Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[C:12]([CH2:14][CH:15]([CH2:18][OH:19])[CH2:16][OH:17])#[N:13].[OH-:20].[Na+]>C1C=CC=CC=1.[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[C:12]([CH2:14][CH:15]([CH2:18][O:19][S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:2])=[O:20])[CH2:16][O:17][S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])#[N:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CCC(CO)CO
Reactant: [OH-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)OCC(CC#N)COS(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
A solution of 60 g tosylchloride in 400 ml benzene is added to a stirred and cooled mixture of 17.5 g 2-cyanomethyl1,3 propanediol, 1.3 g triethylbenzylammonium chloride and 150 ml 30% (w/w) aqueous NaOH solution. This mixture is stirred overnight. The organic and aqueous layers are separated and the aqueous layer is washed with diethylether. The combined organic phase is washed with water until neutral, dried and evaporated. 2-Cyanomethyl-1,3-bis(tosyloxy)propane is obtained in a obtained in a yield of 62 g; liquid. Identification by means of IR, NMR and mass spectra.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][O:11][C:5]=2[CH:4]=1)#[CH:2].I[C:17]1[CH:18]=[CH:19][C:20]2[O:24][CH2:23][CH2:22][C:21]=2[CH:25]=1>>[O:24]1[C:20]2[CH:19]=[CH:18][C:17]([C:2]#[C:1][C:3]3[CH:15]=[CH:14][C:6]4[O:7][CH2:8][C:9]([CH3:12])([CH3:13])[CH2:10][O:11][C:5]=4[CH:4]=3)=[CH:25][C:21]=2[CH2:22][CH2:23]1
Reactant: C#Cc1ccc2c(c1)OCC(C)(C)CO2
Reactant: Ic1ccc2c(c1)CCO2
Product: CC1(C)COc2ccc(C#Cc3ccc4c(c3)CCO4)cc2OC1

Procedure:
The title compound is prepared in analogy to example 1 from 7-ethynyl-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine (6) (example 1d) and 5-iodo-2,3-dihydro-benzofuran. MS (ESI) 320.1 (M•)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.OO.C([O-])([O-])=O.[K+].[K+].O=P(Cl)(Cl)[Cl:23]>C(O)(C(F)(F)F)=O.CCCCCCC.CCOC(C)=O>[Br:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][C:7]=1[Cl:23]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1nc(Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(Cl)cc(Cl)c1Br
Temperature: 60 °C
Yield: 49 %

Procedure:
To a stirred solution of methyl 3-bromo-6-chloropyridine-2-carboxylate (1.92 g, 7.67 mmol) in TFA (18 ml) was added hydrogen peroxide (30% w/w aqueous solution, 5.22 ml, 53.7 mmol) and the reaction mixture was heated at 60° C. for 21 h. The reaction mixture was then cooled and slowly poured onto saturated K2CO3 solution (100 ml), followed by extraction of the aqueous layer with EtOAc (3×100 ml), washing of the combined organic phases with brine (2×50 ml), drying (Na2SO4) and evaporation. The desired 3-bromo-6-chloro-2-(methoxycarbonyl)pyridin-1-ium-1-olate (2.61 g, ˜75% purity) was used crude in the next stage of the synthesis without any further purification. To the crude 3-bromo-6-chloro-2-(methoxycarbonyl)pyridin-1-ium-1-olate (˜75% purity, 2.61 g, 7.35 mmol) was added POCl3 (3.42 ml, 36.7 mmol) and the solution was heated to 100° C. for 4 h. After cooling the POCl3 was remove in vacuo to give a white solid which was columned over silica eluting with 0% to 10% of EtOAc in heptane to afford the title compound as a pale yellow powder (1.07 g, 49% over two steps). LC-MS 99%, 2.02 min (3.5 minute LC-MS method), m/z=283.7/285.7/287.7, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.56 (s, 1H) 4.00 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8](F)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16].[CH3:19][O:20][C:21]([C:23]1[N:24]=[CH:25][NH:26][CH:27]=1)=[O:22]>O1CCCC1.CS(C)=O>[CH3:19][O:20][C:21]([C:23]1[N:24]=[CH:25][N:26]([C:8]2[CH:9]=[C:4]([C:3]([O:2][CH3:1])=[O:18])[C:5]([N+:15]([O-:17])=[O:16])=[CH:6][C:7]=2[C:11]([F:14])([F:13])[F:12])[CH:27]=1)=[O:22]
Reactant: COC(=O)c1c[nH]cn1
Reactant: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cn(-c2cc(C(=O)OC)c([N+](=O)[O-])cc2C(F)(F)F)cn1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
A solution of 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid methyl ester (1 g, 3.74 mmol) and 1H-imidazole-4-carboxylic acid methyl ester (0.53 g, 4.12 mmol) in 10 ml of tetrahydrofuran and 2 ml of DMSO is heated to reflux for 90 hours. The solution is allowed to 5 cool to room temperature and evaporated. The residue is crystallized from dichloromethane and hexane to give 1.12 g (3 mmol, 80%) of 1-(5-methoxycarbonyl-4-nitro-2-trifluoromethyl-phenyl) -1H-imidazole-4-carboxylic acid methyl ester, m.p. 136 -138° C., ES-MS: m/z 374 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:24])=[C:19]([CH:23]=1)[C:20](Cl)=[O:21]>C(Cl)Cl>[F:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:24])=[C:19]([C:20]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:21])[CH:23]=1
Reactant: C1COCCN1
Reactant: Cc1ccc(F)cc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(F)cc1C(=O)N1CCOCC1
Reaction time: 0.25 h
Yield: 98.1 %

Procedure:
To a solution of morpholine (870 mg, 10 mmol) and triethylamine (1.1 g, 10.8 mmol) in CH2Cl2 (15 mL) was added a solution of 5-fluoro-2-methylbenzoyl chloride (1.72 g, 10 mmol) in CH2Cl2 (5 mL), dropwise, and the mixture stirred for 15 min. The mixture was then washed with water, and the organic phase dried (MgSO4), filtered, and concentrated to obtain 2.19 g (Yield 98%) of the title compound as a solid: 1H NMR (500 MHz, CDCl3) δ ppm: 2.27 (3H, s) 3.24 (2H, d, J=4 Hz) 3.58 (2H, s) 3.79 (4 H, dd, J=18, 3.8 Hz) 6.88 (1H, dd, J=8.2, 2.8 Hz) 6.92-7.05 (1 H, m) 7.18 (1 H, dd, J=8.4, 5.3 Hz).
Reaction SMILES: [N:1]1([CH2:7][CH:8]=O)[CH2:6][CH2:5][CH2:4][N:3]=[CH:2]1.[NH3:10].[H][H]>[Ni].C(O)C>[NH2:10][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][CH2:4][N:3]=[CH:2]1
Reactant: O=CCN1C=NCCC1
Reactant: [H][H]
Reactant: N
Agent: [Ni]
Solvent: CCO
Product: NCCN1C=NCCC1

Procedure:
A suspension of 0.20 g. of Raney nickel, 6.3 g. of 1,4,5,6-tetrahydropyrimidine-1-acetaldehyde and 1.7 g. of ammonia in 50 ml. of ethanol is shaken under 20 atmospheres of hydrogen at 40° C. until one equivalent is absorbed. The catalyst is filtered off and the solvent is removed in vacuo to give 1-(2-aminoethyl)-1,4,5,6-tetrahydropyrimidine.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.[Cl:17][C:18]1[CH:19]=[C:20]([F:42])[C:21]([C:40]#[N:41])=[C:22]([C:24]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)=[N:25]S(C(C)(C)C)=O)[CH:23]=1.Cl.CO>C1COCC1>[Cl:17][C:18]1[CH:23]=[C:22]2[C:21]([C:40]([NH2:41])=[N:25][C:24]2([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)[C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)=[C:20]([F:42])[CH:19]=1
Reactant: COc1cccc(C(=NS(=O)C(C)(C)C)c2cc(Cl)cc(F)c2C#N)c1
Reactant: FC(F)(F)c1cc(Br)ccn1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(C2(c3ccnc(C(F)(F)F)c3)N=C(N)c3c(F)cc(Cl)cc32)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 39.2 %

Procedure:
tert-Butyllithium (1.7 M in pentane, 6.59 mL, 11.20 mmol) was added dropwise to THF (10 mL) at −100° C. under an argon atmosphere. A solution of 4-bromo-2-trifluoromethylpyridine (1.266 g, 5.60 mmol) in THF (1 mL) was added dropwise followed by the addition of N-((5-chloro-2-cyano-3-fluorophenyl)(3-methoxyphenyl)methylene)-2-methylpropane-2-sulfinamide (2 g, 5.09 mmol) in THF (6 mL). The resulting reaction mixture was left on the thawing cooling bath for 30 min then the cooling bath was removed and the mixture was stirred at rt for 1.5 h. Hydrogen chloride in methanol solution (20.36 mL, 25.45 mmol) was added and the mixture was stirred at rt for 1 h. The mixture was concentrated and purified on a silica gel column eluted with 0-10% 0.1M NH3 in MeOH in DCM to afford 870 mg (39%) of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[H-].[Na+].[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1.CN(C=O)C>C1COCC1>[ClH:13].[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[N:17]=[CH:16][N:15]=[C:14]2[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccncc1
Reactant: O=C1Cc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2c(C3C(=O)Nc4ccccc43)ncnc2cc1OCc1ccncc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.8 %

Procedure:
A solution of oxindole (232 mg, 1.74 mmol) in THF (3 ml) was added dropwise under nitrogen, to sodium hydride (70 mg, 1.74 mmol, prewashed with hexane) in THF (3 ml). The mixture was stirred for 30 minutes at ambient temperature and 4-chloro-6-methoxy-7-(4-pyridylmethoxy)quinazoline (175 mg, 0.58 mmol) and then DMF (2 ml) was added. The mixture was heated at 60° C. for 1 hour and the THF was removed by evaporation. The residue was partitioned between cooled 2M hydrochloric acid and ethyl acetate. The organic layer was extracted with 2M hydrochloric acid. The aqueous layers were combined, washed with ethyl acetate and ether, basified with aqueous sodium hydrogen carbonate and extracted with methylene chloride. The organic layer was washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by chromatography on neutral aluminium oxide eluting with methylene chloride/methanol (90/10 followed by 80/20 and 75/25). The purified solid product was dissolved in methanol/methylene chloride and SM methanolic hydrogen chloride (0.5 ml) was added. The volatiles were removed by evaporation, the residue was resuspended in ether, collected by filtration, washed with ether and dried under vacuum to give 6-methoxy4-(oxindol-3-yl)-7-(4-pyridylmethoxy)quinazoline hydrochloride (50 mg, 21%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([N:9]1[CH:18]=[C:17]3[CH2:19][CH2:20][CH2:21][C:15]4[C:16]3=[C:11]([CH:12]=[CH:13][CH:14]=4)[C:10]1=[O:22])[CH2:2]2.[Cl:23](O)(=O)(=O)=O>C(O)(=O)C>[CH:13]1[CH:12]=[C:11]2[C:10]([N:9]([C@H:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)[CH2:18][C@H:17]3[CH2:19][CH2:20][CH2:21][C:15](=[C:16]23)[CH:14]=1)=[O:22].[ClH:23]
Reactant: [O-][Cl+3]([O-])([O-])O
Reactant: O=c1c2cccc3c2c(cn1C1CN2CCC1CC2)CCC3
Solvent: CC(=O)O
Product: Cl
Product: O=C1c2cccc3c2[C@H](CCC3)CN1[C@@H]1CN2CCC1CC2

Procedure:
Palonosetron hydrochloride was prepared from 2-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1H-benz[de]isoquinolin-1-one of formula-H using acetic acid and perchloric acid as reaction solvent
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:8]=[C:7]([C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=1.[C:12]1([S:18]([N:21]2[C:29]3[CH:28]=[C:27]([C:30]4[CH:31]=[C:32]5[CH:38]=[N:37][N:36]([S:39]([C:42]6[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=6)(=[O:41])=[O:40])[C:33]5=[N:34][CH:35]=4)[CH:26]=[C:25]([NH2:48])[C:24]=3[CH:23]=[N:22]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.O>C(Cl)(Cl)Cl>[Cl:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([NH:48][C:25]2[CH:26]=[C:27]([C:30]3[CH:31]=[C:32]4[CH:38]=[N:37][N:36]([S:39]([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)(=[O:41])=[O:40])[C:33]4=[N:34][CH:35]=3)[CH:28]=[C:29]3[C:24]=2[CH:23]=[N:22][N:21]3[S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: Nc1cc(-c2cnc3c(cnn3S(=O)(=O)c3ccccc3)c2)cc2c1cnn2S(=O)(=O)c1ccccc1
Reactant: O=C(Cl)c1cccc(CCl)n1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2cnc3c(cnn3S(=O)(=O)c3ccccc3)c2)cc2c1cnn2S(=O)(=O)c1ccccc1)c1cccc(CCl)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-(hydroxymethyl)-2-pyridinecarboxylic acid (500 mg, 3.27 mmol) in chloroform (10 ml) and N,N-dimethylformamide (DMF) (0.1 ml) was added thionyl chloride (1 ml, 13.70 mmol) and the mixture heated at 65° C. for 1 hr. Solvent was removed in vacuo and the residue was azeotroped with chloroform (5 ml) then dried on a high vacuum line for 30 mins to afford an orange oil (650 mg), presumed to be 6-(chloromethyl)-2-pyridinecarbonyl chloride. To solution of 1-(phenylsulfonyl)-6-[1-(phenylsulfonyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-1H-indazol-4-amine (581 mg, 1.095 mmol) in chloroform (5 ml) at 0° C. was added DIPEA (0.383 ml, 2.190 mmol). 6-(chloromethyl)-2-pyridinecarbonyl chloride (330 mg, 1.737 mmol) in chloroform (5 ml) was added dropwise and the mixture was stirred at 0° C. for 15 min then allowed to warm to room temperature and stirred for another 30 mins. Water (10 ml) was added to quench the reaction and the mixture was extracted with DCM (2×20 ml), separating the layers using a hydrophobic frit. The solvent was removed in vacuo to give a brown solid, which was triturated with ether (5 ml). The resultant cream solid was filtered off and dried in a vacuum oven for 30 mins to afford the title compound (658 mg).
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:11][C:12]1[C:21](Cl)=[N:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1.O(C(C)(C)C)[K]>>[Cl:11][C:12]1[C:21]([O:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: OCCOc1ccccc1
Reactant: Clc1nc2ccccc2nc1Cl
Agent: CC(C)(C)O[K]
Product: Clc1nc2ccccc2nc1OCCOc1ccccc1

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step 1, starting from 2-phenoxyethanol (3.7 g, 26.8 mmol), 2,3-dichloroquinoxaline (1.33 g, 6.7 mmol) and KO-t-Bu (0.75 g, 6.7 mmol): yield 0.74 g (37%); mp 99.5-101.5° C.; HRMS mn/z calcd for C16H13ClN2O2 (M)+ 300.0666, found 300.0672. Anal. (C16H13ClN2O2) C, H, N.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14].CCCCCC.CCOC(C)=O>CC#N>[CH2:17]([O:16][C:12](=[O:15])[CH2:13][CH2:14][N:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[CH:9]1)[CH3:18]
Reactant: C=CC(=O)OCC
Reactant: c1ccc(-c2c[nH]cn2)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCCCCC
Product: CCOC(=O)CCn1cnc(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
4-Phenylimidazole (1.884 g, 13 mmol) and KF/Al2O3 (0.113 g, 10 mol %) were dissolved in 30 mL of CH3CN, added with ethyl acrylate (1.301 g, 13 mmol) and stirred at room temperature. Initiation and termination of the reaction were confirmed by TLC (hexane:EtOAc=1:1). Upon completion of the reaction, KF/Al2O3 was filtrated under reduced pressure, water was added to the reaction mixture, and the aqueous phase was extracted with methylene chloride. The organic layer was dried with MgSO4, filtrated and then concentrated under reduced pressure to obtain the target compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[C:22]([O:26][CH3:27])=[CH:23][CH:24]=[CH:25][C:20]=3[Cl:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1cccc(Cl)c1B(O)O
Product: CCCNC(=O)c1nnc2c(-c3c(Cl)cccc3OC)cccc2c1N
Yield: 36.5 %

Procedure:
Using Method G, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (600 mg) and 2-chloro-6-methoxy-phenylboronic acid (1051 mg) were reacted to afford the title compound (263 mg) as a off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.55(br, 1H), 7.94-7.88 (m, 1H), 7.79-7.65 (m, 2H), 7.37-7.29 (m, 1H), 7.15 (m, 1H), 6.94 (m, 1H), 3.65 (s, 3H), 3.44 (apparent quartet, J=7.0 Hz, 2H), 1.64 (apparent sextet, J=7.0 Hz, 2H), 0.99 (t, J=7.0 Hz, 3H). MS APCI, m/z=371 (M+H) HPLC 1.86 min.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:10][C:9]=1[OH:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[C:22]([NH:30][C:31](OC2C=CC=CC=2)=[O:32])[C:23](=[CH:28][CH:29]=1)[C:24]([O:26][CH3:27])=[O:25]>>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:31]([NH:30][C:22]2[CH:21]=[C:20]([Cl:19])[CH:29]=[CH:28][C:23]=2[C:24]([O:26][CH3:27])=[O:25])=[O:32])(=[O:16])=[O:15])=[CH:10][C:9]=1[OH:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(S(N)(=O)=O)cc1O
Product: COC(=O)c1ccc(Cl)cc1NC(=O)NS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(O)c1
Yield: 100.9 %

Procedure:
From 1.0 g (3.66 mmol) of 4-t-butoxycarbonyl-3-hydroxybenzenesulfonamide and 1.12 g (3.66 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate in a similar manner to Preparation Example 7, 1.79 g (yield 100%) of methyl 2-{[(4-t-butoxycarbonyl-3-hydroxybenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate (property: colorless amorphous, PMR (δppm, DMSO-d6): 1.57 (9H, s), 3.87 (3H, s), 7.14 (1H, d), 7.40-7.45 (2H, m), 7.85 (1H, d), 7.92 (1H, d), 8.32 (1H, d), 10.13 (1H, s), 10.82 (1H, s)) was obtained.
Reaction SMILES: Cl.Cl.N[C:4]1[CH:10]=[C:9]([NH2:11])[C:7]([OH:8])=[CH:6][C:5]=1O.[CH3:13]S(O)(=O)=O.O(C1C=CC(OC2C=CC=CC=2)=CC=1)C1C=CC=CC=1>>[O:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[CH:10][C:9]=2[N:11]=[CH:13]1
Reactant: Nc1cc(N)c(O)cc1O
Reactant: CS(=O)(=O)O
Agent: Cl
Agent: c1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1
Product: c1ccc2ocnc2c1
Temperature: 95 °C
Reaction time: 48 h

Procedure:
Under nitrogen atmosphere, 1.00 g (4.69 mmoles) of 4,6-diaminoresorcinol dihydrochloride and 1.62 g (6.26 mmoles) of oxy-bis(4-benzoic acid) are mixed and 29.1 ml of 10-1 methanesulfonic acid solution is added. The mixture is stirred and heated to 95° C. for 24 hours and then cooled to 50° C. A 0.41-g (1.56-mmole) quantity of p-diphenoxybenzene is added and stirring is continued at 50° C. for 48 hours. The resulting copolymer is precipitated in aqueous potassium hydroxide in a blender, washed with water until neutral and dried to constant weight in a vacuum oven at about 50° C. Its inherent viscosity in concentrated sulfuric acid at 25° C. and about 0.2028 g/dL concentration is measured to be about 0.99 dL/g. Its inherent viscosity in methanesulfonic acid at about 0.05 g/dL concentration and about 25° C. is measured to be 4.42 dL/g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:30])[CH:12]2[CH2:29][N:16]3[C:17]4[C:22]([C:23]([CH2:24][C:25]([O:27]C)=[O:26])=[C:15]3[CH2:14][CH2:13]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO.[Li+].[OH-].CC(O)=O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:30])[CH:12]2[CH2:29][N:16]3[C:17]4[C:22]([C:23]([CH2:24][C:25]([OH:27])=[O:26])=[C:15]3[CH2:14][CH2:13]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1c2n(c3ccccc13)CC(N(C)S(=O)(=O)c1ccc(F)cc1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CN(C1CCc2c(CC(=O)O)c3ccccc3n2C1)S(=O)(=O)c1ccc(F)cc1
Reaction time: 2 h
Yield: 49 %

Procedure:
To a solution of the product of Step 11 (0.38 g) in 10 mL of THF were added 5 mL of MeOH and 5 mL of 1N LiOH. After stirring for 2 h, 2 mL of AcOH was added and the mixture was partitioned between 50 mL of EtOAc and 20 mL of brine. The EtOAc extract was dried over Na2SO4 and filtered. The filtrate was concentrated and the residue was swished from 3:1 EtOAc/hexane to give 0.18 g of the title compound. 1H NMR (500 MHz, acetone-d6) δ 8.11 (m, 2H), 7.53 (d, 1H), 7.47 (t, 2H), 7.28 (d, 1H), 7.10 (dd, 1H), 7.04 (dd, 1H), 4.53 (m, 1H), 4.20 (m, 1H), 3.90 (t, 1H), 3.67 (d, 1H, A of AB), 3.60 (d, 1H, B of AB), 3.15 (m, 1H), 2.97 (3H), 2.85-2.92 (m, 1H), 1.90-2.00 (m, 1H), 1.70 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:33])[C:5]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][CH:7]=1.[NH:34]1[CH:38]=[CH:37][N:36]=[C:35]1[NH:39][C:40](N1C=CN=C1)=[O:41].CCN(C(C)C)C(C)C>CN(C=O)C>[NH:34]1[CH:38]=[CH:37][N:36]=[C:35]1[NH:39][C:40]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:8][C:5]2[C:4]([CH3:33])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:16][C:17]2[C:22]([C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12]1)=[O:41]
Reactant: O=C(Nc1ncc[nH]1)n1ccnc1
Reactant: Cc1cc(Cl)cnc1CN(Cc1ncccc1C(C)(C)c1ccc(F)cc1)C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Cl)cnc1CN(Cc1ncccc1C(C)(C)c1ccc(F)cc1)C1CCN(C(=O)Nc2ncc[nH]2)CC1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
The amine from above (131 mg, 0.28 mmol), and imidazole-1-carboxylic acid (1H-imidazol-2-yl)-amide (168 mg, 0.56 mmol) were combined in DMF (4.0 mL) and treated with DIPEA (0.29 mL, 1.7 mmol). The solution was stirred at 75° C. for 2 hours and then concentrated under reduced pressure. This afforded, after column chromatography with silica gel (25:1:0.1 CH2Cl2:MeOH:NH4OH), COMPOUND 307 (72 mg, 45%). 1H NMR (CDCl3): δ 1.30 (q, 2H, J=11.1 Hz), 1.59 (s, 6H), 1.66 (d, 2H, J=12.3 Hz), 2.26 (s, 3H), 2.61 (br t, 3H, J=11.7 Hz), 3.35 (s, 2H), 3.65 (s, 2H), 4.14 (d, 2H, J=13.2 Hz), 6.68 (s, 2H), 6.86 (m, 4H), 7.19 (br, 2H), 7.37 (s, 1H), 7.82 (d, 1H, J=7.5 Hz), 8.20 (s, 1H), 8.48 (br d, 1H). 13C NMR (CDCl3) δ 18.40, 18.81, 28.08 (2C), 31.12 (2C), 42.14, 44.20 (2C), 54.06, 54.67, 58.01, 115.13 (d, 2C, J=84 Hz), 121.44, 127.07 (d, 2C, J=30 Hz), 130.07, 133.81, 134.84, 137.31, 142.96, 144.59 (2C), 145.07, 145.36, 146.61 (2C), 155.31, 155.96, 157.96, 161.91 (d, 1C, 975 Hz). ES-MS m/z 577 (M+H). Anal. Calcd. for C31H35N7OClF.0.2CH2Cl2O.0.2H2O: C, 62.46; H, 6.02; N, 16.32; Cl, 8.85; F, 3.16. Found: C, 62.60; H, 6.02; N, 16.09; Cl, 8.79; F, 2.94.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:28]([F:31])([F:30])[F:29])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[N:18]([CH2:24][C:25]([OH:27])=O)[N:17]=[CH:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:28]([F:29])([F:31])[F:30])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[N:18]([CH2:24][C:25]([NH:35][CH2:34][C:33]([F:37])([F:36])[F:32])=[O:27])[N:17]=[CH:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: NCC(F)(F)F
Reactant: O=C(O)Cn1ncc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc2c1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Cn1ncc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc2c1=O)NCC(F)(F)F
Reaction time: 18 h
Yield: 63.8 %

Procedure:
To a stirred solution of (E)-2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1-oxophthalazin-2(1H)-yl)acetic acid (0.15 g, 0.31 mmol) in CH2Cl2 (20.0 ml) was added 2,2,2,-trifluoroethanamine (0.03 g, 0.31 mmol), PyBOP (0.17 g, 0.34 mmol) and DIPEA (0.15 ml, 0.93 mmol) at ambient temperature, and the reaction was stirred for 18 h. The reaction mixture was diluted with CH2Cl2 and washed with 3N HCl (2×20 mL), NaHCO3 (2×20 mL) and brine solution (2×). The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 20-25% EtOAc/petroleum ether) to afford the title compound as a brown solid (0.11 g): mp 172-175° C.; 1H NMR (400 MHz, CDCl3) δ 8.83 (t, J=6.6 Hz, 1H), 8.42 (t, J=14.7 Hz, 1H), 8.22 (d, J=8.1 Hz, 1H), 8.13 (t, J=6.3 Hz, 1H), 7.98-7.86 (m, 2H), 7.16-7.07 (m, 1H), 7.01-6.93 (m, 1H), 4.96-4.81 (m, 3H), 4.00-3.88 (m, 2H); ESIMS m/z 554.0 ([M−H]−).