Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C@H:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([N:18]([CH3:25])[CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:17])[CH:14]=2)[CH2:9][CH2:8]1)=[O:5].Cl[C:31]1[S:35][N:34]=[C:33]([CH3:36])[N:32]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C@H:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([N:18]([CH3:25])[CH:19]3[CH2:20][CH2:21][N:22]([C:31]4[S:35][N:34]=[C:33]([CH3:36])[N:32]=4)[CH2:23][CH2:24]3)=[O:17])[CH:14]=2)[CH2:9][CH2:8]1)=[O:5]
Reactant: CN(C(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CC2)C1CCNCC1
Reactant: Cc1nsc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1nsc(N2CCC(N(C)C(=O)c3ccc4c(c3)[C@H](NC(=O)c3ccccc3Cl)CC4)CC2)n1
Temperature: 80 °C
Yield: 59 %

Procedure:
A mixture of (R)-3-(2-chlorobenzamido)-N-methyl-N-(piperidin-4-yl)-2,3-dihydro-1H-indene-5-carboxamide (see stage 2 illustrative compound H-214) (230 mg, 0.559 mmol, 1 eq), 5-chloro-3-methyl-1,2,4-thiadiazole (83 mg, 0.615 mmol, 1.1 eq) and Cs2CO3 (363 mg, 1.118 mmol, 2 eq) in dioxane (10 ml) was heated for 2 h at 80° C. When the reaction was complete according to TLC monitoring, the reaction mixture was concentrated under reduced pressure. The residue was taken up in dichloromethane (50 ml), washed with water (30 ml) and saturated sodium chloride solution (30 ml) and dried over sodium sulfate. The solvent was removed by distillation under reduced pressure and the crude product was purified by column chromatography (Alox, 0.5% methanol/dichloromethane). The desired product was in the form of a white solid. Yield: 59% (170 mg, 0.333 mmol)
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:6]=1[C:7](OC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.O>[C:1]([C:5]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:6]=1[CH2:7][OH:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(N)ccc1C(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(N)cc1CO
Yield: 19.4 %

Procedure:
To a solution of methyl 2-tert-butyl-5-aminobenzoate (159 mg, 0.72 mmol) in THF (5 mL) was added dropwise LiAlH4 (1.4 mL, 1M in THF, 1.4 mmol) at 0° C. The reaction mixture was refluxed for 2 h, diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. After filtration, the filtrate was concentrated to give (2-tert-butyl-5-aminophenyl)methanol (E-8) (25 mg, 20%), which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J=8.5 Hz, 1H), 6.87 (d, J=2.6 Hz, 1H), 6.56 (dd, J=8.4, 2.7 Hz, 1H), 4.83 (s, 2H), 1.36 (s, 9H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[NH:5][C:6]=1[CH3:7].C(N1C=CN=C1)([N:13]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1>[I:1][C:2]1[CH:3]=[C:4]([C:8]([NH2:13])=[O:10])[NH:5][C:6]=1[CH3:7]
Reactant: Cc1[nH]c(C(=O)O)cc1I
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1[nH]c(C(N)=O)cc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of EXAMPLE 23B (7.7 g) in tetrahydrofuran (20 mL) at 0° C. was added carbonyldiimidazole (14.9 g). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0° C. and ammonium hydroxide (3 mL) was added. The mixture was stirred at room temperature for 2 hours and concentrated. The residue was dissolved in ethyl acetate, washed with brine and concentrated to provide the title compound.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8](N)[CH:7]=1)(=[O:5])=[O:4].[OH-].[Na+].C(Cl)Cl.N([O-])=[O:19].[Na+]>O.C(Cl)Cl.O>[CH3:2][S:3]([C:6]1[CH:7]=[C:8]([OH:19])[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1cccc(O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
The title compound was prepared by a slightly modified literature procedure.*3-aminophenyl methyl sulfone hydrochloride (1.18 g, 5.70 mmol) was suspended in water/CH2Cl2. The mixture was neutralized with 25% aqueous NaOH. The CH2Cl2 layer was isolated and evaporated to dryness. Aqueous H2SO4 (60%; 10 mL) was added to the residue and the solution was cooled to 0° C. A solution of NaNO2 (0.345 g, 5.00 mmol) in water (5 mL) was added dropwise. The solution was stirred at 0° C. for 30 min. and at 90° C. for 30 min. The reaction mixture was allowed to come to room temperature. Extraction with CH2Cl2, drying (MgSO4), and concentration gave 0.39 g (40%) of the title compound as a solid. MS m/z 172 (M)+. HRMS m/z calcd for C7H8O3S (M)+172.0194, found 172.0198.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[NH2:19][C:20]1[CH:21]=[C:22]([C:26]#[CH:27])[CH:23]=[CH:24][CH:25]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOCC>[F:9][C:8]([F:11])([F:10])[C:4]1[CH:3]=[C:2]([C:27]#[C:26][C:22]2[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=2)[NH2:19])[CH:7]=[CH:6][CH:5]=1
Reactant: C#Cc1cccc(N)c1
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Nc1cccc(C#Cc2cccc(C(F)(F)F)c2)c1
Temperature: 65 °C
Yield: 70.5 %

Procedure:
A multinecked round bottom flask fitted with a mechanical stirrer, reflux condenser, and thermometer was flushed and maintained under positive pressure of nitrogen. The flask was charged with 100.0 g (0.44 mol) of 3-bromobenzotrifluoride, 300 ml of dried, degassed triethylamine, 51.5 g (0.44 mol) of 3-aminophenylacetylene, 0.35 g (0.499 mmol) of bis(triphenylphosphine) palladium II chloride, 1.6 g (6.09 mmol) of (triphenylphosphine), and 0.1 g (0.52 mmol) of cuprous iodide. The reaction mixture was heated at 65° C. for 20 hours at which point gas chromatography showed the reaction to be complete. The product mixture was cooled to room temperature followed by the addition of 200 ml of ether. Removal of the triethylamine hydrobromide salt by-product by suction filtration followed by concentration of the filtrate under reduced pressure gave the crude product as a light off-white solid. Short path distillation of the crude product under reduced pressure gave 81.0 g (0.31 mol, 71% yield) of the product as a colorless liquid which crystallized on standing.
Reaction SMILES: C([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[O:23]C2C=CC=C3C=2N(C(C2C=CC=CC=2)C2C=CC=CC=2)C(C)=C3)[CH:16]=[C:15]1[CH3:47])(C1C=CC=CC=1)C1C=CC=CC=1>CO.C1(C)C=CC=CC=1.[OH-].[Pd+2].[OH-]>[CH3:47][C:15]1[NH:14][C:22]2[C:17]([CH:16]=1)=[CH:18][CH:19]=[CH:20][C:21]=2[OH:23]
Reactant: Cc1cc2cccc(Oc3cccc4cc(C)n(C(c5ccccc5)c5ccccc5)c34)c2n1C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cc2cccc(O)c2[nH]1
Yield: 50.1 %

Procedure:
Benzhydryl-2-methyl-1H-indol-7-yl-ether (85 mg, 0.271 mmol) in methanol (MeOH) (3 mL) and toluene (3 mL) was hydrogenated in the presence of 20% palladium hydroxide (Pd(OH)2) (40 mg) at 40 p.s.i for 70 min at room temperature. The catalyst was filtered off, filtrate concentrated and the residue purified by silica gel flash chromatography to give subtitled compound (20 mg).
Reaction SMILES: [CH2:1]([N:3]([C@H:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([O:10]C(C)(C)C)=[O:9])[C:4](=[O:6])[CH3:5])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:3]([C@H:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([OH:10])=[O:9])[C:4](=[O:6])[CH3:5])[CH3:2]
Reactant: CCN(C(C)=O)[C@@H](C(=O)OC(C)(C)C)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(C(C)=O)[C@@H](C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a solution of product from example 122B (81 mg, 0.293 mmol) in CH2Cl2 (3 mL) was added 2,2,2-trifluoroacetic acid (1.5 mL, 0.293 mmol), and the resulting mixture was stirred at rt for 1 hr. The mixture was concentrated in vacuo to give the title compound (50 mg, 77%).
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[CH3:19][C:20]1([CH3:32])[C:24]([CH3:26])([CH3:25])[O:23][B:22]([C:27]2[CH:28]=[N:29][NH:30][CH:31]=2)[O:21]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:19][C:20]1([CH3:32])[C:24]([CH3:25])([CH3:26])[O:23][B:22]([C:27]2[CH:31]=[N:30][N:29]([CH:6]3[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]3)[CH:28]=2)[O:21]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 100 °C
Yield: 38.8 %

Procedure:
A mixture of tert-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (7.33 g, 26.2 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.09 g, 26.2 mmol), and Cs2CO3 (12.8 g, 39.3 mmol) in DMF (50 mL) was heated at 100° C. for 24 h. The mixture was cooled to RT and diluted with water (100 mL) and extracted with EtOAc (3×60 mL). The combined organic phases were washed with water (3×50 mL), brine (50 mL), and dried over anhydrous sodium sulfate. The residue was purified by flash chromatography (20 to 40% ethyl acetate:hexanes) to afford 3.84 g (39%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.81 (s, 1H), 7.74 (s, 1H), 4.17-4.35 (m, 3H), 2.89 (m, J=11.12 Hz, 2H), 2.14 (d, J=14.65 Hz, 2H), 1.90 (qd, J=12.25, 4.42 Hz, 3H), 1.48 (s, 9H), 1.33 (s, 12H); MS (ESI): 379.15 [M+H]+; HPLC tR=3.17 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH:15]([NH2:18])([CH3:17])[CH3:16]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:18][CH:15]([CH3:17])[CH3:16])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: CC(C)N
Solvent: ClCCl
Product: CC(C)NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
4-Chloro-3-nitrobenzenesulfonyl chloride (2 g) and isopropylamine (2.1 ml) in dichloromethane (30 ml) was stirred at room temperature for 2 h. The mixture was washed with water, 2M hydrochloric acid, water, dried and evaporated under reduced pressure. Yield 2.2 g.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].Cl[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[O:15][CH3:16]>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[O:15][CH3:16]
Reactant: COc1c(F)cccc1CCl
Reactant: OCCCCl
Product: COc1c(F)cccc1COCCCCl

Procedure:
In an analogous manner to that described in (δ) 1-chloromethyl-3-fluoro-2-methoxy-benzene was reacted with 1-chloro-3-propanol to yield 1-(3-chloro-propoxymethyl)-3-fluoro-2-methoxy-benzene as a colorless liquid; MS: 232 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24]OS(C)(=O)=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:30][CH2:31][CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1>>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][NH:30][CH2:31][CH2:32][C:33]2[N:37]=[CH:36][NH:35][CH:34]=2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][CH:12]([CH2:13]3)[CH2:17]1)[CH2:9]2)=[O:5]
Reactant: NCCc1c[nH]cn1
Reactant: CS(=O)(=O)OCCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCNCCc2c[nH]cn2)ccc1Cl

Procedure:
Synthesized from 2-chloro-5-[3-[(methylsulfonyl)oxy]propyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 6e, 1 mg) and histamine according to the procedure described in Example 6f to afford the title compound.
Reaction SMILES: [C:1]1([S:7]([NH:10][NH2:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12](=O)[C:13]1[O:17][CH:16]=[CH:15][CH:14]=1>CO>[O:17]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:12]=[N:11][NH:10][S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9]
Reactant: O=Cc1ccco1
Reactant: NNS(=O)(=O)c1ccccc1
Solvent: CO
Product: O=S(=O)(NN=Cc1ccco1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A four neck flask (1 liter) equipped with a thermometer, a reflux condenser and a stirrer was charged with 86 g (0.5 mol) of benzenesulfonohydrazide and 700 ml of methanol, and 57.6 g (0.6 mol) of furfural was dropwise added thereto in one hour while stirring at room temperature and heated under reflux for about 5 hours. The reaction liquid was cooled down to 20° C. or lower, and then crystal was filtered off and dried under reduced pressure, whereby white crystal was obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=O)[CH3:16])[C:10]=2[OH:18])=[CH:5][CH:4]=1)[CH3:2].[NH:19]([C:21]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)=[S:22])[NH2:20].CN(C)C=O>Cl.O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:20][NH:19][C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[S:22])[CH3:16])[C:10]=2[OH:18])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(-c2c(O)c(C(C)=O)nn2C)cc1
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(-c2c(O)c(C(C)=NNC(=S)Nc3ccc(C(=O)O)cc3)nn2C)cc1
Yield: 72.7 %

Procedure:
1-[5-(4-Ethylphenyl)-1-methyl-4-hydroxy-1H-pyrazol-3-yl]ethanone (0.159 mmol, 38.8 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.159 mmol, 33.6 mg) were stirred with dimethylformamide (2.3 mL) and three drops of concentrated hydrochloric acid at room temperature for 23.5 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (50.6 mg, yield 730).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:5]=[C:4]([OH:15])[CH:3]=1.[C:16]1([S:22]([CH2:24][CH2:25][CH2:26][CH2:27]Br)=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][C:7]([CH3:13])([CH3:14])[C:6]=2[CH:5]=[C:4]([O:15][CH2:27][CH2:26][CH2:25][CH2:24][S:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:23])[CH:3]=1
Reactant: O=S(CCCCBr)c1ccccc1
Reactant: CC1(C)OC(=O)Nc2c(Cl)cc(O)cc21
Product: CC1(C)OC(=O)Nc2c(Cl)cc(OCCCCS(=O)c3ccccc3)cc21

Procedure:
Prepared analogously to Example 4 from 8-chloro-6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-phenylsulfinyl-butylbromide.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([I:16])[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:19]1[CH2:29][CH2:28][CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C.O1CCOCC1>[CH2:26]([O:25][C:23]([CH:22]1[CH2:28][CH2:29][N:19]([C:2]2[CH:18]=[CH:17][C:5]([C:6](=[O:7])[NH:8][C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([I:16])[CH:10]=3)=[CH:4][N:3]=2)[CH2:20][CH2:21]1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1I
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(I)c3)cn2)CC1
Yield: 75.2 %

Procedure:
A solution of 6-chloro-N-(3-iodo-4-methyl-phenyl)-nicotinamide (360 mg, 0.97 mmol), ethyl isonipecotate (460 mg, 2.91 mmol), diisopropylethyl amine (0.51 mL, 2.91 mmol) and a catalytic amount of DMAP in dioxane (15 mL) was heated at 120° C. in a sealed tube until consumption of the limiting reagent, as judged by TLC. The reaction mixture was then cooled and partitioned between EtOAc and water. The organic layer was then dried over Na2SO4, filtered and concentrated. The residue was purified with a silica gel column and 0-50% EtOAc in hexanes gradient to afford the product (360 mg, Yield 75%). HRMS m/z calcd for C21H24N3O3I [M+H]+: 494.0935. Found: 494.0935.
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:21]3[O:20][C:19]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[N:18][C:17]=3[C:16]([O:28][CH:29]([F:31])[F:30])=[CH:15][CH:14]=2)=[O:12])=CC=1)([O-])=O.[NH2:32][C:33]1[N:37]([CH3:38])[N:36]=[CH:35][C:34]=1[C:39]#[N:40]>>[C:39]([C:34]1[CH:35]=[N:36][N:37]([CH3:38])[C:33]=1[NH:32][C:11]([C:13]1[C:21]2[O:20][C:19]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:18][C:17]=2[C:16]([O:28][CH:29]([F:30])[F:31])=[CH:15][CH:14]=1)=[O:12])#[N:40]
Reactant: Cn1ncc(C#N)c1N
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC(F)F)c2nc(N3CCCCC3)oc12
Product: Cn1ncc(C#N)c1NC(=O)c1ccc(OC(F)F)c2nc(N3CCCCC3)oc12
Yield: 14.9 %

Procedure:
Starting from 4-difluoromethoxy-2-(piperidin-1-yl)-benzooxazole-7-carboxylic acid 4-nitro-phenyl ester (0.35 g) and 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (0.197 g). Purification by column chromatography on silica eluting with 50% ethyl acetate in heptane afforded the title compound as a white solid (50 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:13]([O-])=O>[C].[Pd].CCO.O>[NH2:13][C:3]1[CH:4]=[C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: CC(C(=O)O)c1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CC(C(=O)O)c1ccc(N)c(N)c1
Reaction time: 5 h

Procedure:
To the flask was added EtOH/H2O (3.5:1, 45 mL) followed by 2-(4-Amino-3-nitro-phenyl)-propionic acid (5.73 g, 27.3 mmol) and 10% palladium carbon (117 mg) at room temperature. The reaction mixture was hydrogenated and stirred for 5 hrs at 64 psi then filtered through celite bed, and washed with EtOH. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using CH2Cl2:MeOH (10:1) as eluant.
Reaction SMILES: Cl.[I:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH:13]3[CH2:15][CH:10]2[CH2:11][NH:12]3)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24]>ClCCl>[C:23]([N:12]1[CH2:11][CH:10]2[CH2:15][CH:13]1[CH2:14][N:9]2[C:6]1[CH:5]=[CH:4][C:3]([I:2])=[CH:8][CH:7]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: Ic1ccc(N2CC3CC2CN3)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC2CC1CN2c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
5-(4-Iodophenyl)-2,5-diazabicyclo[2.2.1]heptane hydrochloride (269 mg, 0.80 mmol) was suspended in dichloromethane (0.3 ml), and triethylamine (0.2 ml) and acetic anhydride (0.09 ml, 0.96 mmol) were added. After stirring at room temperature for 1 hr, dichloromethane was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2-acetyl-5-(4-iodophenyl)-2,5-diazabicyclo[2.2.1]heptane (255 mg, yield 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:26])=[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:36]([CH3:38])[CH3:37].O>CN(C=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[S:16][C:13]=3[N:14]([CH:36]([CH3:38])[CH3:37])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)Br
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CN3CCOCC3)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)sc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 38 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)thieno[2,3-b]pyridine-5-carboxamide (418 mg) from Example No. 41 and potassium carbonate (152 mg) are suspended in DMF (10 mL) and to the mixture is added 2-bromopropane (103 μL). The reaction mixture is stirred at room temperature for 4 h. Additional 2-bromopropane (103 μL) is added and the mixture is heated to 60° C. for 20 h. The reaction mixture is allowed to cool to room temperature, is poured into water (25 mL), and then extracted with EtOAc (3×25 mL). The organic layer is dried (Na2SO4) and concentrated. The resulting crude solid is purified by recrystallization from ethanol to afford 173 mg (38%) of the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[NH2:3]/[C:4](/[C:11]([F:14])([F:13])[F:12])=[CH:5]\[C:6]([O:8]CC)=O.[CH3:15][O:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20]([C:24]2[C:28]3[CH:29]=[C:30]([N:33]=[C:34]=[O:35])[CH:31]=[CH:32][C:27]=3[S:26][N:25]=2)=[CH:19][CH:18]=1>CCOCC.CN(C)C=O>[CH3:15][O:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20]([C:24]2[C:28]3[CH:29]=[C:30]([N:33]4[C:6](=[O:8])[CH:5]=[C:4]([C:11]([F:12])([F:13])[F:14])[NH:3][C:34]4=[O:35])[CH:31]=[CH:32][C:27]=3[S:26][N:25]=2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: COc1ccc(-c2nsc3ccc(N=C=O)cc23)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(-c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)[nH]c4=O)cc23)cc1C
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 70.3 %

Procedure:
A mixture of 60% sodium hydride in mineral oil (15.9 g, 0.397 mol) and N,N-dimethylformamide is cooled to -10° C., treated over one hour with a solution of ethyl 3-amino-4,4,4-trifluorocrotonate (72.7 g, 0.397 mol) in ether, warmed to and stirred at room temperature for 90 minutes, cooled to -70° C., treated over 80 minutes with a solution of 3-(6-methoxy-m-tolyl)-1,2-benzisothiazol-5-yl isocyanate (107 g, 0.361 mol) in N,N-dimethylformamide while maintaining the temperature below about -65° C., slowly warmed to and stirred at room temperature overnight, and poured onto ice. The resultant aqueous mixture is washed with ethyl acetate, acidified to pH 2 with concentrated hydrochloric acid, and extracted with diethyl ether. The organic extract is dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as an orange oil (110 g, 70.5%) which is identified by NMR spectral analyses.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[NH:4][CH3:5].C(N(C(C)C)CC)(C)C.Cl[C:20]([O:22][CH3:23])=[O:21]>ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[N:4]([CH3:5])[C:20](=[O:21])[O:22][CH3:23]
Reactant: CNc1ccccc1Br
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N(C)c1ccccc1Br
Reaction time: 8 h

Procedure:
2-Bromo-N-methylaniline (1.00 g, 5.37 mmol) and diisopropylethylamine (2.0 ml, 11.50 mmol) were dissolved in dichloromethane (50 mL) and cooled in an ice bath. Methyl chloroformate (1.0 ml, 12.94 mmol) was added dropwise and the reaction stirred overnight. The reaction mixture was partitioned between water (200 mL) and ethyl acetate (200 mL). The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[F:9][C:10]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:11]=1[C:12]([NH:14][C:15]1[S:16][C:17]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[C:18](C2C=CC=CN=2)[N:19]=1)=[O:13]>>[F:40][C:36]1[CH:37]=[CH:38][CH:39]=[C:10]([F:9])[C:11]=1[C:12]([NH:14][C:15]1[S:16][C:17]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[C:18]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=2)[N:19]=1)=[O:13]
Reactant: O=C(Nc1nc(-c2ccccn2)c(-c2cccc(C(F)(F)F)c2)s1)c1c(F)cccc1F
Reactant: Cc1cccc(Br)n1
Product: Cc1cccc(-c2nc(NC(=O)c3c(F)cccc3F)sc2-c2cccc(C(F)(F)F)c2)n1

Procedure:
Compound 108 was prepared from 22a and 2-bromo-6-methylpyridine as described for the preparation of Compound 107.