Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[CH:12][C:11]3=[O:26])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[CH2:28][CH2:29][CH2:30][Cl:31].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[Cl:31][CH2:30][CH2:29][CH2:28][N:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=4)=[CH:12][C:11]3=[O:26])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2[nH]ncc2c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2CCCCl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (278 mg, 0.783 mmol) in DMSO (4.0 mL) was added 3-bromo-1-chloropropane (1.23 g, 7.83 mmol) and Cs2CO3 (765 mg, 2.35 mmol), and the reaction was stirred at ambient temperature for 18 h. The reaction was diluted with H2O (25 mL) and extracted with EtOAc (3×25 mL). The extracts were washed with brine (25 mL), dried over Na2SO4, and concentrated. Flash chromatography (silica gel, CH2Cl2/MeOH, 100:1) yielded 1-(1-(3-chloropropyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one. To a solution of 1-(1-(3-chloropropyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (84 mg, 0.19 mmol) in DMF (1.0 mL) was added K2CO3 (0.13 g, 0.97 mmol), dimethylamine (1.94 mL, 3.88 mmol, 2.0 M in THF) and KI (32 mg, 0.19 mmol), and the reaction was heated to 45° C. for 18 h. The reaction mixture was cooled, diluted with H2O (25 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (25 mL), dried over Na2SO4, filtered and concentrated. Flash chromatography (Biotage 25+M column, CH2Cl2/MeOH/NH4OH, 50:1:0 to 20:1:0.1) provided the title compound (54 mg, 63%): 1H NMR (500 MHz, CDCl3) δ 8.06 (s, 1H), 7.75-7.70 (m, 5H), 7.60-7.43 (m, 3H), 6.92-6.91 (m, 1H), 6.53-6.51 (m, 1H), 4.49 (t, J=6.8 Hz, 2H), 2.29 (t, J=6.8 Hz, 2H), 2.23 (s, 6H), 2.13-2.08 (m, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]([OH:12])=[O:11])[N:9]=1)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH:34][C:35]([NH:37][NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:36])=[CH:28][CH:27]=1.O>C(OCC)(=O)C>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]([O:12][C:26]2[CH:27]=[CH:28][C:29]([CH2:32][CH2:33][NH:34][C:35]([NH:37][NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:36])=[CH:30][CH:31]=2)=[O:11])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NNC(=O)NCCc1ccc(O)cc1
Reactant: CC(=O)Nc1nc(C(=O)O)cs1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)Nc1nc(C(=O)Oc2ccc(CCNC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Temperature: 50 °C
Reaction time: 2 h
Yield: 44.4 %

Procedure:
To a suspension of 2-(acetylamino)-1,3-thiazole-4-carboxylic acid (559.5 mg, 3.005 mmol) in anhydrous N,N-5 dimethylformamide (10 ml) was added 1,1′-carbonyldiimidazole (534.2 mg, 3.294 mmol), and the mixture was stirred at 50° C. for 2 hr. tert-Butyl 2-{[2-(4-hydroxyphenyl)ethyl]carbamoyl}hydrazinecarboxylate (591.6 mg, 2.003 mmol) was added, and the mixture was stirred at 50° C. for 24 hr and at room temperature for 17 hr. Water (50 ml) and ethyl acetate (50 ml) were added to the reaction mixture and the mixture was stirred, stood still and then partitioned. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with 0.5M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Methanol (20 ml) and tert-butyl methyl ether (40 ml) were added to the residue and the precipitated solid was collected by filtration and dried under reduced pressure to give 4-[2-({[2-(tert-butoxycarbonyl)hydrazino]carbonyl}amino)ethyl]phenyl 2-(acetylamino)-1,3-thiazole-4-carboxylate (417.7 mg, 0.890 mmol, yield 44.5%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[C:20]([OH:24])(=[O:23])[CH:21]=O>O1CCOCC1>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=[CH:21][C:20]([OH:24])=[O:23])[C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=CC(=O)O
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: O=C(O)C=C1CCc2ccc([N+](=O)[O-])cc2C1=O
Temperature: 90 °C

Procedure:
A mixture of 7-nitro-l-tetralone (30 g) (manufactured by Lancaster Co.), 80% sulfuric acid (10 ml) and dioxane (60 ml) was heated to 90° C. and a 40% glyoxylic acid aqueous solution (30 ml) was added by three portions of 10 ml each at an interval of 1 hour and heated and refluxed for 3 hours. After allowing to cool the reaction mixture, the precipitated solid was filtered, washed with cold water and dried under reduced pressure to obtain 7-nitro-1-oxo-1,2,3,4-tetrahydro-2-naphthylideneacetic acid (33.3 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:3]=1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1)([O-:20])=[O:19].N1C=CC=CC=1>O>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:2]3[CH:7]=[C:6]([N:8]4[CH2:12][CH2:11][CH2:10][CH2:9]4)[N:5]=[C:4]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)[N:3]=3)[CH2:29][CH2:28]2)=[CH:25][CH:26]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: Clc1cc(N2CCCC2)nc(N2CCCC2)n1
Solvent: O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(N2CCN(c3cc(N4CCCC4)nc(N4CCCC4)n3)CC2)cc1
Temperature: 100 °C
Yield: 49 %

Procedure:
2.52 g (10 mmole) of 4-chloro-2,6-di-pyrrolidin-1-yl-pyrimidine (J. Med. Chem. (1990) 33 (4), 1145-1151) and 2.07 g (10 mmole) of 4-nitrophenylpiperazine are dissolved in a 250 ml flask containing 20 ml of anhydrous pyridine, under an argon atmosphere. The reaction mixture is heated at 100° C. for 48 hours. After cooling down, the contents of the flask are poured into 250 ml of water and the product is extracted using twice 50 ml of CH2Cl2. The organic phase is then washed with 50 ml of brine, dried over magnesium sulphate, filtered and concentrated under vacuum. The residue is purified on a silica column (eluent: Heptane/AcOEt: 2/1). An orange solid is obtained with a yield of 49%. Melting point: 200-201° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH2:17][CH2:18][CH3:19])=[CH:13][CH:12]=[CH:11][C:10]=2[O:20][CH3:21])=[O:5])[CH3:2].C([NH-])C.Cl[C:26](OC)=[O:27]>>[CH2:1]([N:3]1[C:4](=[O:5])[C:6]2[CH:7]=[N:8][C:9]3[C:10]([O:20][CH3:21])=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]=2[N:16]([CH2:17][CH2:18][CH3:19])[C:26]1=[O:27])[CH3:2]
Reactant: CCCNc1c(C(=O)NCC)cnc2c(OC)cccc12
Reactant: COC(=O)Cl
Agent: CC[NH-]
Product: CCCn1c(=O)n(CC)c(=O)c2cnc3c(OC)cccc3c21

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.94 mmol) was treated with 1-aminopropane following general procedure B to afford 8-methoxy-4-propylamino-quinoline-3-carboxylic acid ethyl ester (260 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into 8-methoxy-4-propylamino-quinoline-3-carboxylic acid ethylamide (200 mg) following general procedure E. The above ethylamide (0.70 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 3-ethyl-7-methoxy-1-propyl-1H-pyrimido[5,4-c]quinoline-2,4-dione (26 mg). LCMS: m/z 314 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[C:4]([Cl:12])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:19]1[CH:23]=[CH:22][CH:21]=[N:20]1>CN(C=O)C>[Cl:12][C:4]1[CH:3]=[C:2]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=1
Reactant: c1cn[nH]c1
Reactant: Nc1nc2cc(Cl)cc(Cl)n2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1nc2cc(Cl)cc(-n3cccn3)n2n1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
5,7-Dichloro[1,2,4]triazolo[1,5-a]pyridin-2-amine (Intermediate 15) (0.5 g, 2.46 mmol), cesium carbonate (1.6 g, 4.93 mmol) and pyrazole (0.5 g, 7.39 mmol) was suspended in DMF (10 mL) and stirred at 70° C. for 2 h after which time LCMS showed desired product formation. The reaction mixture was filtered through celite, which was washed with further DMF and the resultant green/brown solution was concentrated in vacuo to give a brown residue, which was partitioned between 10% IPA/DCM (20 mL) and water (10 mL), the organic layer was separated and the aqueous extracted with further 10% IPA/DCM (2×10 mL). The organic layers were combined and dried (MgSO4), filtered and concentrated in vacuo to give the desired product as a brown solid (0.4 g, 69%). 1H NMR (DMSO) δ 9.16 (d, J=2.6 Hz, 1H), 7.99 (d, J=1.4 Hz, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.36 (d, J=2.1 Hz, 1H), 6.72 (dd, J=2.4, 1.9 Hz, 1H), 6.46 (s, 2H). MS: 235.12 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:15]=3)[C:10]([S:25][CH3:26])=[CH:9]2)=[N:6][CH:7]=1.[OH:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[OH:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:3]=[N:4][C:5]([N:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]5[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)=[O:18])[CH:15]=4)[C:10]([S:25][CH3:26])=[CH:9]3)=[N:6][CH:7]=2)=[CH:30][CH:29]=1
Reactant: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Reactant: OB(O)c1ccc(O)cc1
Product: CSc1cn(-c2ncc(-c3ccc(O)cc3)cn2)c2cc(C(=O)N3CCOCC3)ccc12

Procedure:
Synthesized from (1-(5-bromopyrimidin-2-yl)-3-(methylthio)-1H-indol-6-yl)(morpholino)methanone (400 mg, 0.923 mmol) and 4-hydroxyphenyl boronic acid (153 mg, 1.108 mmol) in analogy to procedure 1d). Pale brown solid. Yield: 280 mg (68% of theory)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([NH:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[N:3]=1.[NH2:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].C(N(CC)CC)C>CC(N(C)C)=O.CCOC(C)=O>[C:31]([O:30][C:29]([NH:28][C@H:23]1[CH2:24][CH2:25][CH2:26][CH2:27][C@H:22]1[NH:21][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([NH:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[N:3]=1)=[O:35])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: COC(=O)c1c(C)nc(Cl)nc1Nc1cccc(C)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COC(=O)c1c(C)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Yield: 62.2 %

Procedure:
A solution of methyl 2-chloro-4-methyl-6-(m-tolylamino)pyrimidine-5-carboxylate (1.2 g, 4.11 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (0.882 g, 4.11 mmol) and triethylamine (1.720 mL, 12.34 mmol) in DMA (10 mL) was heated at 90° C. for 4 h. The solution was then diluted with EtOAc, washed with brine and water. The organic extract was dried and concentrated under reduced pressure to give a light yellow residue; white crystals were formed upon triturating with ACN (5 mL). The resultant solid was filtered, washed with ACN, and dried to give the title compound as white solid (1.2 g, 62%). [M+H] calc'd for C25H35N5O4, 470; found, 470.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[C:4]([CH3:10])[CH:3]=1.S(Cl)([Cl:13])=O>ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Cl:13])=[C:4]([CH3:10])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(Br)ccc1CO
Solvent: ClCCl
Product: Cc1cc(Br)ccc1CCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-2-methylbenzyl alcohol (9.0 g) in dichloromethane (50 mL) was added thionyl chloride (3.8 mL) under ice-cooling, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give 4-bromo-2-methylbenzyl chloride (9.8 g). To a suspension of sodium hydride (60%, 2.1 g) in tetrahydrofuran (90 mL) was added ethyl 4-methyl-3-oxo-pentanoate (7.5 g) under ice-cooling, and the reaction mixture was stirred at room temperature for 1 hour. 4-Bromo-2-methyl-benzyl chloride (9.8 g) was added to the reaction mixture, and the resulting mixture was stirred at 70° C. for 3 days. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the mixture was extracted with diethyl ether. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. To a solution of the residue in toluene (20 mL) was added hydrazine monohydrate (5.4 mL), and the mixture was stirred at 90° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was treated with n-hexane-diethyl ether (10/1) to crystallize. The crystals were collected by filtration and washed with n-hexane, water and n-hexane successively, and dried under reduced pressure to give the title compound (12.4 g).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[CH2:22]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)[CH2:23][CH2:24][CH3:25].[OH-].[Na+]>C(Cl)Cl>[CH3:25][CH2:24][CH2:23][CH2:22][O:26][C:27]1[CH:28]=[CH:29][C:30]([C:31]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:32])=[CH:34][CH:35]=1
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.9 %

Procedure:
To a solution of 92 mg of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 2 ml of methylene chloride is added 100 mg of triethylamine followed by 130 mg of 4-(n-butyloxy)benzoyl chloride. The reaction mixture is stirred at room temperature for 24 hours and then treated with 4 ml of 1N sodium hydroxide. The mixture is extracted with 10 ml of ethyl acetate and the extract washed with 1N sodium hydroxide and 5 ml of brine. The organic layer is dried over anhydrous sodium sulfate and filtered through hydrous magnesium silicate. The filtrate is concentrate in vacuo to a residue which is stirred with ether-hexanes to give 160 mg of the desired product as a white solid:mass spectrum (CI), 361 (MH+).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH2:10])[CH:9]=[C:4]2[CH:3]=[N:2]1.[F:11][C:12]1[C:20]([N:21]([CH3:28])[S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23])=[CH:19][CH:18]=[C:17]([F:29])[C:13]=1[C:14]([OH:16])=[O:15].[F:30][C:31]1[C:39]([NH:40][S:41]([CH2:44][CH2:45][CH3:46])(=[O:43])=[O:42])=[CH:38][CH:37]=[C:36]([F:47])[C:32]=1[C:33]([OH:35])=[O:34]>>[F:11][C:12]1[C:20]([N:21]([CH3:28])[S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23])=[CH:19][CH:18]=[C:17]([F:29])[C:13]=1[C:14]([NH:10][C:8]1[CH:9]=[C:4]2[C:3]([O:34][CH3:33])=[N:2][NH:1][C:5]2=[N:6][CH:7]=1)=[O:15].[F:11][C:12]1[C:20]([N:21]([CH3:28])[S:22]([CH2:25][CH2:26][CH3:27])(=[O:23])=[O:24])=[CH:19][CH:18]=[C:17]([F:29])[C:13]=1[C:14]([OH:16])=[O:15].[F:30][C:31]1[C:39]([NH:40][S:41]([CH2:44][CH2:45][CH3:46])(=[O:42])=[O:43])=[CH:38][CH:37]=[C:36]([F:47])[C:32]=1[C:33]([OH:35])=[O:34]
Reactant: Nc1cnc2[nH]ncc2c1
Agent: CCCS(=O)(=O)N(C)c1ccc(F)c(C(=O)O)c1F
Agent: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Product: CCCS(=O)(=O)N(C)c1ccc(F)c(C(=O)Nc2cnc3[nH]nc(OC)c3c2)c1F
Yield: 66.4 %

Procedure:
2,6-Difluoro-N-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(N-methylpropylsulfonamido)benzamide (66.4% yield) was prepared according to Example 1, Step E, substituting 3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-amine for 1H-pyrazolo[3,4-b]pyridin-5-amine and 2,6-difluoro-3-(N-methylpropylsulfonamido)benzoic acid for 2,6-difluoro-3-(propylsulfonamido)benzoic acid. 2,6-Difluoro-3-(N-methylpropylsulfonamido) benzoic acid was isolated by column chromatography in 18% yield as a minor byproduct from Example C. 1H NMR (400 MHz, CDCl3) δ 9.86 (br s, 1H), 8.54 (s, 1H), 8.50 (br s, 1H), 8.64 (s, 1H), 8.10 (br s, 1H), 7.54-7.60 (q, 1H), 7.03-7.07 (t, 1H), 4.11 (s, 3H), 3.32 (s, 3H), 3.08-3.12 (t, 2H), 1.89-1.95 (m, 2H), 1.06-1.11 (t, 3H); m/z (APCI-pos) M+1=440.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17](O)=[O:18])[CH:13]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:68]([NH:75][CH2:76][CH2:77][CH2:78][NH2:79])([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:79][CH2:78][CH2:77][CH2:76][NH:75][C:68](=[O:69])[O:70][C:71]([CH3:72])([CH3:73])[CH3:74])=[O:18])[CH:13]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCNC(=O)OC(C)(C)C)c[nH]4)c3)cc2F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (400 mg, 0.86 mmol), HATU (380 mg, 1.0 mmol) and N,N-diisopropylethylamine (244 mg, 1.9 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of N-Boc-1,3-propanediamine (174 mg, 1.0 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water with vigorous stirring. 1M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give tert-butyl (3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)carbamate as white solid. Yield: 500 mg, 94%.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[Li]CCCC.CCCCCC.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C.Cl>C1COCC1>[CH3:10][O:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:8][C:7]=1[B:24]([OH:29])[OH:25]
Reactant: COc1ccc(C(F)(F)F)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(F)(F)F)cc1B(O)O
Temperature: -30 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
A solution of 4-trifluoromethylanisole (8 g; 45 mmol) in dry THF (80 ml) at −30° C. under N2 was added a solution of 2.5 M n-BuLi in hexane (20 ml; 50 mmol). The reaction mixture was stirred for 1 h at −30° C., then cooled to −70° C. and added B(Oi-Pr)3 (14.1 ml; 64 mmol). The reaction mixture was allowed to slowly warm up to rt. over night. The reaction mixture was added 2 M HCl (40 ml) and THF was removed by evaporation. The aqueous remanense was extracted with Et2O (4×20 ml) and the combined organic fractions were extracted with 1 M NaOH (5×17 ml). The combined aqueous fractions were neutralized by 10 M HCl. The precipitate formed was isolated by filtration and washed with 1 M HCl to give 8.1 g (81%) product.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].C(N(CC)CC)C.[O:27]1[C:31]2[NH:32][CH2:33][C:34]3[N:35]([CH:37]=[CH:38][CH:39]=3)[CH2:36][C:30]=2[CH:29]=[CH:28]1>C(Cl)Cl>[O:27]1[C:31]2[N:32]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=4[CH3:1])=[CH:8][CH:9]=3)=[O:12])[CH2:33][C:34]3[N:35]([CH:37]=[CH:38][CH:39]=3)[CH2:36][C:30]=2[CH:29]=[CH:28]1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: c1cc2n(c1)Cc1ccoc1NC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccoc32)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a mixture of 1.1 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 10 ml of methylene chloride, cooled to 0° C. is added 1.5 mmol of triethylamine. To the mixture is added 1 mmol of 9,10-dihydro-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepine and the mixture stirred at room temperature for 2 hours. The reaction mixture is concentrated in vacuo and the residue is dissolved in 100 ml of ethyl acetate and washed with water, 2N citric acid, aqueous NaHCO3 and brine. The solution is dried with Na2SO4 and the volatiles concentrated in vacuo to give a solid which is purified by flash chromatography to give the desired product.
Reaction SMILES: [CH3:1][C:2]#[N:3].CC([O-])(C)C.[K+].[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15]>C1COCC1>[Br:10][C:11]1[CH:12]=[C:13]([CH:14]([OH:15])[CH2:1][C:2]#[N:3])[CH:16]=[CH:17][CH:18]=1
Reactant: CC#N
Reactant: O=Cc1cccc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CCC(O)c1cccc(Br)c1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of THF (200 mL) and CH3CN (7.8 mL, 148 mmol) cooled to −50° C., was added KOtBu (18.16 g, 162 mmol) in portions by maintaining the temperature at −50° C. After stirring for 30 min, 3-bromobenzaldehyde (25 g, 135 mmol) was charged maintaining the same internal temperature. After stirring for 30 min, the reaction mixture was warmed to 0° C. and stirred for additional 3 h. This was recooled to −10° C. and quenched with excess water. Extraction with ethyl acetate yielded the crude product, which was purified by flash chromatography (0 to 20% EtOAc-hexanes gradient) to give 23 as light yellow oil. Yield (21 g, 69%): 1H NMR (400 MHz, DMSO-d6) δ 7.61 (s, 1H), 7.49 (bd, J=7.8 Hz, 1H), 7.47 (bd, J=7.6 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 6.09 (d, J=4.4 Hz, 1H), 4.92 (m, 1H), 2.81-2.95 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:9]=[C:10]([CH:27]=[CH:28][CH:29]=1)[CH2:11][NH:12][C:13]([C:15]1[CH:16]=[N:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:19][CH:20]=1)=[O:14])(=[O:7])=[O:6].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:38]1[C:43]([C:44](O)=[O:45])=[CH:42][C:41]2[C:47]([O:49][C:50]3([C:60]4[CH:61]=[CH:62][C:63]([OH:65])=[CH:64][C:59]=4[O:58][C:52]4[CH:53]=[C:54]([OH:57])[CH:55]=[CH:56][C:51]3=4)[C:40]=2[CH:39]=1)=[O:48]>CN(C)C=O>[OH:57][C:54]1[CH:53]=[C:52]2[C:51](=[CH:56][CH:55]=1)[C:50]([C:40]1[CH:39]=[CH:38][C:43]([C:44](=[O:45])[NH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]3[CH:29]=[CH:28][CH:27]=[C:10]([CH2:11][NH:12][C:13]([C:15]4[CH:20]=[N:19][C:18]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)=[N:17][CH:16]=4)=[O:14])[CH:9]=3)(=[O:6])=[O:7])=[CH:42][C:41]=1[C:47]([OH:49])=[O:48])=[C:60]1[C:59](=[CH:64][C:63](=[O:65])[CH:62]=[CH:61]1)[O:58]2
Reactant: NCCNS(=O)(=O)c1cccc(CNC(=O)c2cnc(-c3ccccc3)nc2)c1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC21c2ccc(O)cc2Oc2cc(O)ccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCCNS(=O)(=O)c1cccc(CNC(=O)c2cnc(-c3ccccc3)nc2)c1)c1ccc(-c2c3ccc(=O)cc-3oc3cc(O)ccc23)c(C(=O)O)c1

Procedure:
To a mixture consisting of N-(3-(N-(2-aminoethyl)sulfamoyl)benzyl)-2-phenylpyrimidine-5-carboxamide (Compound 19, 8.7 mg) in N,N-dimethylformamide (1 mL) was added 250 mM potassium phosphate buffer, pH 8 (2 mL) and 5-carboxyfluorescein, succinimidyl ester (5-FAM, SE; Biotium Catalog No. 90029; 10 mg). The mixture was stirred in the dark until the reaction was complete. The crude product was purified by preparative thin-layer chromatography (75:15:2 chloroform-methanol-water) to afford the title compound (approximately 4 mg); MS (ESI−) m/z 768 (M−1).