Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(O)C.[S:22]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])(=[O:24])[NH2:23].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[S:4][C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:2]([C:29]3[CH:30]=[CH:31][C:26]([S:22](=[O:25])(=[O:24])[NH2:23])=[CH:27][CH:28]=3)[CH:6]=2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)cc2)cc1Br
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(Cl)cc2)cc1-c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Yield: 76.27 %

Procedure:
(compound 33a, 1.45 g, 4.19 mmol) in a mixture of toluene:ethanol (10:40 ml) was added (4-sulfamoylphenyl)boronic acid (0.84 g, 4.19 mmol) and potassium carbonate (1.16 g, 8.39 mmol) at 25° C. Nitrogen gas was bubbled through the reaction mixture for 15 minutes. To the reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.24 g, 0.20 mmol) under nitrogen atmosphere and the reaction mixture was heated at about 95 to about 100° C. for 16 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite, the celite cake was washed with Ethanol (2×25 ml). The filtrate so obtained was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 50% ethyl acetate in hexanes as an eluent to obtain the title compound (1.35 g, 76.27%).
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]([Cl:8])([Cl:7])[Cl:6])=[O:2].[I:10][C:11]1[CH:19]=[C:15]([C:16]([OH:18])=[O:17])[C:14]([NH2:20])=[CH:13][CH:12]=1.N1C=CC=CC=1>ClCCl>[I:10][C:11]1[CH:12]=[CH:13][C:14]([NH:20][C:1]([O:3][CH2:4][C:5]([Cl:8])([Cl:7])[Cl:6])=[O:2])=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(I)cc1C(=O)O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.4 %

Procedure:
A solution of Troc—Cl (2.88 mL, 20.9 mmol) in dry dichloromethane (20 mL) was added drop wise to a solution of 5-iodoanthranilic acid 131 (5 g, 19 mmol) and pyridine (3.1 mL, 38 mmol) in dry dichloromethane (30 mL) at 0° C. The solution was stirred for 5 hours at room temperature and then washed with 1N HCl (2×25 mL), water (1×25 mL) and brine (1×25 mL). The organic phase was dried over MgSO4 and evaporated, residue was recrystallized from ethyl acetate to afford the title compound as a yellow solid (6.2 g, 75%): m.p. 248 C (ethyl acetate). 1H NMR (CDCl3, DMSO-d6) δ 4.83 (s, 2H); 7.78-7.82 (dd, J=9.2, J=2.2 Hz, 1H); 8.18 (d, J=9 Hz, 1H); 8.38 (d, J=2.2 Hz, 1H); 9.0-10.5 (bs, 1H); 11.04 (s, 1H). 13C NMR (CDCl3, DMSO-d6) δ 74.4, 84.6, 95.2, 117.7, 120.7, 140, 140.8, 142.8, 151.5, 169. MS: m/e (relative intensity) 437 (M−1, 60), 289 (55), 272 (37), 245 (100), 218 (27). HRMS Calculated for C10H7Cl3INO4: 436.8485. Found: 436.8485.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[O:12][N:11]=[C:10]([C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=2[CH2:20][CH2:21][C:22](O)=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:34][C@H:35]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>O.CN(C=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([C:8]1([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[O:12][N:11]=[C:10]([C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=2[CH2:20][CH2:21][C:22]([NH:34][C@H:35]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:36][C:37]([O:39][C:40]([CH3:42])([CH3:43])[CH3:41])=[O:38])=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CC1(C(=O)OC(C)(C)C)CC(c2cc(O)ccc2CCC(=O)O)=NO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)CCc1ccc(O)cc1C1=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 47.8 %

Procedure:
A mixture of 3-(2-(5-(tert-butoxycarbonyl)-5-(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)-4-hydroxyphenyl)propanoic acid (214 mg), di-tert-butyl L-aspartate hydrochloride (161 mg), WSC (89 mg), HOBt (77 mg), triethylamine (0.080 mL), and DMF (2 mL) was stirred at room temperature for 3 days. To the reaction mixture, water was added, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (154 mg).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]=C=O)=[O:4].[NH2:10][C:11]1[NH:12][C:13]2[C:18]([C:19]=1[C:20]([NH2:22])=[O:21])=[CH:17][CH:16]=[C:15]([O:23][CH3:24])[CH:14]=2.N.CO>O1CCCC1>[NH2:5][C:3]([NH:10][C:11]1[NH:12][C:13]2[C:18]([C:19]=1[C:20]([NH2:22])=[O:21])=[CH:17][CH:16]=[C:15]([O:23][CH3:24])[CH:14]=2)=[O:4]
Reactant: COc1ccc2c(C(N)=O)c(N)[nH]c2c1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1
Reaction time: 2.5 h
Yield: 89.2 %

Procedure:
Trichloroacetyl isocyanate (1.7 mL, 14 mmol) was added dropwide to a solution of 2-amino-6-methoxyindole-3-carboxamide (Reference compound No.2-1, 2.9 g, 14 mmol) in anhydrous tetrahydrofuran (50 mL) at −40° C. over a period of 10 minutes and the mixture was stirred for 2.5 hours. Moreover, 2.0 M ammonia in methanol solution (40 mL, 80 mmol) was added thereto and the mixture was stirred overnight at room temperature. The reaction solution was concentrated in vacuo, and the obtained solid was filtered off and washed with a mixed solvent of chloroform-methanol (50 mL). The solid was dried at 40° C. under reduced pressure to give the title compound (3.1 g) as a gray solid (88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:18][CH3:19])[CH:13]2[CH2:16][N:15]([CH3:17])[CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Cl.[NH2:21][CH2:22][C:23]1[C:24](=[O:33])[NH:25][C:26]([CH3:32])=[CH:27][C:28]=1[CH:29]([CH3:31])[CH3:30]>>[CH:7]([OH:9])=[O:8].[Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:18][CH3:19])[CH:13]2[CH2:16][N:15]([CH3:17])[CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:21][CH2:22][C:23]1[C:24](=[O:33])[NH:25][C:26]([CH3:32])=[CH:27][C:28]=1[CH:29]([CH3:30])[CH3:31])=[O:9]
Reactant: CCN(c1cc(Cl)cc(C(=O)O)c1C)C1CN(C)C1
Reactant: Cc1cc(C(C)C)c(CN)c(=O)[nH]1
Agent: Cl
Product: CCN(c1cc(Cl)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CN(C)C1
Product: O=CO

Procedure:
The same way for the previous compound 5-chloro-3-(ethyl(1-methylazetidin-3-yl)amino)-2-methyl-N-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)benzamide formate prepared, the titled compound prepared using 5-chloro-3-(ethyl(1-methylazetidin-3-yl)amino)-2-methylbenzoic acid and 3-(Aminomethyl)-6-methyl-4-(propan-2-yl)-1,2-dihydropyridin-2-one HCl salt. After purification by reverse phase HPLC/MS (CAN-H2O containing 0.1% formic acid), the titled compound was obtained. 1H-NMR (500 MHz, CD3OD) δ ppm 8.43-8.25 (br, 1H), 7.15 (d, J=2.0 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 6.25 (s, 1H), 4.52 (s, 2H), 4.40-4.34 (m, 1H), 4.29-4.21 (br, 2H), 3.90-3.79 (br, 2H), 3.48-3.40 (m, 1H), 3.00 (q, J=7.0 Hz, 2H), 2.92 (s, 3H), 2.34 (s, 3H), 2.28 (s, 3H), 1.24 (d, J=7.0 Hz, 6H), 0.90 (t, J=7.0 Hz, 3H). MS (ES) (M+H) 445.47.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][CH:8]=[N+:9]([O-])[C:10]=2[CH:11]=1.[Cl-].C(=O)([O-])[O-:15].[K+].[K+]>C(Cl)(Cl)Cl.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[NH:9]2)=[N:4][CH:3]=1
Reactant: [O-][n+]1cccc2ncc(Br)cc21
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=c1ccc2ncc(Br)cc2[nH]1
Reaction time: 8 h
Yield: 41.1 %

Procedure:
To a mixture of 3-bromo-1,5-naphthyridine-5-oxide (C-3) (70.0 g, 311 mmol, 1.0 eq) and 4-toluolsulfonyl chloride (71.16 g, 373 mmol, 1.2 eq) in CHCl3 (1200 mL) was added a solution of potassium carbonate (146 g, 1056 mmol, 3.4 eq) in H2O (500 mL) at RT. The resulting mixture was stirred overnight and diluted with H2O (500 mL). The solid was collected by filtration, washed with water, dried in vacuo to afford the desired product 7-bromo-1,5-naphthyridin-2(1H)-one (C-4) (28.8 g, 41.2% yield). 1H NMR (300 MHz, DMSO-d6) δ: 11.90 (bs, 1H), 8.51 (s, 1H), 7.88 (d, J=9.6 Hz, 1H), 7.81 (s, 1H), 6.74 (d, J=9.6 Hz, 1H); ESI-MS m/z: 225.1 [M+H]+.
Reaction SMILES: C(OC(=O)[CH2:5][NH:6][S:7](C1C=CC(OCC#CC)=CC=1)(=[O:9])=[O:8])C.C(=O)([O-])[O-].[K+].[K+].Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](CCl)[CH:30]=1>CN(C=O)C.CCOCC.O>[N:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=1[CH2:5][NH:6][SH:7](=[O:9])=[O:8]
Reactant: ClCc1cccnc1
Reactant: CC#CCOc1ccc(S(=O)(=O)NCC(=O)OCC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: O=[SH](=O)NCc1ccccn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 201 %

Procedure:
To a solution of 0.300 g (0.965 mmol) of the product of Example 20 in 5.0 mL of DMF was added 0.419 g (3.038 mmol) of potassium carbonate followed by 0.166 g (1.013 mmol) of 3-picolyl chloride hydrochloride. The resulting mixture was stirred at room temperature for 15 h and then diluted with ether and water. The organics were washed with water, dried over Na2SO4, filtered and concentrated in vacuo to give a pale yellow solid. The solid was washed with ether/hexanes (1:1) and dried in vacuo to provide 0.334 g (86%) of the N-picolyl sulfonamide as a tan solid. Electrospray Mass Spec 402.9 (M+H)+
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18](B5OC(C)(C)C(C)(C)O5)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Br[C:33]1[CH:34]=[C:35]([C:39]2[NH:43][N:42]=[N:41][N:40]=2)[CH:36]=[CH:37][CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:37]5[CH:38]=[CH:33][CH:34]=[C:35]([C:39]6[N:40]=[N:41][NH:42][N:43]=6)[CH:36]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Brc1cccc(-c2nnn[nH]2)c1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1cccc(-c2nn[nH]n2)c1
Temperature: 110 °C

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide (42.1 mg, 0.100 mmol), 5-(3-bromophenyl)-tetrazole (22.5 mg, 0.100 mmol), a 1 M aqueous solution of potassium carbonate (0.50 mL), Pd-FibreCat 1007 (6 mg), and ethanol (0.50 mL) were combined. The mixture was heated at 110° C. for 5 min (5 min ramp time) in a microwave reactor. After cooling, the mixture was filtered and purified by prep-HPLC to provide 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-3′-(2H-tetrazol-5-yl)-biphenyl-3-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 439.2, found 440.2 (M+1)+; Retention time 2.59 minutes.
Reaction SMILES: [NH2:1][NH2:2].[NH2:3][C:4]1[C:5]2[C:30]([CH3:36])([C:31]([O:33]CC)=O)[C:29](=[O:37])[NH:28][C:6]=2[N:7]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][CH2:20][C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[N:11]=2)[N:9]=1>>[NH2:3][C:4]1[C:5]2[C:30]([CH3:36])([C:31]([NH:1][NH2:2])=[O:33])[C:29](=[O:37])[NH:28][C:6]=2[N:7]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][CH2:20][C:21]([F:27])([F:26])[C:22]([F:24])([F:23])[F:25])[N:11]=2)[N:9]=1
Reactant: CCOC(=O)C1(C)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Reactant: NN
Product: CC1(C(=O)NN)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Temperature: 80 °C

Procedure:
Hydrazine (2 mL, 63.7 mmol) was added to ethyl 4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylate, as prepared by the procedure described in Example 158, (400 mg, 0.761 mmol) and the reaction mixture was heated to 80° C. for 30 min. The reaction was then cooled to room temperature and concentrated in vacuo. Excess hydrazine was azeotropically removed by treatment with acetonitrile (3×4 mL). The product was lyophilized from water/acetonitrile overnight to give the title compound as a pale yellow solid which was used in the next step without further purification. m/z=486.01 (M+H).
Reaction SMILES: C([Si]([O:8][CH2:9][C@@H:10]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])[CH3:11])(C)C)(C)(C)C.C([Li])(CC)C.[B:26](OC(C)C)([O:31]C(C)C)[O:27]C(C)C>C1COCC1>[F:18][C:16]1[CH:17]=[C:12]([C@@H:10]([CH3:11])[CH2:9][OH:8])[C:13]([O:19][CH3:20])=[CH:14][C:15]=1[B:26]([OH:31])[OH:27]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(F)cc1[C@@H](C)CO[Si](C)(C)C(C)(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1cc(B(O)O)c(F)cc1[C@@H](C)CO
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 81.9 %

Procedure:
To a solution of 25B (1.12 g, 3.75 mmol) in THF (20 mL) was dropwise added sec-butyllithium (3.22 mL, 4.50 mmol) at −78° C. and stirred at −78° C. for 10 min. Triisopropyl borate (1.743 mL, 7.50 mmol) was added and the mixture was slowly warmed up to r.t. overnight. The reaction was quenched by 6.0 ml of 1N HCl and the mixture was stirred at r.t. for 4 h. TBS is ˜60% removed. Addition 4 ml of 1 N HCl was gassed and the mixture was heated at 50° C. for 1 h. The mixture was concentrated and purified by prep HPLC to yield 25C (700 mg, 3.07 mmol, 82% yield) as a white solid. MS (ESI) m/z: 227.5 (M−H)+. 1H NMR (400 MHz, methanol-d3) δ ppm 6.87-6.94 (2H, m), 3.81 (3H, s), 3.70 (1H, dd, J=10.77, 5.93 Hz), 3.51 (1H, dd, J=10.55, 7.47 Hz), 3.32-3.37 (1H, m), 1.22 (3H, d, J=7.03 Hz).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]([F:25])([F:24])[F:13]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2C(F)(F)F)c(C)c1
Yield: 96 %

Procedure:
A suspension of methyl 4-bromo-3-methylbenzoate (ABCR AV19078; 3 g; 13.10 mmol; 1 eq.), 2-(trifluoromethyl)phenylboronic acid (Aldrich 393606; 2.74 g; 14.41 mmol; 1.10 eq.), potassium carbonate (9.05 g; 65.48 mmol; 5 eq.) and tetrakis(triphenylphosphine)palladium(0) (1.51 g; 1.31 mmol; 0.10 eq.) in toluene (15 mL) and water (15 mL) was refluxed for 3 hours. The resulting mixture was filtered through a short pad of Celite, which was further washed with toluene. After evaporation of the solvent, the residue was taken up in ethyl acetate and washed successively with sat. aq. NaHCO3, water and brine, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (3.7 g, 96%) as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-:10])=[O:9].[CH3:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-:10])=[O:9].[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]=[N:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CNc1ccccc1
Solvent: Nc1ccccc1
Solvent: O=[N+]([O-])c1ccccc1
Product: C=Nc1ccccc1
Temperature: 160 °C

Procedure:
The procedure was the same as for Example 1 with the exception that aniline was omitted from the initial reaction solution. As the reactor contents heated to 160° C., approximately 30% of the nitrobenzene was converted. Complete nitrobenzene conversion required 5.5 hours at 160° C. and yielded 0.068 mole methyl N-phenyl carbamate (68% selectivity), 0.022 mole aniline, 0.007 mole N-methylene aniline, and 0.001 mole (N-methylaniline (summed to 30% selectivity to aniline).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([Br:9])[CH:5]=[CH:4][C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19](Br)=[O:20].O>CN(C)C=O.C(OCC)(=O)C>[Br:9][C:6]1[CH:5]=[CH:4][C:3]2[O:10][CH2:18][C:19](=[O:20])[NH:1][C:2]=2[C:7]=1[CH3:8]
Reactant: Cc1c(Br)ccc(O)c1N
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Br)ccc2c1NC(=O)CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.3 %

Procedure:
An ice cold suspension of 2-amino-4-bromo-3-methylphenol (3.81 g, 18.86 mmol) and potassium carbonate (10.42 g, 75 mmol) in N,N-Dimethylformamide (DMF) (25 mL) was treated by dropwise addition of bromoacetyl bromide (1.971 mL, 22.63 mmol). The mixture was warmed to ambient temperature and stirred for one hour. Water was added and the mixture was diluted with ethyl acetate. There were insoluble solids, so the entire mixture was passed through a fine glass frit to afford 6-bromo-5-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one as an off-white solid (1.20 g, 26%). The filtrate was extracted with ethyl acetate. The extracts were washed with water, then brine, dried over sodium sulfate, filtered and concentrated to give slightly impure 6-bromo-5-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one as a reddish-brown solid (3.05 g, 67%): 1H NMR (400 MHz, DMSO-d6) δ ppm 10.40 (br. s., 1 H), 7.15 (d, J=8.6 Hz, 1 H), 6.79 (d, J=8.6 Hz, 1 H), 4.50 (s, 2 H), 2.30 (s, 3 H); LC/MS (m/z) ES+=242 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:22]=[CH:21][C:12]([CH2:13][NH:14][C:15]([CH:17]2[CH2:20][NH:19][CH2:18]2)=[O:16])=[CH:11][C:10]=1[O:23][CH3:24])C1C=CC=CC=1>C(O)C.C(O)(=O)C.CO.[Pd]>[OH:8][C:9]1[CH:22]=[CH:21][C:12]([CH2:13][NH:14][C:15]([CH:17]2[CH2:18][NH:19][CH2:20]2)=[O:16])=[CH:11][C:10]=1[O:23][CH3:24]
Reactant: COc1cc(CNC(=O)C2CNC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CO
Product: COc1cc(CNC(=O)C2CNC2)ccc1O
Reaction time: 1 h
Yield: 96.6 %

Procedure:
The N-(4-benzyloxy-3-methoxybenzyl)-3-azetidinecarboxamide (386 mg) of Example 14 (3) was dissolved in a mixture of ethanol (10 ml), acetic acid (0.5 ml) and methanol (5 ml), and 10% palladium on carbon (30 mg) was added thereto to carry out catalytic hydrogenation at room temperature. After 1 hour, the catalyst was filtered and the solvent was evaporated to obtain 270 mg of N-(4-hydroxy-3-methoxybenzyl)-3-azetidinecarboxamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=1.ClC(Cl)(Cl)C(=N)O[C:15]([CH3:18])([CH3:17])[CH3:16].[Na+].[Cl-].CCOC(C)=O>C1COCC1>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:9])=[N:6][CH:7]=1
Reactant: Cc1cnc(C(=O)O)cn1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cnc(C(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A boron trifluoride-diethyl ether complex (91.7 μL) was added dropwise to a suspension of 2-methylpyrazine-5-carboxylic acid (1 g) and tert-butyl 2,2,2-trichloroacetimidate (4.75 g) in THF (20 mL) under ice-cooling. The reaction solution was warmed to RT, followed by stirring for 2 h. A saturated NaCl solution and EtOAc were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous MgSO4, and the insoluble matter was separated by filtration. The filtrate was concentrated and purified by silica gel column chromatography to obtain the title compound (1.4 g). 1H-NMR (CDCl3) δ (ppm): 1.65 (s, 9H), 2.65 (s, 3H), 8.57 (d, J=1.2 Hz, 1H), 9.10 (d, J=1.6 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:21][C@@H:22]2[CH2:26][CH2:25][CH2:24][O:23]2)[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][C:17]([F:20])([F:19])[F:18])=[CH:5][C:6]=1[C:7](O)=[O:8].CN(C(O[N:35]1N=N[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.C1(N)CCCCC1>CN(C)C=O>[CH:36]1([NH:35][C:7]([C:6]2[CH:5]=[C:4]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][C:17]([F:18])([F:19])[F:20])[N:3]([CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][O:23]3)[C:2]=2[CH3:1])=[O:8])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1c(C(=O)O)cc(-c2ccccc2OC(F)(F)F)n1C[C@@H]1CCCO1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: NC1CCCCC1
Product: Cc1c(C(=O)NC2CCCCC2)cc(-c2ccccc2OC(F)(F)F)n1C[C@@H]1CCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.5 %

Procedure:
To a solution of 77 mg of 2-methyl-1-[(S)-1-(tetrahydro-furan-2-yl)methyl]-5-(2-trifluoromethoxy-phenyl)-1H-pyrrole-3-carboxylic acid in 3 ml of dimethylformamide were added 74 mg of TBTU, 179 μl of N,N-diisopropylethylamine and 26 μl of cyclohexylamine and the reaction mixture was stirred at ambient temperature for 18 hours. After such time the reaction mixture was then concentrated in vacuo and purified by column chromatography (SiO2, heptane/ethyl acetate) to give 70 mg of the title compound as a colorless solid, MS (ISP) 451.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][CH2:11][CH2:12][C:13]#[N:14])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.Cl.[NH2:18][O:19][CH2:20][CH2:21][NH2:22].N1C=CC=CC=1>C(O)C>[ClH:1].[NH2:22][CH2:21][CH2:20][O:19][N:18]=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:10][CH2:11][CH2:12][C:13]#[N:14]
Reactant: N#CCCCC(=O)c1ccc(Cl)c(Cl)c1
Reactant: NCCON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: N#CCCCC(=NOCCN)c1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 6.9 mmol (1.67 g) of 3', 4'-dichloro-4-cyanobutyrophenone (melting point 53°-54° C), 6.9 mmol (1.03 g) of 2-aminooxyethylamine dihydrochloride, 6.9 mmol (0.56ml) of pyridine and 5 ml of absolute ethanol was refluxed for 3.5 hours.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:14]([S:15][CH3:16])=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8].O.Cl>CO>[CH3:3][O:4][C:5]1[C:14]([S:15][CH3:16])=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=[CH:11][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1ccc(C(F)(F)F)c(SC)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1c(C(=O)O)ccc(C(F)(F)F)c1SC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
16 ml of 20% strength aqueous sodium hydroxide solution were added to 16.0 g (57.1 mmol) of methyl 2-methoxy-3-methylthio-4-(trifluoromethyl)benzoate in 160 ml of methanol, and the mixture was stirred at RT for 4 h. For work-up, the mixture was freed from the solvent and the residue was taken up in a little water. The mixture was cooled in an ice bath and then acidified with dilute HCl. The mixture was stirred at RT for 5 min, and the contents were then filtered. This gave 15.3 g of 2-methoxy-3-methylthio-4-(trifluoromethyl)benzoic acid as residue.