Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](=O)([O-])[O-].[K+].[K+].CI.Cl>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18])[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cccc(NCCCCOCc2ccccc2)c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(CCCCOCc1ccccc1)c1cccc(C#N)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 95.2 %

Procedure:
3-(4-Benzyloxybutylamino)benzonitrile (0.22 g) and potassium carbonate (0.21 g) were suspended in N,N-dimethylformamide (5 mL). To the reaction mixture was added methyl iodide (0.16 g), and the mixture was stirred at 50° C. for 16 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine successively and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (ethyl acetate/hexane=1/1) to give the title compound (0.22 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.NC[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1.C1CCN2C(=[N:36]CCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:36][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: C1CCC2=NCCCN2CC1
Agent: Cl
Solvent: COCCOC
Product: N#Cc1c(NCc2ccc(S(N)(=O)=O)cc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 4-(aminoethyl)benzenesulfonamide hydrochloride and DBU in DME. ES-MS m/e (%): 369 ([M—H]−, 100).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C:12]1[C:13](Cl)=[N:14][C:15]([Cl:19])=[C:16]([F:18])[CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>CC(N(C)C)=O>[CH2:1]([O:8][N:9]1[C:10](=[O:11])[C:12]2[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[N:14][C:13]=2[N:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[F:23])[C:31]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccccc1F
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1c2cc(F)c(Cl)nc2n(-c2ccccc2F)c(=O)n1OCc1ccccc1
Yield: 77.8 %

Procedure:
Using the General Method 5, the reaction of N-benzyloxy-2,6-dichloro-5-fluoro-3-pyridinecarboxamide (Example M-2, 2.00 g, 6.34 mmol) and 60% NaH in oil (300 mg, 7.52 mmol) with 2-fluorophenyl isocyanate (1.07 mL, 9.51 mmol) in DMA afforded 2.05 g of the title compound as a solid, mp 199-200° C.
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:12]3[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[CH3:24].[ClH:28].O1CCOCC1>C(OCC)(=O)C>[ClH:28].[N:9]12[CH2:14][CH2:13][CH:12]([CH2:11][CH2:10]1)[CH:7]([O:6][C:5]1[CH:15]=[CH:16][C:2]([C:20]3[CH:21]=[CH:22][C:23]([CH3:24])=[C:18]([NH2:17])[CH:19]=3)=[CH:3][CH:4]=1)[CH2:8]2
Reactant: Cc1ccc(B(O)O)cc1N
Reactant: Ic1ccc(OC2CN3CCC2CC3)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc(OC3CN4CCC3CC4)cc2)cc1N

Procedure:
The product of Example 1A (330 mg, 1 mmol) was treated with 3-amino-4-methyl-phenylboronic acid (Lancaster, 302 mg, 2 mmol) according to the procedure of Example 1B. The free base of the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3H2O, 90:10:2, Rf. 0.10) as oil (230 mg, yield, 75%). The free base of the title compound (230 mg, 0.75 mmol) in ethyl acetate (5 mL) was treated with 4M HCl in 1,4-dioxane (0.5 mL, 2 mmol). The title compound was obtained as solid (180 mg, yield, 74%): 1H NMR (MeOH-d4, 300 MHz) δ 1.85-2.19 (m, 3H), 2.28-2.38 (m, 1H), 2.43 (s, 3H), 2.51-2.57 (m, 1H), 3.31-3.45 (m, 5H), 3.82-3.89 (m, 1H), 4.93-4.99 (m, 1H), 7.13 (dt, J=8.8, 3.0 Hz, 2H), 7.44 (d, J=8.8 Hz, 1H), 7.56-7.66 (m, 4H) ppm. MS (DCl/NH3) m/z 309 (M+H)+. Anal. Calculated for C19H22N2O.2.0HCl.0.1H2O: C, 62.70; H, 6.89; N, 7.31. Found: C, 62.52; H, 6.59; N, 7.35.
Reaction SMILES: C(OC([N:8]([C:10]1([C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[CH2:12][CH2:11]1)[CH3:9])=O)(C)(C)C.C(N(CC)CC)C.F[C:26]1[CH:27]=[CH:28][C:29]2[C:39](=[O:40])[C:38]([C:41]([OH:43])=[O:42])=[CH:37][N:31]3[C@@H:32]([CH3:36])[CH2:33][O:34][C:35]=1[C:30]=23>CS(C)=O>[CH3:36][C@@H:32]1[N:31]2[CH:37]=[C:38]([C:41]([OH:43])=[O:42])[C:39](=[O:40])[C:29]3[CH:28]=[CH:27][C:26]([N:15]4[CH2:16][CH2:17][C@@H:13]([C:10]5([NH:8][CH3:9])[CH2:11][CH2:12]5)[CH2:14]4)=[C:35]([C:30]=32)[O:34][CH2:33]1
Reactant: CN(C(=O)OC(C)(C)C)C1([C@@H]2CCNC2)CC1
Reactant: C[C@H]1COc2c(F)ccc3c(=O)c(C(=O)O)cn1c23
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CNC1([C@@H]2CCN(c3ccc4c(=O)c(C(=O)O)cn5c4c3OC[C@@H]5C)C2)CC1
Temperature: 100 °C
Yield: 70.4 %

Procedure:
After adding 3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cyclopropyl]pyrrolidine (125 mg, 521 μmol) and triethylamine (0.50 ml) to dried dimethyl sulfoxide (1 ml), 10-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (132 mg, 500 μmol) was added thereto and stirred while heating in an oil bath of 100° C. for 20 hours under a nitrogen atmosphere. After concentrating the reaction solution under a reduced pressure, the residue was dissolved in chloroform (100 ml). After washing the organic layer with a 10% aqueous citric acid solution (50 ml) and saturated saline solution (50 ml), the organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and after adding concentrated hydrochloric acid (3 ml) to the residue while cooling with ice, it was stirred at room temperature for 30 minutes. After adding water (3 ml) to the reaction solution and washing the yellow acidic aqueous solution with chloroform (50 ml×3), the pH was adjusted to 12.0 with an aqueous sodium hydroxide solution. After adjusting the pH of the basic aqueous solution to 7.4 with 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×3) was performed. After drying over anhydrous sodium sulfate, the solvent was evapolated under a reduced pressure. The residue thus obtained was then purified by recrystallization from ethanol-ammonia water and then dried under a reduced pressure. 135 mg (70%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:23]=[C:21](C)[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[OH:24])(C(C)(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:45]1[C:49](=[O:50])[C:48]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:47]2[C:46]1=[O:55].CCOCC>C1COCC1>[C:49]1(=[O:50])[N:45]([O:8][CH2:9][C@H:10]2[O:14][C@@H:13]([N:15]3[CH:23]=[CH:21][C:19](=[O:20])[NH:18][C:16]3=[O:17])[CH2:12][C@@H:11]2[OH:24])[C:46](=[O:55])[C:47]2=[CH:54][CH:53]=[CH:52][CH:51]=[C:48]12
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O
Temperature: 0 °C
Yield: 62 %

Procedure:
To a solution of 5′-O-t-butyldimethylsilylthymidine (1, 21.36 g, 60 mmol, prepared according to the procedure of Nair, et al., Org. Prep. Procedures Int. 1990, 22, 57 in dry THF (750 ml)), triphenylphosphine (17.28 g, 66 mmol) and N-hydroxyphthalimide (10.74 g, 66 mmol) were added. The solution was cooled to 0° C. and diisoprbpylazodicarboxylate (15.15 g, 75 mmol) was added dropwise over a period of 3 hr while stirring under nitrogen. The reaction mixture was then stirred at room temperature for 12 hr. The solution was evaporated and the residue was dissolved in CH2Cl2 (750 ml), extracted with sat. NaHCO3 (200 ml), and water (200 ml), dried (MgSO4), filtered and concentrated to furnish yellow oily residue. Silica gel column chromatography (100% hexanes, and then hexanes:Et2O gradient to 90% Et2O) of the residue gave compound 2 as a colorless glass (18.68 g, 62%); 1H NMR (CDCl3) δ 0.05 [2s, 6, (CH3)2], 0.91 [s, 9, (CH3)3], 2.0 (s, 3, CH3), 2.5-2.65 (m, 2, 2′CH2), 4.05-4.2 (m, 2, 5′CH2), 4.25-4.35 (m, 1, 4′H), 5.0 (m, 1, 3′H), 6.15 (m, 1, 1′H), 8.6 (br s, 1, NH), and aromatic protons. Anal. Calcd. for C24H31N3O7Si: C, 57.46;H, 6.23; N, 8.37. found : C, 57.20; H, 6.26; N, 8.27.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][C@@H:9]([C@H:15]([OH:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:10](OCC)=[O:11])=[O:7])=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[CH3:30][NH2:31]>C(O)C>[CH3:30][NH:31][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[C:5]1[CH:24]=[CH:25][C:2]([F:1])=[CH:3][C:4]=1[C:26]([F:29])([F:28])[F:27])[C@H:15]([OH:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22]
Reactant: CN
Reactant: CCOC(=O)[C@@H](NC(=O)c1ccc(F)cc1C(F)(F)F)[C@H](O)c1ccccc1C
Solvent: CCO
Product: CNC(=O)[C@@H](NC(=O)c1ccc(F)cc1C(F)(F)F)[C@H](O)c1ccccc1C
Temperature: 32.5 °C
Reaction time: 1.5 h

Procedure:
3.4 g (0.0082 mol) of ethyl (2S,3R)-2-(4-fluoro-2-trifluoromethylbenzoylamino)-3-hydroxy-3-o-tolylpropionate were dissolved in ethanol. Methylamine gas was introduced at room temperature. After 1.5 h, the mixture was warmed to 30-35° C. for 1 h. Removal of the solvents gave 3.1 g of the title compound as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)=[C:7]([C:12]#[N:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[NH:27][C:28](=[O:31])[CH:29]=[CH2:30].NC1C=C2C(=CC=1NC(=O)C=C)N=CC(C#N)=C2NC1C=C(OC)C(OC)=C(OC)C=1.[NH:63]1[CH2:68][CH2:67][O:66][CH2:65][CH2:64]1>CN(C)C=O>[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)=[C:7]([C:12]#[N:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[NH:27][C:28](=[O:31])[CH2:29][CH2:30][N:63]1[CH2:68][CH2:67][O:66][CH2:65][CH2:64]1
Reactant: C1COCCN1
Reactant: C=CC(=O)Nc1cc2c(Nc3cc(OC)c(OC)c(OC)c3)c(C#N)cnc2cc1N
Agent: C=CC(=O)Nc1cc2ncc(C#N)c(Nc3cc(OC)c(OC)c(OC)c3)c2cc1N
Solvent: CN(C)C=O
Product: COc1cc(Nc2c(C#N)cnc3cc(N)c(NC(=O)CCN4CCOCC4)cc23)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
A mixture of 0.025 g (0.06 mmol) of N-[7-amino-3-cyano-4-(3,4,5-trimethoxyanilino)-6-quinolinyl]acrylamide and N-[6-amino-3-cyano-4-(3,4,5-trimethoxyanilino)-7-quinolinyl]acrylamide and 0.05 mL (6.0 mmol) of morpholine in 0.2 mL of N,N-dimethylformamide is stirred at room temperature overnight and the solvent is evaporated to dryness to yield an oil. The oil is triturated with diethyl ether several times and dried to yield 0.03 g of N-[7-amino-3-cyano-4-(3,4,5-trimethoxyanilino)-6-quinolinyl]-3-(4-morpholinyl)propanamide and N-[6-amino-3-cyano-4-(3,4,5-trimethoxyanilino)-7-quinolinyl]-3-(4-morpholinyl)propanamide as a yellow solid.
Reaction SMILES: [O:1]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:13]O>OS(O)(=O)=O>[O:1]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)CCOc1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCOc1ccccc1
Yield: 92.5 %

Procedure:
3-phenoxypropionic acid (5.0 g, 30 mmol) was dissolved in MeOH (12 mL) and H2SO4 (18 M, 3 drops) was added. The mixture was place in the microwave reactor (T: 140° C., t: 5 min). The solvent was evaporated, the mixture was partitioned in EtOAc (30 mL) and NaOH (2N, 20 mL). The organic phase was dried over MgSO4, filtered, and evaporated to give methyl 3-phenoxypropanoate (5.0 g, 27.7 mmol, 92.5%).
Reaction SMILES: F[C:2]1[C:7]([C:8](=O)[CH3:9])=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.O.[NH2:13][NH2:14].O.CCO>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:11][C:4]1[N:3]=[C:2]2[NH:13][N:14]=[C:8]([CH3:9])[C:7]2=[CH:6][CH:5]=1
Reactant: NN
Reactant: CC(=O)c1ccc(F)nc1F
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: Cc1n[nH]c2nc(F)ccc12
Reaction time: 1.5 h

Procedure:
To a stirred solution of 7.46 g (47.51 mmol) of 1-(2,6-difluoropyridin-3-yl)ethanone (37-2) in 50 mL of CH2Cl2 under nitrogen was added dropwise titanium (IV) isopropoxide. The resulting solution was stirred vigorously for 15 minutes before hydrazine hydrate (4.62 g, 95.0 mmol) was added slowly to form a thick slurry. The reaction mixture was stirred for 1 hour before the addition of 11 mL of H2O, and the resulting mixture stirred for 1.5 hours until completion as determined by LC/MS analysis. The solid matter was filtered off and the filterate was condensed to yield a white solid. EtOH (100 mL) was added to the crude intermediate and the mixture was heated to reflux for 6 hours. After the reaction was complete as determined by LC/MS analysis the solvent was removed to yield the desired product. No further purification was necessary. 1H NMR (CDCl3): 2.56 (s, 3H), 6.78 (d, 1H), 8.08 (t, 1H).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14].O>CN1C(=O)CCC1>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([CH3:10])=[CH:9][C:2]=1[N:12]([CH3:11])[S:13]([CH3:16])(=[O:15])=[O:14])#[N:5]
Reactant: Cc1ccc(C#N)c(F)c1
Reactant: CNS(C)(=O)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc(C#N)c(N(C)S(C)(=O)=O)c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
2-fluoro-4-methylbenzonitrile (4.6 g, 34.4 mmol) and N-methyl-methanesulphonamide (7.5 g, 68.7 mmol) are dissolved in 15 mL NMP and stirred for 16 h at 120° C. After the reaction has ended the reaction mixture is mixed with 70 mL water and the solid B-1a (HPLC-MS: tRet.=1.22 min; MS (M+NH4)+=242) is suction filtered and used without any further purification.
Reaction SMILES: [OH:1][C@H:2]([C:22]1[CH:23]=[CH:24][C:25]([O:41]COCC[Si](C)(C)C)=[C:26]([N:28](COCC[Si](C)(C)C)[S:29]([CH3:32])(=[O:31])=[O:30])[CH:27]=1)[CH2:3][NH:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.O.F[B-](F)(F)F.[Li+]>C(#N)C>[OH:41][C:25]1[CH:24]=[CH:23][C:22]([C@@H:2]([OH:1])[CH2:3][NH:4][CH2:5][CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[CH:12][CH:13]=2)=[CH:27][C:26]=1[NH:28][S:29]([CH3:32])(=[O:31])=[O:30]
Reactant: COc1ccc(-c2ccc(OCCNC[C@H](O)c3ccc(OCOCC[Si](C)(C)C)c(N(COCC[Si](C)(C)C)S(C)(=O)=O)c3)cc2)cc1
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(-c2ccc(OCCNC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)cc2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
N-[5-{(R)-1-hydroxy-2-[2-(4′-methoxybiphenyl-4-yloxy)ethylamino]ethyl}-2-(2-trimethylsilylethoxymethoxy)-phenyl]-N-(2-trimethylsilylethoxymethyl)methanesulfonamide was dissolved in acetonitrile (0.25 mL). Water (0.05 mL) and a 1 mol/L solution of lithium tetrafluoroborate in acetonitrile (0.26 mL) were added to the solution, and the mixture was stirred at 80° C. for 3 hrs. The reaction mixture was purified by reverse phase column chromatography (Shiseido Capcell Pak MG ODS, 5 μm, 120 Å, 20×50 mm, Flow rate 30 mL/minute, linear gradient 0.1% aqueous formic acid/acetonitrile=90/10-10/90 over 5 minutes). The fraction was concentrated in vacuo to afford the title compound (0.009 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[N+:10]([O-])([OH:12])=[O:11].O.C(Cl)Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClC(Cl)C>[F:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=1
Reactant: Oc1ccc(F)c(F)c1
Reactant: O=[N+]([O-])O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cc(F)c(F)cc1O
Temperature: 25 °C
Reaction time: 14 h
Yield: 29.7 %

Procedure:
A solution of 3,4-difluorophenol (5.0 g, 38.4 mmol) and tetrabutylammonium bromide (1.239 g, 3.8 mmol) in dichloroethane (30 mL) were added into a 250 mL round-bottomed flask. The mixture was stirred for 45 min before nitric acid (86 g, 96.09 mmol) (7%) was added. The reaction was stirred at RT for 14 h. Water (100 mL) and DCM (50 mL) was added. After stirring for another 10 min, the mixture was partitioned, and the aqueous layer was extracted with DCM (1×20 mL). The combined organic layer was dried (Na2SO4), and concentrated to give the crude product. The crude product was purified by chromatography on silica gel using EtOAc/hexance (0-50%, 30 min). Collected fractions were concentrated to give the title product (2.0 g, 30% yield).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]([F:22])([F:21])[O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:18][C:17]1[CH:19]=[CH:20][C:14]([O:13][C:12]([F:11])([F:21])[F:22])=[CH:15][CH:16]=1
Reactant: Clc1nc2ccccc2s1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Product: FC(F)(F)Oc1ccc(Nc2nc3ccccc3s2)cc1

Procedure:
The title compound was synthesised from 2-chloro-benzothiazole (commercially available) and 4-trifluoromethoxyaniline (commercially available) according to the procedure described for Example A. MS (m/z): 310.0 (MH+, 100%).
Reaction SMILES: [C:1]1(=[O:22])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH:13][C@H:14]([C:18]([OH:20])=O)[CH:15]([CH3:17])[CH3:16])=[O:12])[C:4](=[O:21])[CH:3]=[CH:2]1.[NH2:23][C@H:24]([C:26]([OH:28])=O)[CH3:25].C(OC(N1C2C(=CC=CC=2)C=CC1OCC)=O)C.[NH2:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH2:55][C@H:56]3[CH:62]=[N:61][C:60]4[CH:63]=[C:64]([O:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][O:75][C:76]5[C:77]([O:104][CH3:105])=[CH:78][C:79]6[C:85](=[O:86])[N:84]7[CH:87]=[C:88]([C:90]8[CH:95]=[CH:94][C:93]([O:96][CH2:97][CH2:98][CH2:99][N:100]([CH3:102])[CH3:101])=[CH:92][CH:91]=8)[CH2:89][C@H:83]7[CH:82]=[N:81][C:80]=6[CH:103]=5)[C:65]([O:67][CH3:68])=[CH:66][C:59]=4[C:58](=[O:106])[N:57]3[CH:107]=2)=[CH:50][CH:49]=1>CO.ClCCl>[CH3:102][N:100]([CH3:101])[CH2:99][CH2:98][CH2:97][O:96][C:93]1[CH:92]=[CH:91][C:90]([C:88]2[CH2:89][C@H:83]3[CH:82]=[N:81][C:80]4[CH:103]=[C:76]([O:75][CH2:74][CH2:73][CH2:72][CH2:71][CH2:70][O:69][C:64]5[C:65]([O:67][CH3:68])=[CH:66][C:59]6[C:58](=[O:106])[N:57]7[CH:107]=[C:54]([C:51]8[CH:50]=[CH:49][C:48]([NH:47][C:26](=[O:28])[C@@H:24]([NH:23][C:18](=[O:20])[C@@H:14]([NH:13][C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:5]9[C:1](=[O:22])[CH:2]=[CH:3][C:4]9=[O:21])[CH:15]([CH3:16])[CH3:17])[CH3:25])=[CH:53][CH:52]=8)[CH2:55][C@H:56]7[CH:62]=[N:61][C:60]=6[CH:63]=5)[C:77]([O:104][CH3:105])=[CH:78][C:79]=4[C:85](=[O:86])[N:84]3[CH:87]=2)=[CH:95][CH:94]=1
Reactant: C[C@H](N)C(=O)O
Reactant: COc1cc2c(cc1OCCCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(OCCCN(C)C)cc4)C[C@H]1C=N3)N=C[C@@H]1CC(c3ccc(N)cc3)=CN1C2=O
Reactant: CC(C)[C@H](NC(=O)CCCCCN1C(=O)C=CC1=O)C(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(cc1OCCCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(OCCCN(C)C)cc4)C[C@H]1C=N3)N=C[C@@H]1CC(c3ccc(NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)CCCCCN4C(=O)C=CC4=O)C(C)C)cc3)=CN1C2=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27 %

Procedure:
A flame-dried flask was charged with maleimidocaproyl-valine-alanine linker (Compound 36 in Example 13 of WO 2011/130613 A1) (9 mg, 24 μmol, 1.5 eq) dissolved in 0.33 mL of 5% methanol in anhydrous dichloromethane. The acid was pre-activated by addition of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (7.1 mg, 29 μmol, 1.8 eq), followed by stirring at room temperature under nitrogen for 15 minutes. The activated acid was then added to a flame-dried flask containing PBD dimer 17 (13 mg, 16 μmol, 1 eq). The reaction was stirred for 7 h at room temperature under nitrogen, at which time LC-MS revealed conversion to product. The material was diluted in dichloromethane and purified by radial chromatography on a 1 mm chromatotron plate eluted with CH2Cl2/MeOH mixtures (100:0 to 80:20) to provide 19 (5.1 mg, 27%). LC-MS: tR 9.09 min, m/z (ES+) found 1188.4 (M+H)+.
Reaction SMILES: ClCCC[N:5]1[C:9]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1.[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:17]1.[CH:31](N(C(C)C)CC)([CH3:33])[CH3:32].[I-].[K+]>C(#N)C>[O:14]([C:11]1[CH:12]=[C:13]([CH2:32][CH2:31][CH2:33][N:28]2[CH2:29][CH2:30][CH:25]([C:18]3[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[S:16][N:17]=3)[CH2:26][CH2:27]2)[C:8]2[N:7]=[N:6][NH:5][C:9]=2[CH:10]=1)[CH3:15]
Reactant: COc1ccc2nnn(CCCCl)c2c1
Reactant: c1ccc2c(C3CCNCC3)nsc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(CCCN2CCC(c3nsc4ccccc34)CC2)c2nn[nH]c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.6 %

Procedure:
N-(3-chloropropyl)-6-methoxyl benzotriazole (0.06 mol) was dissolved into 150 ml of acetonitrile, 4-(3-benzisothiazolyl) piperidine (0.05 mol), diisopropylethylamine (0.2 mol) and potassium iodide (0.05 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, purified, eluted with dichloromethane/methanol mixture to produce 13.17 g N-(3-(6-methoxyl benzotriazolyl)propyl)-4-(3-benzisothiazolyl)piperidine (I-100) with a yield of 69.1%. ESI-MS [M+H]+: m/z 426.2.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C([NH:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=1)[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1/[C:19](=[CH:24]\[O:25][CH3:26])/[C:20]([O:22][CH3:23])=[O:21])=O.O.C(=O)(O)[O-].[Na+]>CO>[NH2:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=1)[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1/[C:19](=[CH:24]\[O:25][CH3:26])/[C:20]([O:22][CH3:23])=[O:21]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cccc(NC=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cccc(N)c1
Reaction time: 0.33 h
Yield: 68.6 %

Procedure:
Phosphoryl chloride (7.8 ml) was added dropwise to a stirred solution of (E)-methyl 2-[2-(3-formamidophenoxy)phenyl]-3-methoxypropenoate (13.67 g) in methanol (100 ml), the temperature during the addition being kept below 50° C. with the aid of a cooling bath. After stirring for 20 minutes, the reaction mixture was poured into water (500 ml), neutralized with sodium bicarbonate and extracted with ether. The extracts were dried and concentrated to give a yellow oil which was chromatographed using ether as the eluant to give (E)-methyl 2-[2-(3-aminophenoxy)phenyl]-3-methoxypropenoate (8.57 g, 68% yield) as a yellow solid, m.p. 83°-85° C.
Reaction SMILES: [N:1]([C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15](=[O:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([F:23])[CH:17]=3)=[CH:9][CH:8]=1)([CH3:6])[CH3:5])=[N+]=[N-].C(O)(=O)C.[ClH:29].CO>C1COCC1.[Zn]>[ClH:29].[NH2:1][C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15](=[O:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([F:23])[CH:17]=3)=[CH:9][CH:8]=1)([CH3:6])[CH3:5]
Reactant: CC(C)(N=[N+]=[N-])c1ccc(-c2cc3ccc(F)cc3c(=O)[nH]2)cc1
Agent: Cl
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(N)c1ccc(-c2cc3ccc(F)cc3c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-[4-(1-azido-1-methyl-ethyl)-phenyl]-7-fluoro-2H-isoquinolin-1-one (141 mg, 0.44 mmol) in 4 ml THF are added zinc dust (143 mg, 2.19 mmol) and acetic acid (250 μl, 4.37 mmol) and the mixture is stirred for 18 hours at room temperature. The suspension is diluted with THF and acidified with a small amount of 25% hydrochloric acid to obtain a clear solution. More THF and methanol are added. The mixture is filtered and the filtrate is evaporated. The residue is triturated with water, the solids are filtered off, washed with water and dried under vacuum to afford 3-[4-(1-amino-1-methyl-ethyl)-phenyl]-7-fluoro-2H-isoquinolin-1-one hydrochloride as white solid;