, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0%-30% ethyl acetate/hexane, gradient elution) to give the title compound (112 mg).
Reaction SMILES: I[C:2]1[C:7]([NH2:8])=[C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[CH:4][N:3]=1>C(#N)C.C(N(CC)CC)C.C(O)C#C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:8][C:7]1[C:2]([C:2]#[C:7][CH2:6][OH:9])=[N:3][CH:4]=[N:5][C:6]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1c(I)ncnc1Oc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#CCO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1c(C#CCO)ncnc1Oc1ccccc1
Yield: 174.8 %

Procedure:
4-Iodo-6-phenoxypyrimidin-5-amine (3.0 g) was dissolved in a mixed solvent of acetonitrile (159 mL)/triethylamine (117 mL), and 2-propyn-1-ol (0.669 mL), trans-dichlorobis(triphenylphosphine)palladium(II) (336 mg) and copper(I) iodide (109.5 mg) were sequentially added. The title compound (2.02 g) was obtained as crystals by the reaction in the same manner as in Example 9 (iv).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=1.C(#N)C.[Mn]([O-])(=O)(=O)=[O:26].[K+].S(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:26])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)c1ccc(-c2cc3c(C=O)c[nH]c3cc2Cl)cc1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)c1ccc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)cc1
Temperature: 30 °C

Procedure:
A vial was charged with 6-chloro-5-[4-(propan-2-yl)phenyl]-1H-indole-3-carbaldehyde, 1 mL acetonitrile, and 500 uL of a 1.0M solution of potassium permanganate in water. The vial was sealed and heated to 30° C. for 16 hrs. Sodium bisulfite (72 mg, 1.0 mmol) was then added and the reaction heated to 30° C. for 1 hr. The reaction was then filtered, and the solvent removed in vacuo. The residue was then purified by reverse phase prep HPLC to give the title compound. MS (AP−) 312 (M−H)−. RT=2.378 Column Xbridge C18 2.1×50 mm 5 μm, Temperature 50° C. Mobile Phase A=0.05% NH4OH in water. Mobile Phase B=100% acetonitrile. Gradient: Initial 5% B Time 0.00 mins, 5% B Time 0.50 mins, 5% B Time 3.40 mins, 100% B Time 4.20 mins, 100% B Time 4.21 mins, 5% B Time 4.70 mins, 5% B Flow rate, 0.8 mL/min Injection volume 2 μL. Agilent 1200 HPLC/1956 MSD/SEDEX 75 ELSD Ionization Mode API-ES Polarity Negative.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=1.[CH2:17]([O:19][P:20]([O:24]CC)[O:21][CH2:22][CH3:23])[CH3:18].O>C(OCC)(=O)C>[CH3:13][C:9]1[N:8]=[C:7]([O:6][C:5]2[CH:4]=[C:3]([CH:16]=[CH:15][CH:14]=2)[CH2:2][P:20](=[O:24])([O:21][CH2:22][CH3:23])[O:19][CH2:17][CH3:18])[CH:12]=[CH:11][CH:10]=1
Reactant: CCOP(OCC)OCC
Reactant: Cc1cccc(Oc2cccc(CCl)c2)n1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOP(=O)(Cc1cccc(Oc2cccc(C)n2)c1)OCC
Temperature: 150 °C
Reaction time: 16 h
Yield: 82.4 %

Procedure:
2-(3-(Chloromethyl)phenoxy)-6-methylpyridine (4.0 g, 17 mmol) from Step 2 was treated neat with triethylphosphite (3.67 mL, 21.4 mmol) and heated to 150° C. After 16 h, the reaction mixture was cooled to room temperature and partioned between water and ethyl acetate. The organic layer was separated and the aqueous was extracted again with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (30-60%, EtOAc:CH2Cl2) to afford the title compound (4.7 g, 82% yield) as a thick oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]([CH:20]1[CH2:22][CH2:21]1)[C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[CH3:2].[C:24](OC(=O)C)(=[O:26])[CH3:25]>C1COCC1.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([N:6]([CH:20]1[CH2:22][CH2:21]1)[C:7](=[O:19])[C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([F:16])([F:17])[F:18])=[CH:12][CH:13]=1)[C:24](=[O:26])[CH3:25])[CH3:2]
Reactant: CCOC(=O)CN(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(C(C)=O)N(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Yield: 13.4 %

Procedure:
To a solution of 6.6 ml (1 M in THF, 7 mmol) of lithium hexamethyldisilylazide cooled to −78° C. under Ar was added, drop wise, a solution of 2.0 g (6 mmol) of [cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-acetic acid ethyl ester in 10 ml of THF. The mixture was stirred for 1 h before 0.7 g of acetic anhydride was added and the mixture was allowed to reach room temperature. After 2 h the reaction was diluted with EtOAc, washed with saturated ammonium chloride solution, the organic phase dried with sodium sulfate and concentrated. Purification by flash column chromatography [n-heptane/EtOAc 1:9 to 3:7] afforded 0.3 g (13%) of the title compound as a colorless oil. MS: 374.2 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[C:16]3[O:15][CH2:14][CH2:13][C:12]=3[CH:11]=[C:10]([CH2:17][C:18]([O:20]CC)=[O:19])[CH:9]=2)=[S:7])=[CH:4][CH:3]=1.CO.[OH-].[Na+]>O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:16]3[O:15][CH2:14][CH2:13][C:12]=3[CH:11]=[C:10]([CH2:17][C:18]([OH:20])=[O:19])[CH:9]=2)=[S:7])=[CH:23][CH:24]=1
Reactant: CCOC(=O)Cc1cc2c(c(C(=S)c3ccc(C)cc3)c1)OCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=S)c2cc(CC(=O)O)cc3c2OCC3)cc1

Procedure:
A solution of ethyl 7-(4-methylthiobenzoyl)-2,3-dihydrobenzofuran-5-ylacetate (10.0 g), 50 ml of methanol, 200 ml of water, and 4 g of sodium hydroxide was heated at reflux for approximately 2 hours. The reaction mixture was cooled and washed with ether. The ether washed aqueous residue was acidified with dilute hydrochloric acid and then extracted with ethyl acetate. The combined organic extracts were washed with water and evaporated to give a residue which was crystallized from acetone/hexane to give 7-(4-methylthiobenzoyl)-2,3-dihydrobenzofuran-5-ylacetic acid, m.p. --150°-152° C.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH:18]O.[Al]>>[CH3:1][N+:2]([O-:18])([CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: OO
Reactant: CCCCCCCCCCCCCCN(C)C
Agent: [Al]
Product: CCCCCCCCCCCCCC[N+](C)(C)[O-]
Temperature: 41 °C

Procedure:
N,N-dimethyl-N-tetradecyl amine (ADMA®14 amine; Albemarle Corporation) (752 g, 3.12 mol) was charged into a 2-liter resin kettle and heated to 41° C. under CO2 blanket before the heating source was removed. Hydrogen peroxide (142 mL, 70%, 3.74 mol) was added over 3.5 hours. The reaction mixture was monitored by 1H-NMR (see Table below). During peroxide addition, the reaction temperature ranged from 41 to 59° C. depending on the peroxide rate of addition. At the end of addition, the slurry was poured into an aluminum pan and was left to stand in a hood over the weekend, after which time 1H-NMR showed complete conversion of the N,N-dimethyl-N-tetradecyl amine to the corresponding oxide. The resulting N,N-dimethyl-N-tetradecyl amine oxide was obtained as snow-white solid block.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)=[N:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[S:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][CH:42]=1)[NH2:39].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[S:35][C:36]1[CH:37]=[C:38]([NH:39][C:12]([NH:11][C:4]2[CH:5]=[C:6]([C:7]([F:8])([F:9])[F:10])[N:2]([CH3:1])[N:3]=2)=[O:20])[CH:40]=[CH:41][CH:42]=1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: Cn1nc(NC(=O)Oc2ccccc2)cc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(F)(F)F)n(C)n4)c3)c2cc1OC
Yield: 17 %

Procedure:
Using the procedure described in Example 159B, phenyl 1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-ylcarbamate described in Example 165A (0.114 g, 0.4 mmol) was reacted with 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.125 g, 0.4 mmol), and N,N-diisopropylethylamine (0.5 mL) in THF (6 mL) at 50° C. for 3 hours, to afford 1-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]-3-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]urea as solid (0.035 g, 17%). 1H NMR (300 MHz, CDCl3) δ 9.43 (br, 1H), 8.77 (s, 1H), 7.80 (m, 1H), 7.63 (d, 1H), 7.44 (t, 1H), 7.38 (m, 2H), 7.28 (s, 1H), 7.20 (s, 1H), 6.31 (s, 1H), 4.08 (s, 3H), 4.06 (s, 3H), 3.91 (s, 3H); LC-MS (ESI) m/z 505 (M+H)+.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])O)#[N:2].S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl.CN(C=O)C>[Cl:19][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])[C:1]#[N:2]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cc(C(O)C#N)ccc1OC
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(C(Cl)C#N)ccc1OC

Procedure:
To a suspension of methyl 5-(1-cyano-1-hydroxymethyl)-2-methoxybenzoate (2.15 g) in chloroform (40 ml) were added thionyl chloride (2.0 ml) and DMF (2 drops), and the mixture was refluxed for 30 minutes under heat. After cooling, the reaction mixture was washed with water, aqueous solution of sodium hydrogencarbonate and saturated brine in sequence and dried over anhydrous sodium sulfate. This was concentrated under reduced pressure to obtain 2.37 g of aimed compound as an oily product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[NH:27]1[CH2:32][CH2:31][S:30][CH2:29][CH2:28]1>CS(C)=O>[CH3:26][O:25][C:4]1[CH:3]=[C:2]([N:27]2[CH2:32][CH2:31][S:30][CH2:29][CH2:28]2)[CH:7]=[CH:6][C:5]=1[C:8]1[O:9][C:10]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:11][N:12]=1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: C1CSCCN1
Solvent: CS(C)=O
Product: COc1cc(N2CCSCC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Temperature: 170 °C
Reaction time: 5 h
Yield: 66.2 %

Procedure:
To a solution of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.57 mmol) in DMSO (2 mL) was added thiomorpholine (0.29 mL, 2.85 mmol) and the reaction mixture was stirred for 5 h at 170° C. After cooling to ambient temperature it was extracted with water (20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers were washed with brine (half-saturated, 20 mL) and aqueous sodium carbonate (saturated, 20 mL). Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20) afforded the title compound (164 mg, 66%) as an off-white solid. MS: m/e=435.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16](O)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.Cl.[NH2:25][C@H:26]([C:31]([O:33][CH3:34])=[O:32])[CH2:27][CH2:28][CH2:29][CH3:30].F[B-](F)(F)F.CN([CH+]N(C)C)C.CN1CCOCC1>ClCCl>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:25][C@H:26]([C:31]([O:33][CH3:34])=[O:32])[CH2:27][CH2:28][CH2:29][CH3:30])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCCC[C@H](N)C(=O)OC
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Agent: CN(C)[CH+]N(C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCC[C@H](NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12)C(=O)OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
500 mg of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid (Example 6A; 1.57 mmol, 1 equivalent) were initially charged in 10 ml of anhydrous dichloromethane, and 313 mg of methyl L-norleucinate hydrochloride (1.73 mmol, 1.1 equivalents), 554 mg of benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate (TBTU; 1.73 mmol, 1.1 equivalents) and 0.864 ml of 4-methylmorpholine (7.85 mmol, 5 equivalents) were added in succession. The reaction mixture was stirred at room temperature for 4 h. The mixture was then diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution, with water and finally with saturated aqueous sodium chloride solution, dried and concentrated. The residue obtained was chromatographed on a 100 g silica gel cartridge (Biotage Isolera; cyclohexane/ethyl acetate gradient as mobile phase). This gave 644 mg of the target compound (91% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[OH:15][CH2:16][CH2:17][CH2:18][S:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([S:19]([CH2:18][CH2:17][CH2:16][OH:15])(=[O:21])=[O:20])=[CH:30][CH:29]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)CCCO)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)CCCO)cc1

Procedure:
5 g of 4-fluorobenzonitrile was used in Procedure Q with 3-mercapto-1-propanol to afford 4-(3-hydroxypropylthio)benzonitrile. 1.8 g of 4-(3-hydroxypropylthio)benzonitrile was reacted via Procedure T to give 4-(3-hydroxypropylthio)benzoic acid. 1.2 g of 4-(3-hydroxypropylthio)benzoic acid was reacted via Procedure R to give 4-(3-hydroxypropylsulfonyl)benzoic acid. 50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(3-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3-hydroxypropylsulfonyl)benzamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH3:21])=[O:5])[CH3:2].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:47])C(=O)C1.O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:21][Br:47])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Temperature: 80 °C
Yield: 82.2 %

Procedure:
To a solution of 1 g of 4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester in 8 mL of carbon tetrachloride was added portionwise 0.1 g of benzoyl peroxide and 0.56 g of NBS. The resulting mixture was heated to 80° C. for 1.5 h. 0.1 g of NBS was added and the reaction mixture was heated to 80° C. overnight. An additional 0.1 g of NBS was added and the reaction mixture was heated to 80° C. for 2 h. It was then poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (heptane 1/toluene 1 followed by pure toluene) to give 1.02 g of 4-bromomethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester. 1 WO02067912
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH:16]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[H][H]>CCOC(C)=O.[Pt]=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:13]2)=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(C2=CCN(C(=O)OC(C)(C)C)C2)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 0.75 h

Procedure:
To a degassed solution of the title compound from Example 136 Step A (3.17 g, 9.99 mmol) in EtOAc (50 mL) was added platinum oxide (0.68 g, 3.00 mmol). The reaction flask was fitted with a hydrogen balloon attached to a 3-way adapter. The reaction mixture was then evacuated and back-filled with hydrogen. After this process was repeated three times, the reaction mixture was placed under a hydrogen atmosphere, and was stirred vigorously. After 45 min, the reaction mixture was filtered though Celite, rinsing with EtOAc. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by chromatography on silica gel (0 to 8% EtOAc in hexanes, 8% EtOAc in hexanes, then 8 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 264.0 [M-t-Boc]+; 1H NMR (500 MHz, CDCl3) δ 7.99 (d, J=8.5 Hz, 2H), 7.30 (d, J=8.0 Hz, 2H), 4.37 (q, J=7.0 Hz, 2H), 3.92-3.76 (br m, 1H), 3.70-3.52 (br m, 1H), 3.48-3.34 (br m, 2H), 3.30 (t, J=10.0 Hz, 1H), 2.34-2.24 (br m, 1H), 1.99 (q, J=10.0 Hz, 1H), 1.48 (s, doubled (rotamers), 9H), 1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][CH:2]([O:6][C:7]1[CH:8]=[C:9]([CH:15]2[CH2:19][NH:18][C:17](=[O:20])[CH2:16]2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:3]1[O:5][CH2:4]1.[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[CH3:14][O:13][C:12]1[CH:11]=[CH:10][C:9]([CH:15]2[CH2:19][NH:18][C:17](=[O:20])[CH2:16]2)=[CH:8][C:7]=1[O:6][CH:2]([CH3:1])[CH:3]([OH:5])[CH2:4][N:30]1[CH2:31][CH2:32][N:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:28][CH2:29]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1ccc(C2CNC(=O)C2)cc1OC(C)C1CO1
Solvent: CCO
Product: COc1ccc(C2CNC(=O)C2)cc1OC(C)C(O)CN1CCN(c2ccccc2)CC1
Yield: 68 %

Procedure:
In accordance with the process set forth in Example 1, 10 mmol of 4-[3-(1-methyl-2,3-epoxypropoxy)-4-methoxyphenyl]-2-pyrrolidone and 10 mmol of 1-phenylpiperazine (95% strength) produce, in a 68% yield, 4-{4-methoxy-3-[3-(4-phenylpiperazin-1-yl)1-methyl-2-hydroxypropoxy]phenyl}-2-pyrrolidone, m.p. 116°-118° (ethanol).