Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14]2)#[N:10]>CCO>[OH:3][NH:2][C:9](=[NH:10])[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(C#N)ccc2[nH]1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc2cc(C(=N)NO)ccc2[nH]1
Temperature: 55 °C
Reaction time: 16 h
Yield: 91.5 %

Procedure:
Hydroxylamine hydrochloride (172 mg) and sodium bicarbonate (415 mg) was added to a solution of ethyl 5-cyano-1H-indole-2-carboxylate (D21) (265 mg) in EtOH (15 mL), in that sequence. The reaction mixture was heated to 55° C. and stirred for 16 hours at that temperature. Another portion of hydroxylamine hydrochloride (69.4 mg) was added, followed by addition of sodium bicarbonate (125.5 mg). The resulting suspension was stirred at 55° C. for 12 hours. The inorganics was filtered off. The solid was washed with dichloromethane (30 mL) and methanol (30 mL). The filtrate was concentrated to afford ethyl 5-[(hydroxyamino)(imino)methyl]-1H-indole-2-carboxylate (D22) (280 mg) as a yellow solid. No purification was attempted. MS (ES): C12H13N3O3 requires 247; found 248.1 (M+H+).
Reaction SMILES: [H-].[Na+].O1CCC[CH2:4]1.[CH3:8][CH:9]([CH3:17])[CH2:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14].IC>O>[CH3:4][CH:12]([C:11](=[O:16])[CH2:10][CH:9]([CH3:17])[CH3:8])[C:13](=[O:15])[CH3:14]
Reactant: CC(=O)CC(=O)CC(C)C
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CC(=O)C(C)C(=O)CC(C)C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To 0.1 mol sodium hydride was added 100 ml anhydrous tetrahydrofuran, then added slowly dropwise 0.1 mol 6-methyl-2,4-heptandione at room temperature. The reaction was stirred for 0.5 hours, then 0.12 mol iodomethane was added dropwise and the reaction was stirred at room temperature for further 10 hours. Upon completing the reaction, 20 ml water was added. The mixture was extracted with ethyl acetate. After removing the solvent, distillation under reduced pressure gave a cut fraction 88-9° C./1 kPa (165-166° C. at atmosphere pressure), and the yield was 94%.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[CH3:32][C:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O>COCCOC>[CH3:32][C:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[CH:35][C:34]=1[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7]
Reactant: Cc1cccc(B(O)O)c1C
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cccc(-c2cc(F)ccc2OCC(=O)N(NC(=O)c2ccccc2)C(C)C)c1C
Yield: 56.6 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 2,3-dimethylphenylboronic acid (27 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-30% ethyl acetate/hexanes gradient to afford the product as a white solid (30 mg, 57%). MS m/e 435.30 (M+H+)
Reaction SMILES: [ClH:1].Cl.N1(CCOC2C=CC(N(C3C=CC(OCCN4CCCCC4)=CC=3)C(=O)C3C=CC([F:26])=CC=3)=CC=2)CCCCC1.Cl.Cl.N1(CCOC2C=CC(N(C3C=CC(OCCN4CCCCC4)=CC=3)C(=O)C3C=CC=CC=3)=CC=2)CCCCC1.Cl.Cl.[N:86]1([CH2:92][CH2:93][O:94][C:95]2[CH:100]=[CH:99][C:98]([N:101]([C:119]3[CH:124]=[CH:123][CH:122]=[CH:121][CH:120]=3)[C:102](=[O:118])[C:103]3[CH:108]=[CH:107][C:106]([O:109][CH2:110][CH2:111][N:112]4[CH2:117][CH2:116][CH2:115][CH2:114][CH2:113]4)=[CH:105][CH:104]=3)=[CH:97][CH:96]=2)[CH2:91][CH2:90][CH2:89][CH2:88][CH2:87]1>>[ClH:1].[ClH:1].[F:26][C:122]1[CH:121]=[CH:120][C:119]([N:101]([C:98]2[CH:97]=[CH:96][C:95]([O:94][CH2:93][CH2:92][N:86]3[CH2:91][CH2:90][CH2:89][CH2:88][CH2:87]3)=[CH:100][CH:99]=2)[C:102](=[O:118])[C:103]2[CH:108]=[CH:107][C:106]([O:109][CH2:110][CH2:111][N:112]3[CH2:113][CH2:114][CH2:115][CH2:116][CH2:117]3)=[CH:105][CH:104]=2)=[CH:124][CH:123]=1
Reactant: O=C(c1ccc(F)cc1)N(c1ccc(OCCN2CCCCC2)cc1)c1ccc(OCCN2CCCCC2)cc1
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)N(c1ccccc1)c1ccc(OCCN2CCCCC2)cc1
Agent: Cl
Agent: O=C(c1ccccc1)N(c1ccc(OCCN2CCCCC2)cc1)c1ccc(OCCN2CCCCC2)cc1
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)N(c1ccc(F)cc1)c1ccc(OCCN2CCCCC2)cc1

Procedure:
N,N-Bis[4-(2-piperidin-1-ylethoxy)-phenyl]-4-fluoro-benzamide dihydrochloride (4s); N,N-Bis[4-(2-piperidin-1-ylethoxy)-phenyl]-benzamide dihydrochloride (4t); and N-[4-(2-piperidin-1-ylethoxy)-phenyl]-N-phenyl-[4-(2-piperidin-1-ylethoxy)]-benz amide dihydrochloride (4u).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:26][C:16]3=[C:17]4[C:21](=[C:22]([CH3:24])[CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:25])[CH2:18]4)(=O)=O)=CC=1.[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1.O>CS(C)=O>[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:34][CH2:11][CH:12]2[O:26][C:16]3=[C:17]4[C:21](=[C:22]([CH3:24])[CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:25])[CH2:18]4)=[CH:31][CH:30]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3cc(C)c4c(c3O2)CC(=O)N4)cc1
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc2c(c3c1NC(=O)C3)OC(CNCc1ccc(F)cc1)CO2
Temperature: 90 °C

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-6-methyl-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (0.28 g, 0.72 mmole) and 4-fluorobenzylamine (0.45 g, 3.6 mmole) were combined in 10 ml of dry DMSO and heated to 90° C. for 4 hours under a nitrogen atmosphere. After cooling to room temperature, 150 ml of water was added and the mixture was extracted twice with 250 ml portions of 35% ethyl acetate in hexane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuum to yield an orange semisolid. Column chromatography on silica gel using 1% methanol/CH2Cl2 as eluant gave the free base of the title compound as a brown oil. This was crystallized from isopropanol with the addition of fumaric acid (0.20 g, 1.7 mmole) to give 0.06 g of the (S) enantiomer of the title compound as a beige solid fumarate, m.p. 233-234° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([C:12]1[N:16]2[CH:17]=[C:18]([CH3:33])[CH:19]=[C:20]([NH:21][CH2:22][C:23]3[C:28]([CH3:29])=[CH:27][C:26]([F:30])=[CH:25][C:24]=3[CH2:31][CH3:32])[C:15]2=[N:14][C:13]=1[CH3:34])(OCC)=[O:8].O.[OH-].[Na+]>O1CCCC1>[CH3:34][C:13]1[N:14]=[C:15]2[C:20]([NH:21][CH2:22][C:23]3[C:28]([CH3:29])=[CH:27][C:26]([F:30])=[CH:25][C:24]=3[CH2:31][CH3:32])=[CH:19][C:18]([CH3:33])=[CH:17][N:16]2[C:12]=1[CH2:7][OH:8]
Reactant: CCOC(=O)c1c(C)nc2c(NCc3c(C)cc(F)cc3CC)cc(C)cn12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(F)cc(C)c1CNc1cc(C)cn2c(CO)c(C)nc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.8 %

Procedure:
To a mixture of LiAlH4 (0.08 g, 2.1 mmol) in tetrahydrofuran (15 ml) was added 3-carboethoxy-2,6-dimethyl-8-(2-ethyl-4-fluoro-6-methylbenzylamino)imidazo[1,2-a]pyridine (0.4g, 1.0) mmol in tetrahydrofuran (15 ml). After stirring the mixture at room temperature for 4 h., 0.1 ml of water was added dropwise, followed by 0.1 ml of 15% sodium hydroxide and then 0.3 ml of water. The solids were removed by filtration and washed thoroughly with tetrahydrofuran. The filtrate and washings were combined and dried and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride:methanol (9:1) as eluent. Crystallization from acetonitril gave 0.32 g (89%) of the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[CH3:25][O:26][CH:27]1[CH:31]([CH:32]=O)[CH2:30][CH:29]([O:34][CH3:35])[O:28]1>C(Cl)Cl.[Zn]>[Br:21][C:20]([Br:24])=[CH:32][CH:31]1[CH2:30][CH:29]([O:34][CH3:35])[O:28][CH:27]1[O:26][CH3:25]
Reactant: COC1CC(C=O)C(OC)O1
Reactant: BrC(Br)(Br)Br
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC1CC(C=C(Br)Br)C(OC)O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.2 %

Procedure:
A mixture of Zn powder (1.65 g, 25.0 mmol), triphenylphosphine (6.54 g, 25.0 mmol), and CBr4 (8.30 g, 25.0 mmol) in dry CH2Cl2 (40 mL) was stirred at ambient temperature. After 24 hours, 2,5-dimethoxy-tetrahydrofuran-3-carboxaldehyde (2.00 g, 12.5 mmol) was added and an exothermic reaction ensued. After 30 minutes, pet ether (100 mL) was added and the resultant upper layer separated. The lower layer was twice diluted with CH2Cl2 (50 mL) and pet ether (50 mL), and the upper layer reserved. The combined upper layers were combined, passed through a pad of SiO2, and concentrated under reduced pressure at 30° C. or below to give 2.18 g (55%) of 3-(2,2-dibromoethenyl)-2,5-dimethoxytetrahydrofuran as a volatile colorless oil, which was a mixture of diastreomers by 1H NMR and used immediately without further purification.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26]OC3C=CC=CC=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].[BrH:39].C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][Br:39])[CH:20]=2)[O:7][C@@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2]
Reactant: Br
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(COc3ccccc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(CBr)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(phenoxymethyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (10.00 g, 18.22 mmol) in acetic acid (31 mL) was added HBr in acetic acid (45.55 mL, 2.5 mL/mmol) and the reaction mixture was stirred at r.t. for 18 h. After the completion of reaction as confirmed by TLC, the reaction mixture was neutralized by the addition of saturated K2CO3 at 0° C. and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL) successively. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 3:7 Ethyl acetate:Pet. Ether) to afford the title compound (7.9 g, 81%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:21]([OH:30])(=[O:29])[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)[SH:24].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][S:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[C:21]([OH:30])=[O:29])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccccc1S
Reactant: CC(C)(C)c1csc(-c2cc3cc(CCl)ccc3o2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1csc(-c2cc3cc(CSc4ccccc4C(=O)O)ccc3o2)n1
Reaction time: 1 h
Yield: 52 %

Procedure:
To a solution of 4-tert-butyl-2-(5-chloromethylbenzofuran-2-yl)thiazole (0.68 g) and thiosalicylic acid (0.72 g) in N,N-dimethylformamide (5 ml), potassium carbonate (0.78 g) was added dropwise at 100° C. After being stirred for one hour, the reaction mixture was cooled, poured into a mixture of ice and diluted aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution to remove thiosalicylic acid, dried over magnesium sulfate and concentrated under reduced pressure. The residue was crystallized with ethyl acetate and filtered to give 4-tert-butyl-2-[5-(2-carboxyphenylthiomethyl)benzofuran-2-yl]thiazole (0.49 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:18](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH3:18])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc(NCC(C)C)c1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cc(Cl)cc(N(C)CC(C)C)c1C
Temperature: 80 °C

Procedure:
To a stirred solution of methyl 5-chloro-3-(isobutyl amino)-2-methylbenzoate (1.0 g, 3.9 mmol) in dry acetonitrile (10 mL), cesium carbonate (2.55 g, 7.8 mmol) and methyl iodide (5.55 g, 39 mmol) were added. The mixture was heated at 80° C. for 12 h. On completion, the mixture was cooled to room temperature and filtered. The residue was washed with ethyl acetate and the filtrate was concentrated to the title compound (1.0 g, 95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1)Br.[Cl:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=1)[O:24][CH2:25][C:26]([NH2:28])=[S:27]>C(#N)C.CO>[Cl:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=1)[O:24][CH2:25][C:26]1[S:27][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:28]=1
Reactant: CSc1ccc(C(Br)C(=O)c2ccccc2F)cc1
Reactant: NC(=S)COc1cccc(Cl)c1
Solvent: CC#N
Solvent: CO
Product: CSc1ccc(-c2sc(COc3cccc(Cl)c3)nc2-c2ccccc2F)cc1
Temperature: 0 °C
Yield: 32.5 %

Procedure:
A solution of 1-(2-fluorophenyl)-2-(4-methylthiophenyl)-2-bromo ethanone, (1.64 g, 4.8 mmol) (Example 34, Step 3) and 3-chlorophenoxy thioacetamide (0.98 g, 4.8 mmol) in 25 mL of acetonitrile was heated to reflux for 14 hours. The solution was diluted with methanol, cooled to 0° C. in an ice bath and a precipitate formed that was removed by filtration to provide pure 2-((3-chlorophenoxy)methyl)-4-(2-fluorophenyl)-5-(4-methylthiophenyl)thiazole (0.69 g; 32%). The filtrate was concentrated in vacuo, and the residue dissolved in ethyl acetate, washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to provide additional product that was crystallized from a mixture of dichloromethane and isooctane to provide 200 mg of additional material for a total yield of 890 mg (42%): mp 115°-118° C.: 1H NMR (CDCl3) 300 MHz 7.52-6.90 (m, 12H), 5.38 (s, 2H), 2.46 (s, 3H). 19F NMR (CDCl3) -113.61 (m). High resolution mass spectrum calc'd. for C23H17ClFNOS2 (M+): 441.0424. Found: 441.0467.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:18](=[CH:19][CH:20]=1)[C:13]1[N:14]=[C:15]([SH:17])[S:16][C:12]=1[CH2:11][CH2:10]2)C.[C:22]1([CH:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][CH2:30]I)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:29][CH2:30][S:17][C:15]2[S:16][C:12]3[CH2:11][CH2:10][C:9]4[C:18](=[CH:19][CH:20]=[C:7]([O:6][CH2:5][C:4]([OH:3])=[O:21])[CH:8]=4)[C:13]=3[N:14]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ICCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1ccc2c(c1)CCc1sc(S)nc1-2
Product: O=C(O)COc1ccc2c(c1)CCc1sc(SCCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 54 %

Procedure:
Using ethyl[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-7-yl)oxy]acetate and 3,3-diphenylpropyl iodide, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 54%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([C:31]4[C:36]([F:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=4[F:39])[NH:23][C:22]4[NH:40][N:41]=[C:42]([CH3:43])[C:21]3=4)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>ClCCl.[O-2].[Mn+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([C:31]4[C:36]([F:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=4[F:39])[N:23]=[C:22]4[NH:40][N:41]=[C:42]([CH3:43])[C:21]=34)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1=C(c2c(F)ccc(F)c2F)Nc2[nH]nc(C)c2C1c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2c(F)ccc(F)c2F)nc2[nH]nc(C)c2c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.2 %

Procedure:
To 2.2 g (3.68 mmol) of ethyl 4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)-3-methyl-6-(2,3,6-trifluorophenyl)-4,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylate in solution in 50 ml of dichloromethane are added 1.6 g (18.41 mmol) of manganese oxide. The reaction mixture is sonicated for 5 min then stirred at room temperature for 20 h. It is filtered on silica (cyclohexane/ethyl acetate eluent: 6:4) to yield 2 g (91%) of ethyl 4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)-3-methyl-6-(2,3,6-trifluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate in the form of a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][C:31]([F:32])([F:33])[F:34])=[CH:26][CH:25]=4)[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Product: Cc1nc(-c2ccn(Cc3ccc(OC(F)(F)F)cc3)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and bromomethyl-4-trifluoromethoxy-benzene as described in Example 49 and isolated as a yellow solid (0.078 g, 52% yield) 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.56 (d, J=4 Hz, 1H), 7.71 (d, J=8 Hz, 1H), 7.41 (d, J=2 Hz, 1H), 7.26-7:31 (m, 3H), 7.17-7.23 (m, 2H), 6.86 (d, J=2 Hz, 1H), 6.10-6.16 (m, 1H), 5.35 (s, 2H), 4.63 (d, J=8 Hz, 2H), 2.75 (s, 3H); MS (M+H)+=474.1; Rt=1.38 min; HRMS (M+H)+=474.12.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[C:3]=1[NH2:13].[N:14]#[C:15]Br>CO>[NH2:14][C:15]1[NH:13][C:3]2[C:4]([CH3:12])=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([CH3:8])=[CH:7][C:2]=2[N:1]=1
Reactant: Cc1cc(N)c(N)c(C)c1[N+](=O)[O-]
Reactant: N#CBr
Solvent: CO
Product: Cc1cc2nc(N)[nH]c2c(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1,2-diamino-3,5-dimethyl-4-nitrobenzene (0.87 g, 4.83 mmol) and cyanogen bromide (0.87 g, 7.73 mmol) in methanol (50 mL) is stirred at room temperature for 16 hours. The mixture is rotary evaporated to afford 2-amino-4,6-dimethyl-5-nitrobenzimidazole. The product is used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.B(Br)(Br)Br>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:12]1([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[OH:2])[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: c1cn[nH]c1
Reactant: COc1ccccc1B(O)O
Agent: [Cu+2]
Agent: BrB(Br)Br
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: Oc1ccccc1-n1cccn1

Procedure:
2-Methoxyphenylboronic acid (2 eq.) and pyrazole (1 eq.) are coupled with copper(II) acetate catalysis as described in Tetrahedron Lett. 39:2941-44, 1998 and the product is demethylated by treatment with boron tribromide in dichloromethane (see, for example, Synth. Commun. 27(20):3581-90, 1997) to yield 2-(pyrazol-1-yl)phenol. This phenolic product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to give the title epoxide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH3:10])[CH3:9])[CH:3]=1.[O:11]1[C:15]2([CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1>>[CH3:9][N:8]([CH3:10])[C:4]1[CH:3]=[C:2]([C:18]2([OH:21])[CH2:19][CH2:20][C:15]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:16][CH2:17]2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CN(C)c1cccc(Br)c1
Product: CN(C)c1cccc(C2(O)CCC3(CC2)OCCO3)c1

Procedure:
The title compound was prepared as a white solid from 1-bromo-3-dimethylamino-benzene (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[S:10][C:11]=2[C:12]([O:14][CH2:15]C)=[O:13])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1.C(Cl)Cl.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][N+:20]([O-:33])=[CH:19][CH:18]=3)[S:10][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-c2cc[n+]([O-])cc2)nc1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.7 %

Procedure:
To a solution of ethyl 4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboxylate (430 mg, 1.20 mmol) in DMF (6.0 mL) was added mCPBA (322 mg, 1.44 mmol) and the mixture was stirred at room temperature overnight. To the reaction was added DCM (30 mL) and saturated sodium bicarbonate (25 mL). The layers were separated and the aqueous layer extracted with DCM (20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/DCM=50/50→100/0) to give 449 mg of the title compound as a white solid (100% yield). LC/MS (FA) ES+ 375. 1H NMR (300 MHz, CDCl3) δ: 8.23-8.20 (m, 2H), 7.84-7.81 (m, 2H), 7.33-7.23 (m, 4H), 4.51 (s, 2H), 4.38 (q, 2H, J=7.2 Hz), 1.39 (t, 3H, J=7.2 Hz).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16]2)=[CH:11][C:10]=1[C:23](=O)[C:24]([N:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1)=[O:25])=O)(C)(C)C.[F-].[Cs+].C[Si]([N:42]=[C:43]=[N:44][Si](C)(C)C)(C)C.Cl>C(#N)C>[NH2:42][C:43]1[N:44]=[C:23]([C:24]([N:26]2[CH2:27][C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:34]2)=[O:25])[C:10]2[C:9](=[CH:14][CH:13]=[C:12]([C:15]3([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16]3)[CH:11]=2)[N:8]=1
Reactant: CCOC(=O)C1(c2ccc(NC(=O)OC(C)(C)C)c(C(=O)C(=O)N3Cc4ccccc4C3)c2)CC1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: CCOC(=O)C1(c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
670 mg of ethyl 1-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]cyclopropanecarboxylate are dissolved in 15 ml of acetonitrile under argon. 213 mg of caesium fluoride and 380 μl of bis(trimethylsilyl)carbodiimide are added to the solution. The mixture is stirred at room temperature for 15 min, and 2.7 ml of hydrochloric acid (1N) are then added, with the product precipitating as white solid. Yield: 510 mg (91%) of ethyl 1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]cyclopropanecarboxylate; LC-MS retention time: 1.65 min (“nonpolar” gradient);