Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:5]2=[O:17].C([O-])([O-])=O.[K+].[K+].Br.Br[CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>CC#N>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([O:1][CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[CH:10][CH:9]=2)[C:5](=[O:17])[N:6]1[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CN1C(=O)c2ccc(O)cc2C1=O
Reactant: BrCc1cccnc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CN1C(=O)c2ccc(OCc3cccnc3)cc2C1=O
Temperature: 80 °C
Yield: 55.4 %

Procedure:
To a solution of methyl 2-(5-hydroxy-1,3-dioxoisoindolin-2-yl)acetate (78 mg, 0.332 mmol) in CH3CN (20 mL), K2CO3 (115 mg, 0.829 mmol) and 3-(bromomethyl)-pyridine hydrobromide (126 mg, 0.497 mmol) were added at room temperature. The reaction was heated at 80° C. for 2 hours. The insoluble was filtered off and washed with DCM; the filtrated was evaporated under vacuum; and the crude was partitioned between a saturated solution of Na2CO3 and DCM. The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated to dryness. The crude was purified by filtration on silica gel cartridge (petroleum ether/EtOAc 1/1 to petroleum ether/EtOAc 2/8) to afford methyl 2-(1,3-dioxo-5-(pyridin-3-ylmethoxy)isoindolin-2-yl)acetate (60 mg, 0.184 mmol, 55.4% yield, MS/ESI+ 327.0 [MH]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[C:11]([CH3:24])=[CH:10][C:9]1([CH3:26])[CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Se](=O)=[O:28]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[C:11]([CH2:24][OH:28])=[CH:10][C:9]1([CH3:26])[CH3:25])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[Se]=O
Reactant: CC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(-c3ccccc3)cc21
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1c2ccc(-c3ccccc3)cc2C(CO)=CC1(C)C
Yield: 23.1 %

Procedure:
A solution of N-tert-butyloxycarbonyl-1,2-dihydro-2,2,4-trimethyl-6-phenyl quinoline (structure 10, where R1 =phenyl) (310 mg, 0.888 mmol) and selenium dioxide (345 mg, 3.11 mmol) in 17 mL of dioxane was heated to reflux for 3 h. The reaction mixture was quenched with 1:1 NaS2O3 (10%) /Na2HCO3 (10%), extracted with dichloromethane, dried (MgSO4), and the organic phase was concentrated in vacuo. Purification by flash chromatography (silica gel, hexane/ethyl acetate, 4:1) gave 212 mg of the intermediate aldehyde along with 75 mg of the desired alcohol of structure 11, where R1 =phenyl. The aldehyde was treated with sodium borohydride in 25 mL of methanol at 0° C. After 1 h at 0° C., the reaction mixture was quenched with water, extracted with ethyl acetate and concentrated in vacuo to give an oil that was purified by flash chromatography (silica gel, hexane/ethyl acetate, 4:1) providing structure 11, where R1 =phenyl (240 mg, 84%). 1H NMR (acetone d6) 7.68 (d, J =9, 2H), 7.61 (d, J=1.8, 1H), 7.47 (dd, J=6.2, 1.8, 1H), 7.41 (d, J=6.4, 2H), 7.29 (m,2H), 5.80 (s, 1H), 4.51 (d, J=6.8, 2H), 4.12 (t, J=6.8,1H), 1.52 (br s, 15H).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[C:24]1([CH2:30][CH:31]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=3)[CH2:33][CH2:32]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[C:24]1([CH2:30][CH:31]2[CH2:32][CH2:33][N:34]([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([NH:42]/[C:4](=[C:11]4\[C:12](=[O:23])[NH:13][C:14]5[C:19]\4=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=5)/[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=4)=[CH:43][CH:44]=3)[CH2:35][CH2:36]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: Nc1ccc(CN2CCC(Cc3ccccc3)CC2)cc1
Solvent: CN(C)C=O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(CN2CCC(Cc3ccccc3)CC2)cc1)c1ccccc1

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(4-phenylmethyl-piperidino)methyl-aniline in DMF.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:31])([F:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[NH:22][N:21]=[C:20]([C:23]([NH:25][CH2:26][C:27]([OH:29])=O)=[O:24])[CH:19]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[N:54]1([C:60]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=2[C:68]([F:71])([F:70])[F:69])=[O:61])[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1>CN(C=O)C.O>[O:29]=[C:27]([N:57]1[CH2:58][CH2:59][N:54]([C:60](=[O:61])[C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=2[C:68]([F:71])([F:69])[F:70])[CH2:55][CH2:56]1)[CH2:26][NH:25][C:23]([C:20]1[CH:19]=[C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([F:10])([F:31])[F:30])[NH:22][N:21]=1)=[O:24]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2C(F)(F)F)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cc(-c2ccccc2C(F)(F)F)[nH]n1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 69.3 %

Procedure:
DIPEA (137 mg, 0.18 mL, 1.06 mmol) was added to a stirred solution of {[5-(2-trifluoromethyl-phenyl)-1H-pyrazole-3-carbonyl]-amino}-acetic acid (95 mg, 0.30 mmol) in DMF (2 mL). HOBT (47 mg, 0.34 mmol) and EDCI (67 mg, 0.34 mmol) were then added at room temperature. After 2 minutes, piperazin-1-yl-(2-trifluoromethyl-phenyl)-methanone hydrochloride salt (90 mg, 0.30 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitated out to afford 115 mg (68.45% yield) of 5-(2-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 93.52%. 1H NMR (DMSO-d6): δ 13.6 (m, 1H), 8.2 (m, 1H), 7.7 (m, 4H), 7.6 (m, 3H), 7.5 (m, 1H), 6.7 (m, 1H), 4.2 (d, 2H), 3.7 (m, 1H), 3.5 (m, 3H), 3.4 (m, 2H), 3.0 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([O:13]CC)=[O:12])=[C:4]([O:16][CH3:17])[CH:3]=1.O[Li].O>C1COCC1.O>[Cl:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[C:4]([O:16][CH3:17])[CH:3]=1
Reactant: CCOC(=O)CNc1cc(I)c(Cl)cc1OC
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)c(I)cc1NCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.9 %

Procedure:
To a solution of ethyl 2-(4-chloro-5-iodo-2-methoxyphenylamino)acetate (8.6 g, 22.9 mmol) in THF (50 mL) and water (50 mL), LiOH.H2O (1.96 g, 45.9 mmol) was added and the resulting mixture was stirred at room temperature for 2 h. The mixture was washed with 20% ethyl acetate/petroleum ether. The aqueous layer was acidified with aqueous HCl (1 M) to adjust PH to 3-4 and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford the desired product (5 g, 64% yield).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:12]([C:9]2[CH:10]=[CH:11][C:5]3[S:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=3[CH:8]=2)=[O:14])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc3c(c2)NC(=O)CS3)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.7 %

Procedure:
3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (556 mg, 2.45 mmol, 1.0 eq) is added at room temperature to a stirred solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.45 mmol, 1.0 eq) in N,N-dimethylformamide (20 mL), followed by 1-hydroxybenzotriazole (421 mg, 2.69 mmol, 1.1 eq), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (550 mg, 2.81 mmol, 1.15 eq) and N,N-diisopropylethylamine (962 μL, 5.50 mmol, 2.25 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×30 mL) and water (30 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: cyclohexane:ethyl acetate:methanol, 1:3:0 to 0/9/1, v/v/v) to afford 4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow solid (621 mg, 62% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([C:29]3[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=3)[C:22]3[C:17](=[CH:18][C:19]([OH:43])=[C:20]([O:41][CH3:42])[CH:21]=3)[C:16]2=[O:44])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu](I)I>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([C:29]3[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=3)[C:22]3[C:17](=[CH:18][C:19]([O:43][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=4)=[C:20]([O:41][CH3:42])[CH:21]=3)[C:16]2=[O:44])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Brc1ccccn1
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(O)cc2c(=O)n1-c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(Oc3ccccn3)cc2c(=O)n1-c1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A suspension of the compound obtained in Example 5 (300 mg), 2-bromopyridine (57 μl), copper iodide (113 mg) and potassium carbonate (82 mg) in dimethylformamide (5 μl) is heated with stirring at 80° C. for five hours. After the reaction is complete, the reaction mixture is extracted with ethyl acetate. The extract is washed with aqueous ammonia, and further washed with water, dried, and concentrated under reduced pressure. The residue is purified by Chromatotron (solvent; hexane:ethyl acetate=1:1) to give 2-[4-(tert-butoxycarbonylamino)phenyl]-6-methoxy-3-methoxycarbonyl-7-(2-pyridyloxy)-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone (40 rag) as listed in Table 20.
Reaction SMILES: Cl.Cl.[CH:3]1([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:30]1[N:35]([CH3:36])[C:34](=[O:37])[CH:33]=[C:32]([C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)[N:31]=1>O1CCCC1>[CH:3]1([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:30]4[N:35]([CH3:36])[C:34](=[O:37])[CH:33]=[C:32]([C:38]5[CH:39]=[CH:40][N:41]=[CH:42][CH:43]=5)[N:31]=4)[CH2:17]3)=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: c1cc(C2CCCNC2)ccc1NC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCCC(c3ccc(NC4CCCCC4)cc3)C2)nc(-c2ccncc2)cc1=O
Reaction time: 12 h
Yield: 95.8 %

Procedure:
To a solution of 3-(4-cyclohexylaminophenyl)-piperidine dihydrochloride salt (1.0 g, 3.02 mmol) and triethylamine (1.5 g, 14.8 mmol) in tetrahydrofuran (20 mL) was added 2-chloro-3-methyl-6-(pyridin-4-yl)-3H-pyrimidin-4-one (0.64 g, 2.89 mmol) portionwise. After stirring for 12 h, the resulting suspension was partitioned between chloroform and 1N sodium hydroxide. The aqueous layer was extracted with chloroform. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to furnish 2-(3-(4-cyclohexylaminophenyl)-piperidin-1-yl)-3-methyl-6-(pyridin-4-yl)-3H-pyrimidin-4-one (1.23 g, 2.77 mmol, 96%) as white crystals.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.C(Cl)CCl.[C:28]([O:32][C:33]([N:35]1[CH2:41][CH2:40][C:39]2[C:42]([NH:47][CH2:48][C:49]3[CH:54]=[CH:53][C:52]([C:55](O)=[O:56])=[C:51]([F:58])[CH:50]=3)=[C:43]([Cl:46])[CH:44]=[CH:45][C:38]=2[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C1COCC1>[C:28]([O:32][C:33]([N:35]1[CH2:41][CH2:40][C:39]2[C:42]([NH:47][CH2:48][C:49]3[CH:54]=[CH:53][C:52]([C:55](=[O:56])[NH:4][CH:1]([CH3:3])[CH3:2])=[C:51]([F:58])[CH:50]=3)=[C:43]([Cl:46])[CH:44]=[CH:45][C:38]=2[CH2:37][CH2:36]1)=[O:34])([CH3:30])([CH3:31])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(NCc3ccc(C(=O)O)c(F)c3)c2CC1
Reactant: CC(C)N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
Add isopropylamine (0.15 mL, 1.8 mmol), HOBT (0.24 g, 1.8 mmol), diisopropylethylamine (0.63 mL, 3.6 mmol) and EDC (0.34 g, 1.8 mmol) to a mixture of 3-tert-butoxycarbonyl-6-(4-carboxy-3-fluoro-benzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.403 g, 0.9 mmol) in anhydrous THF (11.8 mL) at room temperature. Stir overnight at room temperature and partition the mixture between EtOAc (250 mL) and saturated aqueous NaHCO3 (100 mL). Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (40 g RediSep® column) eluting with hexane/EtOAc (19:1 to 1:1 gradient over 30 min; 50 mL/min) to afford 3-tert-butoxycarbonyl-7-chloro-6-(3-fluoro-4-isopropylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a thick colorless oil (0.439 g, 100%). MS (ES+) m/z: 490.2 (M+H)+.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[O:45][C:30]3=[CH:31][N:32]=[C:33]([C:35]4[CH:40]=[CH:39][C:38]([C:41]([NH2:43])=O)=[CH:37][C:36]=4[F:44])[CH:34]=[C:29]3[CH:28]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl>[C:14]([O:18][C:19]([N:21]1[CH2:22][CH2:23][CH:24]([C:27]2[O:45][C:30]3=[CH:31][N:32]=[C:33]([C:35]4[CH:40]=[CH:39][C:38]([C:41]#[N:43])=[CH:37][C:36]=4[F:44])[CH:34]=[C:29]3[CH:28]=2)[CH2:25][CH2:26]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(C(N)=O)cc4F)ncc3o2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(C#N)cc4F)ncc3o2)CC1
Reaction time: 0.5 h

Procedure:
Trifluoroacetic anhydride (26 μL) is added to a solution of 4-[5-(2-fluoro-4-aminocarbonyl-phenyl)-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (40 mg) and triethylamine (51 μL) in dichloromethane (3 mL) at room temperature. The solution is stirred at room temperature for 2 h before another portion of trifluoroacetic anhydride (26 μL) and triethylamine (51 μL) is added. The solution is stirred for 0.5 h and then aqueous NaHCO3 solution is added. The resulting mixture is extracted with dichloromethane and the combined extracts are washed with brine, dried (Na2SO4), and concentrated. The residue is triturated with ether and then with methanol to give the title compound. LC (method 3): tR=1.52 min; Mass spectrum (ESI+): m/z=422 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Br:11][C:12]1[CH:13]=[N:14][C:15](Cl)=[C:16]([CH:26]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]>C(O)CC(C)C.BrC1C=NC(Cl)=C(C=1)C(NC1C=CC=CC=1)=O>[Br:11][C:12]1[CH:13]=[N:14][C:15]([NH:10][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)=[C:16]([CH:26]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]
Reactant: O=C(Nc1ccccc1)c1cc(Br)cnc1Cl
Reactant: COc1ccc(N)cc1F
Solvent: CC(C)CCO
Product: COc1ccc(Nc2ncc(Br)cc2C(=O)Nc2ccccc2)cc1F
Temperature: 200 °C
Yield: 373.9 %

Procedure:
5-bromo-2-chloro-N-phenylnicotinamide (224 mg, 719 μmol) and 3-fluoro-4-methoxybenzenamine (316.7 mg, 2244 μmol) were suspended in isoamyl alcohol (1.5 ml) in a reaction microwave vessel which was sealed. This vessel was heated in the Biotage Initiator microwave at 200° C. for 20 minutes, with 45 seconds of stirring beforehand, and then cooled to room temperature. This process was repeated using 5-bromo-2-chloro-N-phenylnicotinamide (810 mg, 2.60 mmol) and 3-fluoro-4-methoxybenzenamine (1.092 g, 7.74 mmol), and isoamyl alcohol (7.5 ml), and then repeated a third time with 5-bromo-2-chloro-N-phenylnicotinamide (1.643 g, 5.28 mmol), 3-fluoro-4-methoxybenzenamine (2.285 g, 16 mmol), and isoamyl alcohol (10 ml). These three sets of reaction were combined, concentrated, treated with Et2O, and filtered. The solid was washed with Et2O, and the filtrate was concentrated and purified on a silica gel filter (˜3 inches, DCM) to afford the desired 5-bromo-2-(3-fluoro-4-methoxyphenylamino)-N-phenylnicotinamide (3.49 g, 8.39 mmol, 75% yield). MS (ESI pos. ion) m/z: 416 (MH+, 79Br), 418 (MH+, 81Br). Calc'd exact mass for C19H15BrFN3O2: 415 (79Br), 417 (81Br).
Reaction SMILES: [CH3:1][C@H:2]([C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH2:15])[C@H:3]([NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])[C:4]([OH:6])=[O:5].[CH3:22][Si](C=[N+]=[N-])(C)C>CO.C1(C)C=CC=CC=1>[CH3:1][C@H:2]([C:14]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH2:15])[C@H:3]([NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])[C:4]([O:6][CH3:22])=[O:5]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C=C(c1ccccc1)[C@@H](C)[C@H](NC(=O)C(F)(F)F)C(=O)O
Solvent: CO
Solvent: Cc1ccccc1
Product: C=C(c1ccccc1)[C@@H](C)[C@H](NC(=O)C(F)(F)F)C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.6 %

Procedure:
Carboxylic acid 14 (544.4 mg, 1.81 mmol) was placed in 1:1 CH3OH-toluene (6 mL) under N2, and trimethylsilyldiazomethane (2 M solution in hexane, 4.0 mL, 8.0 mmol) was added. The solution was stirred at ambient temperature for 16 h. The solvent was evaporated, and the residue was chromatographed (silica gel, 17 g; 9:1 hexane-EtOAc) to yield 0.46 g (81%) of 15 as a colorless oil: Rf0.54 (4:1 hexane-EtOAc); 1H NMR δ 7.33 (5H, m), 6.48 (1H, br d), 5.34 (1H, s), 5.11 (1H, d, J=0.8 Hz), 4.64 (1H, dd, J=8.7 and 4.0 Hz), 3.76 (3H, s), 3.48 (1H, m), 1.26 (3H, d, J=7.1 Hz).
Reaction SMILES: P(Br)(Br)Br.[CH3:5][O:6][C:7](=[O:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21](O)[CH3:22])[C:16]=1[CH3:24].O1CCCCC1[O:32][NH2:33]>N1C=CC=CC=1.CN(C)C=O>[CH3:5][O:6][C:7](=[O:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([NH:33][OH:32])[CH3:22])[C:16]=1[CH3:24]
Reactant: NOC1CCCCO1
Reactant: COC(=O)c1ccccc1Nc1cccc(C(C)O)c1C
Agent: BrP(Br)Br
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1Nc1cccc(C(C)NO)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosphorus tribromide (4.2 mL, 1 M solution in dichloromethane) is added dropwise to a solution of 2-[[3-(1-hydroxyethyl)-2-methylphenyl]amino]benzoic acid methyl ester (2.0 g, 7.0 mmol) and pyridine (2 drops) in dicholoromethane (50 mL) at 0° C. After the reaction mixture is stirred at room temperature for 1 hour, it is poured into a solution of O-tetrahydropyranylhydroxylamine (8.2 g, 70 mmol) in dimethylformamide (50 mL). The dichloromethane is evaporated under reduced pressure, and the reaction mixture is stirred overnight at room temperature. The reaction mixture is diluted with 200 mL water and extracted with 300 mL ether. The organic layer is washed with water and brine, and then evaporated to an oil. The crude intermediate THP-protected hydroxylamine is taken up in methanol and acidified with concentrated HCl to pH=1. The reaction mixture is heated at reflux for 30 minutes, cooled, and quenched by the careful addition of saturated aqueous sodium bicarbonate. The methanol is evaporated under reduced pressure and the product is extracted into ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate, and evaporated to give the crude hydroxylamine as an oil.
Reaction SMILES: [CH3:1][N:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[S:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[N:28]=[C:29]([NH2:32])[S:30][CH:31]=1>>[CH3:1][N:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[S:3]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:32][C:29]2[S:30][CH:31]=[C:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[N:28]=2)=[O:12])=[CH:13][CH:14]=1)(=[O:4])=[O:5]
Reactant: CN(c1ccccc1)S(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: Nc1nc(-c2ccccn2)cs1
Product: CN(c1ccccc1)S(=O)(=O)c1ccc(C(=O)Nc2nc(-c3ccccn3)cs2)cc1

Procedure:
4-(N-methyl-N-phenylsulfamoyl)benzoic acid (16) (100 mg, 0.31 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (50 mg, 0.28 mmol) using method C. The residue was purified using flash chromatography eluting with 50-100% EtOAc in hexanes. The resulting solid was triturated with diethyl ether to give 4-(N-methyl-N-phenylsulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as an orange solid. Yield: 31 mg (24%). 1H-NMR: 8.63-8.61 (m, 1H), 8.28 (d, J=8.5 Hz, 2H), 8.02 (d, J=8.0 Hz, 1H), 7.94-7.88 (m, 2H), 7.68 (d, J=8.5 Hz, 2H), 7.40-7.30 (m, 4H), 7.13 (d, J=7.0 Hz, 2H), 3.20 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[CH2:12]1COCC1.[N+](=C)=[N-]>C(OCC)C>[Cl:11][C:6]1[C:7]([CH2:8][C:9](=[O:10])[CH3:12])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: O=CCc1c(Cl)ncnc1Cl
Reactant: C1CCOC1
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: CC(=O)Cc1c(Cl)ncnc1Cl
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A 500 mL two necked round bottom flask was charged with 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde (1.2 g), dry diethyl ether (80 mL) and dry THF (80 mL). The reaction mixture was cooled to 0° C. and diazomethane solution in diethyl ether (30 mL) was slowly added under nitrogen atmosphere at 0° C. The reaction mixture was stirred at room temperature for 24 hours under nitrogen atmosphere before being quenched by acetic acid (20 mL), followed by water (100 mL). Aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic layer was washed with brine (50 mL) and dried over anhydrous Na2SO4. Evaporation of solvents under reduced pressure gave crude 1-(4,6-dichloropyrimidin-5-yl)propan-2-one (0.94 g) which was used as was. 1H NMR (DMSO-d6): δ 2.32 (s, 3H), 4.19 (s, 2H), 8.85 (s, 1H).