Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[S:25][C:24]3[CH:23]=[C:22]([CH2:26][CH3:27])[N:21]([CH2:28][C:29](=[O:36])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:20](=[O:37])[C:19]=3[C:18]=2[O:38][CH2:39][CH3:40])=[O:16])[CH2:10][CH2:9]1)=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO.O>C1COCC1>[CH2:39]([O:38][C:18]1[C:19]2[C:20](=[O:37])[N:21]([CH2:28][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:22]([CH2:26][CH3:27])=[CH:23][C:24]=2[S:25][C:17]=1[C:15]([NH:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6](=[O:7])[CH2:5][OH:4])[CH2:9][CH2:10]1)=[O:16])[CH3:40]
Reactant: CCOc1c(C(=O)NC2CCN(C(=O)COC(C)=O)CC2)sc2cc(CC)n(CC(=O)c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOc1c(C(=O)NC2CCN(C(=O)CO)CC2)sc2cc(CC)n(CC(=O)c3ccccc3)c(=O)c12
Yield: 67.6 %

Procedure:
A mixed solution of 2-[4-({[3-ethoxy-6-ethyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno[3,2-c]pyridin-2-yl]carbonyl}amino)piperidin-1-yl]-2-oxoethyl acetate (90 mg, 0.18 mmol) and potassium carbonate (39 mg, 0.28 mmol) in THF (8 mL)-methanol (2 mL)-water (2 mL) was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the residue was partitioned between ethyl acetate and saturated sodium hydrogen carbonate solution. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (64 mg, 69%) as white crystals.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([N:11]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:12](=[O:19])[N:13]([CH3:18])[C:14]3=[O:17])=[N:9]2)=[CH:3][CH:2]=1.[Li+].CC([N-]C(C)C)C.[I:38]I>C1COCC1>[C:1]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[C:16]([I:38])=[C:15]3[C:10]([N:11]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:12](=[O:19])[N:13]([CH3:18])[C:14]3=[O:17])=[N:9]2)=[CH:5][CH:6]=1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2cn(Cc3ccc(-c4ccccc4)cc3)nc21
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(I)n(Cc3ccc(-c4ccccc4)cc3)nc21
Temperature: -78 °C

Procedure:
2-(biphenyl-4-ylmethyl)-7-isobutyl-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (203 mg, 0.523 mmol) is dissolved in anhydrous THF (5 mL), and then cooled to −78° C. 1.8 M solution of LDA in THF (600 uL) is added dropwise with rigorous stirring at −78° C., followed by the addition of iodine (160 mg, 0.63 mmol) in THF. The reaction mixture is stirred at −78° C. for an hour, and then is allowed to warm up to room temperature before quenching. The mixture is poured into saturated NH4Cl solution, and then extracted with ethyl acetate three times. The combined organic phase is washed with potassium iodide aqueous solution (1 M), water, and then dried over Na2SO4. Solvent is removed under reduced vacuum to give crude product was white solids. MS (ESI) m/z 515.1 [M+H]+.
Reaction SMILES: O=C1C(=[C:11]([C:14]#[N:15])[C:12]#[N:13])C2C(=CC=C(S(N3CCCC3COC3C=CC=CC=3)(=O)=O)C=2)N1.[Br:32][C:33]1[CH:66]=[CH:65][C:36]([CH2:37][N:38]2[C:46]3[C:41](=[CH:42][C:43]([S:47]([N:50]4[CH2:54][CH2:53][CH2:52][CH:51]4[CH2:55][O:56][C:57]4[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=4)(=[O:49])=[O:48])=[CH:44][CH:45]=3)[C:40](=O)[C:39]2=[O:64])=[CH:35][CH:34]=1>>[Br:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:37][N:38]2[C:46]3[C:41](=[CH:42][C:43]([S:47]([N:50]4[CH2:54][CH2:53][CH2:52][CH:51]4[CH2:55][O:56][C:57]4[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=4)(=[O:49])=[O:48])=[CH:44][CH:45]=3)[C:40](=[C:11]([C:14]#[N:15])[C:12]#[N:13])[C:39]2=[O:64])=[CH:65][CH:66]=1
Reactant: O=C1C(=O)N(Cc2ccc(Br)cc2)c2ccc(S(=O)(=O)N3CCCC3COc3cccnc3)cc21
Reactant: N#CC(C#N)=C1C(=O)Nc2ccc(S(=O)(=O)N3CCCC3COc3ccccc3)cc21
Product: N#CC(C#N)=C1C(=O)N(Cc2ccc(Br)cc2)c2ccc(S(=O)(=O)N3CCCC3COc3cccnc3)cc21
Yield: 45 %

Procedure:
2-{1-(4-Bromo-benzyl)-2-oxo-5-[2-(pyndine-3-yloxymethyl)-pyrrolidine-1-sulfonyl]-1,2-dihydro-indol-3-yl-idene}-malononitrile (30c) was prepared according to the same procedure for compound 26 except using 28c, to afford 16 mg (45%) of 30c as a purple solid, mp 232.3° C. (decomp). 1H NMR (300 MHz, CDCl3) δ 8.50 (s, 1H), 8.21 (m, 1H), 8.16 (s, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.51 (d, J=8.1 Hz, 2H), 7.20 (m, 4H), 6.84 (d, J=8.7 Hz, 1H), 4.89 (m, 2H), 4.20 (m, 1H), 4.02 (m, 2H), 2.05-1.78 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([NH:35][CH:32]4[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]4)=[O:23])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Reactant: CS(=O)(=O)N1CCC(N)CC1
Product: CS(=O)(=O)N1CCC(NC(=O)c2cnn3ccc(N4CCC[C@@H]4c4cncc(F)c4)nc23)CC1
Yield: 100 %

Procedure:
Prepared by the method as described in Example 1 using (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation I) and 1-(methylsulfonyl)piperidin-4-amine to yield the title compound as a white solid (44 mg, 100% yield). MS (apci) m/z=488.1 (M+H).
Reaction SMILES: [C:1]1([NH2:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)=O.[BH4-].[Na+].[OH-].[Na+]>CO>[NH:7]([CH2:8][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)c1ccccc1-c1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccccc1-c1ccc(CNc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.2 %

Procedure:
Phenylamine (56 mg) was added to the compound (120 mg) prepared in Example 4 in methanol solution (3 mL) and stirred for 4 hours at room temperature. The reaction mixture was added to sodium borohydride (37 mg) and stirred for 1.5 hours. To alkalinize, 5 mol/L sodium hydroxide solution was added to the concentrated reaction mixture and then extracted with ethyl acetate. The organic layer was washed with saturated sodium and dried by anhydrous sodium sulfate, and then concentrated to obtain the titled compound (124 mg) having the following physical data by purifying the obtained residue by silica gel column chromatography (diethyl ether:hexane=1:2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)=[N:6][CH:7]=1
Reactant: Clc1ccc(Br)cn1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccc(Br)cn2)CC1
Temperature: 120 °C
Yield: 62 %

Procedure:
5-Bromo-2-chloropyridine (1.0 g), N-methylpiperazine (1.56 g, 3 eq), and potassium carbonate (2.16 g, 3 eq) were combined in N-methylpyrrolidinone (5 mL) and heated to 120° C. overnight. The crude mixture was then cooled to room temperature and diluted with water. The solid product was collected by filtration, then washed with more water and dried under vacuum (824 mg, 62% yield). 1H-NMR (300 MHz, CDCl3) δ 8.18 (d, 1H), 7.50 (dd, 1H), 6.53 (d, 1H), 3.50 (m, 4H), 2.50 (m, 4H), 2.33 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([NH:8][S:17]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)(=[O:19])=[O:18])=[N:6][CH:7]=1
Reactant: Cc1cc(Cl)cnc1N
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Product: Cc1cc(Cl)cnc1NS(=O)(=O)c1ccc(F)cc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 47.6 %

Procedure:
To a solution of 5-chloro-3-methylpyridin-2-amine (500 mg, 3.51 mmol) in pyridine (7 mL) stirred in air at room temperature was added a solution of 4-fluorobenzene-1-sulfonyl chloride (819 mg, 4.21 mmol) in pyridine (7 mL). The reaction mixture was stirred at 20° C. for 16 hours then the solvent was evaporated in vacuo. The crude was passed through an aminopropyl (NH2) solid phase extraction (SPE) cartridge eluting with methanol followed by 2M ammonia/methanol, then a sulphonic acid (SCX) SPE cartridge eluting with methanol followed by 2M ammonia/methanol. The appropriate fractions were combined and evaporated under a stream of nitrogen to give the crude product. The crude was purified by flash silica (Si) chromatography (0-100% ethyl acetate-cyclohexane+0-20% methanol gradient). The appropriate fractions were combined and evaporated in vacuo to give the title compound (502 mg) as an off-white solid. LCMS (2 min, formic) Rt 1.02 min, m/z (ES+) 301 (M+H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[CH:24]=[C:23]([F:25])[C:22](Br)=[CH:21][C:20]=1[O:27][CH3:28])[C:14]([CH3:29])=[CH:13][C:12]2=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[C:20]([O:27][CH3:28])=[CH:21][C:22]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=3)=[C:23]([F:25])[CH:24]=1)[C:14]([CH3:29])=[CH:13][C:12]2=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(Br)c(F)cc1-n1c(C)cc(=O)c2cc(SCc3ccccc3)ccc21
Reactant: OB(O)c1cccc(F)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: O
Solvent: C1COCCO1
Product: COc1cc(-c2cccc(F)c2)c(F)cc1-n1c(C)cc(=O)c2cc(SCc3ccccc3)ccc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a suspension of 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-methylquinolin-4(1H)-one (1.0 g, 2.06 mmol) and 3-fluorophenylboronic acid (0.462 g, 3.30 mmol) in 1,4-dioxane (7.74 mL) and water (2.58 mL) was added potassium carbonate (0.856 g, 6.19 mmol) and tetrakis(triphenylphosphine)palladium (0.239 g, 0.206 mmol). The reaction was sparged with argon and then stirred at 80° C. After 1 hour, the reaction mixture was partitioned between water and ethyl acetate, and the organic layer was concentrated. The crude product was purified by column chromatography, eluting with 10-50% (3:1 ethyl acetate/ethanol) in heptane to provide 6-(benzylthio)-1-(2,3′-difluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-2-methylquinolin-4(1H)-one (1.0 g, 2.0 mmol, 97% yield) as a yellow oil. m/z (ESI) 500.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:20]([N:21]([CH3:37])[C:22](=[O:36])[CH2:23][NH:24][C:25](=[O:35])[CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)=[CH:19][CH:18]=[C:17]([Cl:38])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.C(OC([N:46]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:47](=[NH:51])SOC)=O)(C)(C)C>C(O)C.[Hg]=O>[Cl:1][C:2]1[C:20]([N:21]([C:22](=[O:36])[CH2:23][NH:24][C:25](=[O:35])[CH:26]=[CH:27][C:28]2[CH:29]=[CH:30][C:31]([NH:34][C:47]([NH:46][C:52]([O:54][C:55]([CH3:56])([CH3:57])[CH3:58])=[O:53])=[N:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])=[CH:32][CH:33]=2)[CH3:37])=[CH:19][CH:18]=[C:17]([Cl:38])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(N)cc4)c3Cl)c2n1
Reactant: COSC(=N)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=[Hg]
Solvent: CCO
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc4)c3Cl)c2n1
Temperature: 40 °C
Reaction time: 1 h
Yield: 165.8 %

Procedure:
to asolution of 8-[2,6-dichloro-3-[N-methyl-N-(4-aminocinnamoylglycyl)amino]benzyloxy]-2-methylquinoline (50 mg) in ethanol (2 ml) were added N,N-bis(tert-butoxycarbonyl)-S-methoxyisothiourea (28 mg) and mercury (II) oxide (21 mg) at ambient temperature and stirred for 1 hours at 40° C. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (8% solution of methanol in chloroform) to give 8-[2,6-dichloro-3-[N-[4-[2,3-bis(tert-butoxycarbonyl)guanidino]-cinnamoylglycyl]-N-methylamino]benzyloxy]-2-methylquinoline (60 mg) as an amorphous powder.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:16]1[CH:21]=[C:20]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=3)[CH:27]=2)[N:19]=[C:18]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[N:17]=1>CN(C=O)C>[CH2:7]([O:14][C:16]1[CH:21]=[C:20]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=3)[CH:27]=2)[N:19]=[C:18]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[N:17]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCc1ccccc1
Reactant: COc1cccc(-c2cncc(-c3cc(Cl)nc(-c4ccccn4)n3)c2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2cncc(-c3cc(OCc4ccccc4)nc(-c4ccccn4)n3)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of potassium tert-butoxide (2 eq, 18.6 mg) in DMF (1 ml) is added benzyl alcohol (2 eq, 7.2 μl) under an inert atmosphere of argon. After stirring at RT for 15 minutes, the mixture is treated dropwise with a solution of 4-chloro-6-[5-(3-methoxy-phenyl)-pyridin-3-yl]-2-pyridin-2-yl-pyrimidine (1 eq, 31 mg) and then allowed to stir at RT for 5 hours. The reaction is quenched with water (4 ml) and the mixture is extracted with EtOAc. The organic extracts are combined, washed with brine, dried (MgSO4) and concentrated in vacuo. The residue is loaded onto a SCX-2 cartridge (1 g) eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are concentrated in vacuo and dried under vacuum overnight to afford the title compound [M+H]+=447 as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].S(=O)(=O)(O)O.[N+:15]([O-])([O-:17])=[O:16].[K+]>ClCCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[CH3:9]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1ccc(F)cc1Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCCl
Product: Cc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 0 °C
Yield: 49.7 %

Procedure:
To a mixture of 20.0 g (0.138 mole) of 2-chloro-4fluorotoluene in 50 ml of 1,2-dichloroethane which had been cooled to 0° C. was added 50 ml of concentrated sulfuric acid. While maintaining the temperature below 10° C., 14.0 g (0.138 mole) of potassium nitrate was added slowly to the mixture. After three hours the reaction mixture was poured into ice, and the resulting mixture was extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was passed through a silica gel column, eluting with heptane. Appropriate fractions were combined, and the solvent was evaporated under reduced pressure, yielding 13.0 g of 2-chloro-4-fluoro-5-nitrotoluene as a yellow solid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:18][C:19]([F:22])([F:21])[F:20])[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9]2)([O-:3])=[O:2].[H-].[Na+].CN(C)C=O.[CH3:30][O:31][CH2:32]Cl>O1CCCC1.C(OCC)(=O)C>[CH3:30][O:31][CH2:32][N:11]1[C:12]2[C:8](=[CH:7][C:6]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[CH:9]=[C:10]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1cc2cc(OC(F)(F)F)cc([N+](=O)[O-])c2[nH]1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(OC(F)(F)F)cc([N+](=O)[O-])c2n1COC
Temperature: 4 °C
Reaction time: 0.33 h
Yield: 74 %

Procedure:
A mixture of ethyl 7-nitro-5-(trifluoromethoxy)-1H-indole-2-carboxylate (1.19 g), 60% sodium hydride (0.18 g) and N,N-dimethylformamide (20 mL) was stirred at 4° C. for 20 min. A solution (5 mL) of chloromethyl methyl ether (0.33 mL) in tetrahydrofuran was added dropwise. After stirring at 4° C. for 3 hr, the reaction solution was diluted with ethyl acetate, washed with aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=5:95-20:80) to give the title compound (1.0 g, yield 74%) as pale-yellow prism crystals.
Reaction SMILES: CC1(C)[O:6][C@H:5]([C:7]([N:9]2[CH2:14][CH2:13][C:12]([C:15]3[C:20]([F:21])=[CH:19][C:18]([N:22]4[CH2:26][C@H:25]([CH2:27][N:28]([C:36]5[CH:41]=[N:40][CH:39]=[CH:38][N:37]=5)C(OC(C)(C)C)=O)[O:24][C:23]4=[O:42])=[CH:17][C:16]=3[F:43])=[CH:11][CH2:10]2)=[O:8])[CH2:4][O:3]1.FC(F)(F)C(O)=O.O>ClCCl>[OH:6][C@@H:5]([CH2:4][OH:3])[C:7]([N:9]1[CH2:14][CH2:13][C:12]([C:15]2[C:20]([F:21])=[CH:19][C:18]([N:22]3[CH2:26][C@H:25]([CH2:27][NH:28][C:36]4[CH:41]=[N:40][CH:39]=[CH:38][N:37]=4)[O:24][C:23]3=[O:42])=[CH:17][C:16]=2[F:43])=[CH:11][CH2:10]1)=[O:8]
Reactant: CC(C)(C)OC(=O)N(C[C@H]1CN(c2cc(F)c(C3=CCN(C(=O)[C@@H]4COC(C)(C)O4)CC3)c(F)c2)C(=O)O1)c1cnccn1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C([C@@H](O)CO)N1CC=C(c2c(F)cc(N3C[C@H](CNc4cnccn4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102 %

Procedure:
3-(4-(1-(2,2-Dimethyl-1,3-dioxolan-4(S)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-5(R)-(N-(t-butoxycarbonyl)pyrazin-2-ylaminomethyl)oxazolidin-2-one (400 mg, 0.65 mM) was dissolved in dichloromethane (4 ml) and treated with trifluoroacetic acid (4 ml) at ambient temperature. After stirring for 30 minutes at ambient temperature, water (0.8 ml) was added, and stirring continued for 2 hours. Solvent was removed, the residue dissolved in methanol (20 ml), and treated with aqueous ammonia to bring the pH to 8; solvent was removed, and the residue chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 5 to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (315 mg ). NMR (DMSO-d6) δ: 2.28 (br, 1H); 2.37 (br, 1H); 3.46 (m, 1H); 3.54 (m, 1H); 3.64 (t, 2H); 3.71 (m, 1H); 3.81 (dd, 1H); 4.10 (overlapping m, 4H); 4.36 (m, 1H); 4.71 (t, 1H); 4.89 (m, 1H); 5.01 (t, 1H); 5.85 (s, 1H); 7.32 (d, 2H); 7.43 (t, 1H); 7.70 (d, 1H); 1H); 7.99 (s, 1H). MS (ESP): 476 (MH+) for C22H23F2N5O5
Reaction SMILES: [OH:1][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[F:45][C:46]1[CH:53]=[CH:52][C:49]([CH2:50]Br)=[CH:48][CH:47]=1>CN(C)C=O.O>[F:45][C:46]1[CH:53]=[CH:52][C:49]([CH2:50][O:38][C:35]2[CH:36]=[CH:37][C:32]([CH:2]([OH:1])[CH:3]([NH:18][C:19]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=34)=[O:20])[CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:16])([F:17])[CH:13]([F:15])[F:14])[CH:6]=3)=[CH:33][CH:34]=2)=[CH:48][CH:47]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(O)cc1)c1cccc2c1C=CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(OCc2ccc(F)cc2)cc1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide (400 mg, 0.755 mmol) in N,N-dimethylformamide (15 ml) were added potassium carbonate (313 mg, 2.27 mmol) and 4-fluorobenzyl bromide (428 mg, 2.27 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the objective substance (381 mg, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([CH:12]=O)=[CH:5]2.[CH2:14]([O:16][C:17]([CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:18])[CH3:15]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([CH:12]=[CH:19][C:17]([O:16][CH2:14][CH3:15])=[O:18])=[CH:5]2
Reactant: O=Cc1cc2cc(Cl)c(Cl)cc2[nH]1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1cc2cc(Cl)c(Cl)cc2[nH]1
Yield: 60.1 %

Procedure:
5,6-Dichloro-1H-indole-2-carboxaldehyde (35 g, 164 mmol) and (ethoxycarbonylmethylene)triphenylphosphorane (60 g, 176 mmol) were dissolved in toluene and refluxed for three hours. The solvent was evaporated under reduced pressure and the reaction mixture was purified by chromatography on silicagel (n-hexane/AcOEt, 8/2) obtaining pure title compound (28 g, 98.5 mmol, yield 60.1%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.N1(C(N2C=CN=C2)=O)C=CN=C1.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH2:32][NH2:33]>C1COCC1>[OH:1][C:2]1[C:3]([C:12]([NH:33][CH2:32][C:28]2[S:27][CH:31]=[CH:30][CH:29]=2)=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: NCc1cccs1
Reactant: O=C(O)c1ccc2cccnc2c1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(NCc1cccs1)c1ccc2cccnc2c1O
Temperature: 45 °C
Reaction time: 24 h
Yield: 53.8 %

Procedure:
A mixture of 8-hydroxyquinoline-7-carboxylic acid (100 mg, 0.53 mmol) and di(1H-imidazol-1-yl)methanone (86 mg, 0.53 mmol) in THF (8 mL) was heated to 45° C. overnight, under nitrogen. The reaction mixture was allowed to cool to RT and thiophene-2-ylmethanamine (30 mg, 0.26 mmol) was added. The resulting mixture was stirred at RT for 24 h. Additional thiophene-2-ylmethanamine (15 mg, 0.1.3 mmol) was added and the reaction mixture was stirred for 60 h at RT. The reaction mixture was quenched with H2O and THF was evaporated to dryness. Saturated solution of sodium hydrogen carbonate was added to the aqueous phase and extracted twice with DCM. The separated organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by SPE-SI cartridge (2 g, DCM to DCM:MeOH 99:1) affording the title compound (40 mg, 0.14 mmol) as a yellow solid.