Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1>>[CH2:26]([N:22]([CH2:23][CH2:24][OH:25])[C:3]1[C:2]([C:32]2[CH:33]=[N:28][CH:29]=[N:30][CH:31]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1)[CH3:27]
Reactant: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Reactant: OB(O)c1cncnc1
Product: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cncnc1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using 5-bromo-6-(ethyl(2-hydroxyethyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 156.1) and pyrimidin-5-ylboronic acid to afford a white solid. UPLC-MS (Condition 3) tR=0.97 min, m/z=448.3 [M+H]+, m/z=446.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.89 (t, J=6.96 Hz, 3H) 3.11-3.16 (m, 2H) 3.34-3.41 (m, 2H) 3.49 (q, J=5.65 Hz, 2H) 4.62 (t, J=5.27 Hz, 1H) 7.36 (d, J=8.41 Hz, 2H) 7.80-7.90 (m, 2H) 8.11 (d, J=2.38 Hz, 1H) 8.78 (d, J=2.26 Hz, 1H) 9.03 (s, 2H) 9.21 (s, 1H) 10.26 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].S(O[CH2:31][CH2:32][O:33][CH:34]([CH3:36])[CH3:35])(=O)(=O)C>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:31][CH2:32][O:33][CH:34]([CH3:36])[CH3:35])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)OCCOS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OCCn1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (0.54 g, 1.71 mmol) and sodium hydride (0.87 g, 3.48 mmol) in dimethylformamide (10 mL). After 30 minutes, add 2-(isopropoxy)ethyl mesylate (0.51 g, 5.5 mmol). Heat to 80° C. After 2 hours, cool the reaction mixture to ambient temperature and partition between dichloromethane and a saturated aqueous sodium bicarbonate solution. Separate the layers and extract the organic layer with brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 1-(t-butoxycarbonyl)-4-(1-(2-(isopropoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:20]=[CH:19][C:12]3[C:13](=[O:18])[NH:14][CH2:15][CH2:16][CH2:17][C:11]=3[CH:10]=2)O1.[NH2:22][C:23]1[N:24]=[CH:25][C:26]([C:30]2[CH:35]=[CH:34][C:33]([S:36]([N:39]([CH2:41][CH3:42])[CH3:40])(=[O:38])=[O:37])=[CH:32][CH:31]=2)=[N:27][C:28]=1Br>>[NH2:22][C:23]1[N:24]=[CH:25][C:26]([C:30]2[CH:35]=[CH:34][C:33]([S:36]([N:39]([CH2:41][CH3:42])[CH3:40])(=[O:37])=[O:38])=[CH:32][CH:31]=2)=[N:27][C:28]=1[C:9]1[CH:20]=[CH:19][C:12]2[C:13](=[O:18])[NH:14][CH2:15][CH2:16][CH2:17][C:11]=2[CH:10]=1
Reactant: CCN(C)S(=O)(=O)c1ccc(-c2cnc(N)c(Br)n2)cc1
Reactant: CC1(C)OB(c2ccc3c(c2)CCCNC3=O)OC1(C)C
Product: CCN(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3ccc4c(c3)CCCNC4=O)n2)cc1
Yield: 25.2 %

Procedure:
General method C was applied to 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one (95 mg, 0.33 mmol) and 4-(5-amino-6-bromopyrazin-2-yl)-N-ethyl-N-methylbenzenesulfonamide (108 mg, 0.29 mmol) to provide 4-(5-amino-6-(1-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yl)pyrazin-2-yl)-N-ethyl-N-methylbenzenesulfonamide (33 mg, 22% yield) after purification by preparatory HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (s, 1H), 8.22 (d, J=8.5 Hz, 2H), 8.12 (t, J=5.8 Hz, 1H), 7.80 (d, J=8.5 Hz, 2H), 7.71 (dd, J=8.0, 1.5 Hz, 1H), 7.62-7.66 (m, 2H), 6.66 (br. s, 2 H), 2.93-3.09 (m, 4H), 2.83 (t, J=1.0 Hz, 2H), 2.67 (s, 3H), 1.94 (dd, J=12.3, 6.0 Hz, 2H), 1.03 (t, J=7.2 Hz, 3H); MS (EI) m/z=452.5 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([CH:22]=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)[CH2:12][O:13][CH3:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].CC(=C)C.Cl([O-])=[O:33].[Na+].O>C(O)(C)(C)C.CCOC(C)=O>[Cl:21][C:19]1[CH:20]=[C:15]([N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:24]([F:26])([F:25])[F:27])[CH:4]=2)(=[O:10])=[O:9])[CH2:12][O:13][CH3:14])[C:16]([C:22]([OH:33])=[O:23])=[N:17][CH:18]=1
Reactant: [O-][Cl+][O-]
Reactant: COCN(c1cc(Cl)cnc1C=O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: C=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: COCN(c1cc(Cl)cnc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-chloro-N-(5-chloro-2-formyl-pyridin-3-yl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (590 mg, 1.33 mmol) in tert-butanol (26 mL) was added isobutylene (5 mL), sodium chlorite (751 mg, 6.66 mmol) sodium dihydrogen phosphate (919 mg, 6.66 mmol) and water (26 mL). After the solution was stirred at room temperature for 3 h, EtOAc (10 mL) was added and the layers were separated. The organic layer was washed with saturated sodium bicarbonate (2×10 mL) and brine (1×10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to yield 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([NH:11][C:12]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[S:13])[N:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:7]=1)=[O:5])[CH3:2].BrN1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[S:13][C:12]([NH:14][C:15](=[O:22])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:11][C:9]=2[N:8]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(NC(=S)NC(=O)c2ccccc2)n(-c2ccccc2)n1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1nn(-c2ccccc2)c2nc(NC(=O)c3ccccc3)sc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
1-Phenyl-5-[3-benzoyl-thioureido]-1H-pyrazole-3-carboxylic acid ethyl ester (500 mg, 1.26 mmol) was dissolved in 25 ml anhydrous CHCl3. N-Bromosuccinimide (225 mg, 1.26 mmol) was added portion wise in 5-10 minutes at 0° C. The reaction mixture was stirred at room temperature for 2 hours. After the completion of reaction, 100 ml of CHCl3 was added to the reaction flask and the organic layer was washed with NaHCO3 (2×30 ml), followed by brine, and dried over Na2SO4. Removal of the solvent gave product, which was sufficiently pure (>95%) for use in the following step. The crude product was further purified by SiO2 column to give 450 mg of title compound (Yield: 91%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[OH:24])=[O:17])[CH2:7][CH2:6]1.[NH2:25][C:26]1[C:34]([Cl:35])=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([O:36][CH3:37])[CH:27]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>C(N(CC)CC)C>[ClH:35].[NH2:25][C:26]1[C:34]([Cl:35])=[CH:33][C:29]([C:30]([NH:3][CH2:4][CH:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[OH:24])=[O:17])[CH2:7][CH2:6]2)=[O:31])=[C:28]([O:36][CH3:37])[CH:27]=1
Reactant: NCC1CCN(CCCCCC(=O)c2ccccc2O)CC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccccc2O)CC1
Yield: 107.8 %

Procedure:
4-Aminomethyl-1-(6-(2-hydroxyphenyl)-6-oxohexyl)piperidine dihydrochloride (1.54 g) as a starting compound, 4-amino-5-chloro-2-methoxybenzoic acid (0.82 g), triethylamine (1.7 ml), 1-hydroxybenzotriazole (0.58 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.82 g) were reacted and purified in the same manner as in Example 270 to give 1.15 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-(2-hydroxyphenyl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide hydrochloride, m.p. 143°-145° C.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([N:20]([CH3:22])[CH3:21])[C:17]([O:23][C@H:24]([CH3:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:16][C:15]=2[N+:32]([O-:34])=[O:33])=[CH:10][CH:9]=1)=[O:7].C1COCC1.Cl>CO.O>[N+:32]([C:15]1[CH:16]=[C:17]([O:23][C@H:24]([CH3:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:18]([N:20]([CH3:21])[CH3:22])=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]([C:6]([OH:7])=[O:5])=[CH:9][CH:10]=1)([O-:34])=[O:33]
Reactant: CCCCCC[C@@H](C)Oc1cc([N+](=O)[O-])c(-c2ccc(C(=O)OC)cc2)cc1N(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCCCC[C@@H](C)Oc1cc([N+](=O)[O-])c(-c2ccc(C(=O)O)cc2)cc1N(C)C
Yield: 103.1 %

Procedure:
Lithium hydroxide monohydrate (96 mg, 2.28 mmol) was added to a stirred solution of compound 64 (49 mg, 0.11 mmol), THF (2 ml), water (3 ml), and methanol (10 ml). The reaction mixture was refluxed overnight and then was acidified with concentrated HCl. The reaction mixture was extracted twice with dichloromethane, the combined organic layers were washed with brine and dried over MgSO4. Evaporation of solvent yielded 47 mg (100%) of a yellow solid. The crude product was carried on without purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH2:21]([S:23](Cl)(=[O:25])=[O:24])[CH3:22]>C(Cl)Cl>[CH2:21]([S:23]([NH:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1)(=[O:25])=[O:24])[CH3:22]
Reactant: NCCSc1cccc2nccn12
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)NCCSc1cccc2nccn12
Yield: 78.1 %

Procedure:
To a solution of 5-[2-(amino)ethylthio]imidazo[1,2-a]pyridine (1.93 g, 10 mmoles) and triethylamine (1.53 ml, 11 mmoles) in methylene chloride (100 ml) was added ethanesulfonyl chloride (0.95 ml, 10 mmoles) at room temperature with stirring and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed in turn with an aqueous saturated sodium bicarbonate solution and water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethanol/ethyl acetate=1:5) to obtain 2.23 g of the desired product (78.2%, colorless crystals).
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=[O:3].[CH2:7]([N:9]1C(=O)C(O)=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[S:10]1(=[O:27])=[O:26])[CH3:8].CN(C=O)C>C(Cl)Cl>[Cl:6][C:1]1[C:2](=[O:3])[N:9]([CH2:7][CH3:8])[S:10](=[O:27])(=[O:26])[C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCN1C(=O)C(O)=C(c2ccc(C(F)(F)F)cc2)S1(=O)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN1C(=O)C(Cl)=C(c2ccc(C(F)(F)F)cc2)S1(=O)=O
Yield: 60.5 %

Procedure:
Oxalyl chloride (0.379 g, 2.99 mmol) was added dropwise to a solution of 2-ethyl-4-hydroxy-5-[4-(trifluoromethyl)phenyl]isothiazol-3(2H)-one 1,1-dioxide (0.480 g, 1.49 mmol) and DMF (0.109 g, 1.49 mmol) in DCM (12 mL). The mixture was refluxed for 1 h. It was evaporated and water was added. The resulting mixture was extracted with EtOAc, and the combined organic layers were washed with brine and evaporated to give the title compound (0.306 g, 71%) as a solid; 1H NMR (500 MHz, DMSO-d6): δ 8.07-8.11 (m, 4H), 3.81 (q, 2H), 1.33 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[CH3:10][NH:11][CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH:12]([NH:11][CH3:10])[CH3:13])=[CH:6][CH:7]=1
Reactant: CCNC
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC(C)Cc1ccc(Cl)nc1
Temperature: 80 °C
Yield: 87.8 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (1.0 g, 6.17 mmole) in 11 mL of dry acetonitrile is added 1.06 mL (12.3 mmol) of methylethylamine followed by 850 mg (6.17 mmol) of potassium carbonate. The reaction is heated at 80° C. for 5 h. After cooling, the reaction mixture is quenched with 5 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 1.0 g (87% yield) of 1-(6-Chloro-pyridin-3-ylmethyl)-methylethylamine. Diagnostic 1H NMR (400 MHz, CDCl3) 1.06 (t, 3H, J=7.1 Hz), 2.14 (s, 3H), 2.40 (q, 2H, J=7.1 Hz), 3.43 (s, 2H), 7.25 (d, 1H, J=8.2 Hz), 7.62 (dd, 1H, J=8.2 and 5.8 Hz); MS (187.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[Cl:10].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:36])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][Br:36])[CH:5]=[CH:4][C:3]=1[Cl:10]
Reactant: Cc1ccc(Cl)c(Br)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(CBr)c(Cl)c1Br
Reaction time: 16 h
Yield: 65.6 %

Procedure:
Place 2-bromo-1,3-dichloro-4-methylbenzene (50 g, 208 mmol) in carbon tetrachloride (400 mL). Add benzoyl peroxide (5 g, 20.8 mmol) and NBS (38.9 g, 219 mmol) and heat to 80° C. and stir for 16 hours. Cool reaction and filter. Dissolve in hexanes and wash with sodium bisulfate and then with sodium bicarbonate. Purify by distillation. Collect product at 135° C. under reduced pressure to give 43.5 g (65%) of 2-bromo-4-(bromomethyl)-1,3-dichlorobenzene.
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:13].[OH-].[Na+]>C(O)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:12](=[O:13])[CH:11]=[CH:1][CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:15][CH:16]=1
Reactant: O=C/C=C/c1ccccc1
Reactant: COc1ccc(C(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(=O)C=CC=Cc2ccccc2)cc1
Reaction time: 12 h
Yield: 72 %

Procedure:
2 ml of trans-cinnamaldehyde and 2.5 g of 4-methoxy acetophenone were dissolved in 50 ml of ethanol at room temperature. 10 ml of sodium hydroxide solution was then added and stirred for 12 h to form yellow solid precipitation. Filtering the precipitation to obtain the compound 1, with yield of 72% and purity of 96.3%. FIG. 1 and FIG. 2 respectively show the NMR and UV spectrum of compound 1; wherein the maximum adsorptive wavelength of compound 1 is 345 nm, and the adsorptive coefficient ε is 4.5×104, both listed on Table 1.
Reaction SMILES: CO.[C:3]([NH:11][C:12]1[CH:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-])=O)[CH:22]=[CH:21][C:13]=1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[C].[Pd].C(OCC)(=O)C>[NH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[NH:25][C:23]1[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])=[C:12]([NH:11][C:3](=[O:10])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:24]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2ccccc2[N+](=O)[O-])cc1NC(=O)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(Nc2ccccc2N)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10 mg of 5% palladium-carbon was added to a mixed solution of 4.0 mL of methanol and 8.0 mL of ethyl acetate containing 50 mg of tert-butyl 2-(benzamido)-4-(2-nitroanilino)benzoate and stirred under hydrogen atmosphere at room temperature for 1 hour and 30 minutes. After insoluble were removed by filtration, the solvent was evaporated under reduced pressure to obtain 46 mg of tert-butyl 4-(2-aminoanilino)-2-(benzamido)benzoate as pale yellow solid.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([N:19]2[CH2:24][C@@H:23]3[CH2:25][C@H:20]2[CH2:21][O:22]3)[CH:16]=[CH:15][C:14]=1[O:26][CH3:27])=[S:11])(=O)C1C=CC=CC=1.C[O-].[Na+]>CO>[CH3:27][O:26][C:14]1[CH:15]=[CH:16][C:17]([N:19]2[CH2:24][C@@H:23]3[CH2:25][C@H:20]2[CH2:21][O:22]3)=[CH:18][C:13]=1[NH:12][C:10]([NH2:9])=[S:11]
Reactant: COc1ccc(N2C[C@@H]3C[C@H]2CO3)cc1NC(=S)NC(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(N2C[C@@H]3C[C@H]2CO3)cc1NC(N)=S
Reaction time: 1 h
Yield: 64.8 %

Procedure:
To a stirred suspension of 7.25 g (18.9 mmol) 1-benzoyl-3-[2-methoxy-5-{(1S,4S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)}-phenyl]-thiourea in 350 ml methanol was added dropwise 7.02 ml (37.8 mmol) 5.4 M sodium methylate solution and stirring continued for 1 h at room temperature. The resulting crystals were collected by filtration to afford 3.42 g (65%) [2-methoxy-5-{(1S,4S)-(2-oxa-5-aza-bicyclo[2.2.1 ]hept-5-yl)}-phenyl]-thiourea as a beige solid. ES-MS m/e (%):302 (M+Na+, 20), 281 (M+H+, 100).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[N:13]3[C:8]([C:9]([NH2:14])=[N:10][CH:11]=[N:12]3)=[C:7]([C:15]3[CH:16]=[CH:17][C:18]4[C:22]([CH:23]=3)=[N:21][N:20]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]=4)[CH:6]=2)[CH2:2]1.[CH3:31][N:32]([CH3:37])[CH2:33][C:34](O)=[O:35].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:24]([N:20]1[CH:19]=[C:18]2[C:22]([CH:23]=[C:15]([C:7]3[CH:6]=[C:5]([CH:3]4[CH2:4][N:1]([C:34](=[O:35])[CH2:33][N:32]([CH3:37])[CH3:31])[CH2:2]4)[N:13]4[C:8]=3[C:9]([NH2:14])=[N:10][CH:11]=[N:12]4)[CH:16]=[CH:17]2)=[N:21]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nc1ncnn2c(C3CNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.4 %

Procedure:
A mixture of 7-azetidin-3-yl-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (20 mg, 0.051 mmol), N,N-dimethylglycine (5.7 mg, 0.056 mmol), EDCl (11.6 mg, 0.061 mmol), HOBt (8.2 mg, 0.061 mmol), and N,N-diisopropylethylamine (26 μL, 0.15 mmol) in DMF (1 mL) was stirred at rt for 16 h. The crude reaction mixture was purified via preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 5 mg (21%) of the desired product. 1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1 H), 7.79-7.85 (m, 2 H), 7.67 (s, 1 H), 7.29-7.37 (m, 5 H), 7.25 (d, 1 H), 6.81 (s, 1 H), 5.65 (s, 2 H), 4.70 (t, 1 H), 4.25-4.54 (m, 4 H), 3.18 (s, 2 H), 2.38 (s, 6 H); ES-MS m/z 481.10 [M+H]+, HPLC RT (min) 2.07.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.[OH:19][CH2:20][CH2:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][N:23]2[CH:24]=[CH:25][N:26]=[C:22]2[CH2:21][CH2:20][OH:19])=[CH:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ICCCc1ccc(OCc2ccccc2)cc1
Reactant: OCCc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OCCc1nccn1CCCc1ccc(OCc2ccccc2)cc1
Yield: 55.1 %

Procedure:
Using benzyl 4-(3-iodopropyl)phenyl ether (5.28 g), 2-(2-hydroxyethyl)imidazole (5.05 g) and potassium carbonate (2.07 g), the same reaction as Reference Example 12-(i) was carried out to yield the titled compound (2.78 g) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:39]3[S:43][C:42]([O:44][CH2:45][CH2:46][O:47][Si](C(C)(C)C)(C)C)=[N:41][CH:40]=3)=[C:13]2[C:24](=[O:38])[N:25]([CH:35]2[CH2:37][CH2:36]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:39]3[S:43][C:42]([O:44][CH2:45][CH2:46][OH:47])=[N:41][CH:40]=3)=[C:13]2[C:24](=[O:38])[N:25]([CH:35]2[CH2:37][CH2:36]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC2CC(c3cnc(OCCO[Si](C)(C)C(C)(C)C)s3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2CC(c3cnc(OCCO)s3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A sol. of compound E8 (0.37 mmol; 0.31 g) in MeOH (3.75 mL) was treated with para-toluenesulfonic acid (0.41 mmol; 78 mg), and the mixture was stirred at rt for 30 min. 10% aq. Na2CO3 (3.0 mL) was added and the solvents were partially removed under reduced pressure. The resulting suspension was extracted with EtOAc (25 mL), washed with 10% aq. Na2CO3 (25 mL), sat. aq. NaHCO3 (25 mL), and brine (25 mL). The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The product (0.26 g; 99%) was used for the next step without purification. LC-MS: tR=1.10 min; ES+: 709.41.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2OS(C(F)(F)F)(=O)=O)[C:10]([O:12][CH3:13])=[O:11])[CH2:3][CH2:2]1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.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>[O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[CH:14]=[CH:15][C:16]=2[C:27]2[CH:28]=[C:29]([O:32][CH3:33])[CH:30]=[CH:31][C:26]=2[F:25])[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C2=CCOCC2)c1
Reactant: COc1ccc(F)c(B(O)O)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: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2=CCOCC2)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
To a stirred solution of 66.46E (555 mg, 1.52 mmol) in DMF (10 mL) at 23° C. was added 2-fluoro-5-methoxyphenylboronic acid (512.3 mg, 3.0 mmol) (commercially available from Aldrich) and potassium carbonate (630.1 mg, 4.56 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (176.8 mg, 0.15 mmol). The mixture was heated to 90° C. After 18 hours, LCMS showed the reaction was complete. The mixture was cooled to room temperature and diluted with water. After extracting three times with EtOAc, the mixture was concentrated in vacuo, and the residue was purified on silica gel (0-50% EtOAc in hexanes) to afford 66.46F (452.7 mg, 87% yield). MS ESI (pos.) m/e: 343.0 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:32]Br>CO>[Br:32][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CO
Product: NS(=O)(=O)c1ccc(C(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
90.3 g of the product of Example 4 are dissolved in 900 ml of methanol, 0.9 g of benzoyl peroxide are then added and 24 ml of bromine are added dropwise. The mixture is stirred under ultra-violet irradiation for 24 h, at ambient temperature, then concentrated. The residue is taken up in water, filtered off, washed with isopropanol and pentane.