Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[F:9].C([Li])CCCCC.[Cl:17][CH2:18][C:19]([CH2:21][Cl:22])=[O:20].[Cl-].[NH4+]>C(OCC)C>[Cl:17][CH2:18][C:19]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[F:9])([OH:20])[CH2:21][Cl:22]
Reactant: O=C(CCl)CCl
Reactant: Fc1c(Cl)cccc1Br
Agent: [Cl-]
Agent: [Li]CCCCCC
Agent: [NH4+]
Solvent: CCOCC
Product: OC(CCl)(CCl)c1cccc(Cl)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
To a solution of 1-bromo-3-chloro-2-fluorobenzene (1.4 g, 6.7 mmol) in dry diethyl ether (25 mL), at −78° C. under nitrogen was added n-hexyllithium (2.5 M in hexane, 3.2 ml, 8.0 mmol) dropwise. The mixture was stirred for 10 min after which a solution of 1,3-dichloroacetone (1.1 g, 7.3 mmol) in dry diethyl ether (10 ml) was added dropwise. The resulting mixture was stirred at −78° C. for 0.5 h and then brought to ambient temperature and stirred for 2 h. Aqueous saturated ammonium chloride (25 ml) was added and the mixture was extracted with ethylacetate (3×25 ml). The combined organic phase was dried (Na2SO4), filtered and evaporated to dryness. The crude product was purified by flash column chromatography on silica gel (ethylacetate/isooctane, 1:9 to 1:1) to give the title compound (0.88 g, 51%). MS m/z (rel. intensity, 70 eV) 257 (M+, 1), 209 (64), 207 (bp), 143 (44), 77 (13).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][C:19]=1B(O)O>>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:19]2[CH:20]=[C:21]([O:24][C:25]([F:27])([F:28])[F:26])[CH:22]=[CH:23][C:18]=2[S:17][CH3:16])[C:11]=1[CH3:12]
Reactant: CSc1ccc(OC(F)(F)F)cc1B(O)O
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Product: CSc1ccc(OC(F)(F)F)cc1-c1nc2cc(F)cc(F)c2c(Cl)c1C

Procedure:
Essentially prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (400 mg, 1.60 mmol) and 2-(methylthio)-5-(trifluoromethoxy)-phenylboronic acid to give 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylthio)-5-(trifluoromethoxy)phenyl)quinoline. Mass Spectrum (ESI) m/e=420.0 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([C:11]([OH:13])=O)[S:8][C:9]=1[CH3:10])[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:45]([C:47]1[CH:52]=[C:51]([C:53](=[NH:56])[NH:54]O)[CH:50]=[C:49]([CH3:57])[C:48]=1[CH2:58][CH2:59][C:60]([OH:62])=[O:61])[CH3:46]>C(Cl)Cl>[CH2:45]([C:47]1[CH:52]=[C:51]([C:53]2[N:54]=[C:11]([C:7]3[S:8][C:9]([CH3:10])=[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[CH:6]=3)[O:13][N:56]=2)[CH:50]=[C:49]([CH3:57])[C:48]=1[CH2:58][CH2:59][C:60]([OH:62])=[O:61])[CH3:46]
Reactant: Cc1sc(C(=O)O)cc1CC(C)C
Reactant: CCc1cc(C(=N)NO)cc(C)c1CCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cc(-c2noc(-c3cc(CC(C)C)c(C)s3)n2)cc(C)c1CCC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.6 %

Procedure:
To a solution of 4-isobutyl-5-methyl-thiophene-2-carboxylic acid (126 mg, 637 μmol) in DCM (5 mL), DIPEA (249 mg, 1.93 mmol) is added followed TBTU (202 mg, 628 μmol). The mixture is stirred at rt for 30 min before 3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenyl]-propionic acid (159 mg, 637 μmol) is added. The mixture is stirred at rt for 16 h before it is diluted with DCM, washed with 1 N aq. HCl solution, dried over Na2SO4, filtered and concentrated. The residue is dissolved in toluene (20 mL) and the reaction mixture is stirred at 110° C. for 18 h. The solvent is evaporated and the crude product is purified by CC on silica gel eluting with DCM containing 5% of methanol to give 3-{2-ethyl-4-[5-(4-isobutyl-5-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-propionic acid (41 mg) as a beige solid; LC-MS: tR=1.17 min, [M+1]+=413.30; 1H NMR (CDCl3): δ 0.94 (d, J=6.4 Hz, 6H), 1.30 (t, J=7.6 Hz, 3H), 1.84-1.96 (m, 1H), 2.43 (s, 3H), 2.45 (s, 3H), 2.46-2.60 (m, 4H), 2.75 (q, J=7.3 Hz, 2H), 3.02-3.12 (m, 2H), 7.66 (s, 1H), 7.79 (s, 1H), 7.81 (s, 1H).
Reaction SMILES: [C:1]1(N2CCCC2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[Na+].[I-].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17].[OH2:24]>CN1C(=O)CCC1>[O:17]=[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C:1]1=[O:24]
Reactant: C1=C(N2CCCC2)CCCC1
Reactant: O=C(CBr)c1ccccc1
Reactant: O
Agent: [I-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(CC1CCCCC1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a 250-mL round-bottomed flask containing 2.4 mL of 1-cyclohex-1-en-1-ylpyrrolidine was added 20 mL anhydrous NMP followed by NaI (0.645 g), under nitrogen. The flask was fitted with an addition funnel containing 2-bromo-1-phenylethanone (4.12 g) dissolved in 35 mL anhydrous NMP, which was dropped into the enamine solution over 60 min. This solution was stirred at ambient temperature for 10 h, then 90 mL of water was added to the solution and it was stirred for another 11 hours, under nitrogen. The solution was then extracted twice with ethyl acetate and water, the organic layers combined and further washed with water (3×), dried over sodium sulphate, filtered and evaporated to give a yellow oil. The oil was purified by Flash chromatography using a gradient cyclohexane:EtOAc (9:1). The product 2-(2-oxo-2-phenylethyl)cyclohexanone was used directly for the next reaction. (4.1 g, 91% yield, 98% purity by HPLC). MS(ESI+): 217.4; MS(ESI−): 215.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:22].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=1.C[Si](C)(C)N[Si](C)(C)C.[K]>C1COCC1>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[N:11]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=3)[CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:22]
Reactant: COc1ccc(C(=O)c2c[nH]c3cccnc3c2=O)cc1C
Reactant: Cc1cccc(CBr)n1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cn(Cc3cccc(C)n3)c3cccnc3c2=O)cc1C
Yield: 37.9 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1 using 75 mg (0.255 mmol) of 3-(4-Methoxy-3-methyl-benzoyl)-1H-[1,5]naphthyridin-4-one, 56.9 mg (0.306 mmol) of 2-bromomethyl-6-methyl-pyridine, 0.61 mL (0.306 mmol, 0.5 M in toluene) of potassium hexamethyldisilazane, and 2.5 mL of THF. The crude product was purified by flash column chromatography using a gradient of 20-100% ethyl acetate in hexane and further purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 38.6 mg of 3-(4-Methoxy-3-methyl-benzoyl)-1-(6-methyl-pyridin-2-ylmethyl)-1H-[1,5]naphthyridin-4-one. LC-MSD, m/z for C24H21N3O3 [M+H]: 400.16 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 1.8 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19]([NH:21][C:22](=[O:31])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[O:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N+:15]([O-])=O>CO.C1COCC1>[NH2:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[O:8][C:7]1[CH:6]=[CH:5][C:4]([NH:18][C:19]([NH:21][C:22](=[O:31])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[O:20])=[CH:3][C:2]=1[F:1]
Reactant: O=C(Cc1ccc(F)cc1)NC(=O)Nc1ccc(Oc2ccncc2[N+](=O)[O-])c(F)c1
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cnccc1Oc1ccc(NC(=O)NC(=O)Cc2ccc(F)cc2)cc1F
Yield: 73.6 %

Procedure:
A suspension of 1-(3-fluoro-4-(3-nitropyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea (125 mg, 0.29 mmol) in 3:1 MeOH/THF (20 mL) was hydrogenated over Pt2O (50 mg) using H2 from a latex balloon for 6 h. The catalyst was filtered off with the aid of Celite® and the filtrate concentrated to give the title compound (85 mg, 74%) as a white solid. 1H NMR (DMSO-d6) δ 11.03 (s, 1H), 10.55 (s, 1H), 8.03 (s, 1H), 7.75 (dd, 1H, J=2.5, 13.2 Hz), 7.65 (d, 1H, J=5.1 Hz), 7.38-7.35 (m, 3H), 7.23-7.16 (m, 3H), 6.42 (d, 1H, J=5.1 Hz), 5.26 (s, 2H), 3.75 (s, 2H); MS (ESI+): m/z 399.35 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH:13]3[CH2:16][C:15]4([CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]4)[CH2:14]3)[CH:12]=2)=[CH:4][C:3]=1[O:29][C@@H:30]([C:32]1[C:37]([Cl:38])=[CH:36][CH:35]=[C:34]([F:39])[C:33]=1[Cl:40])[CH3:31].C([O-])([O-])=O.[Na+].[Na+].O>C(O)=O.CCOC(C)=O>[CH2:14]1[C:15]2([CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)[CH2:16][CH:13]1[N:11]1[CH:12]=[C:8]([C:5]2[CH:4]=[C:3]([O:29][C@@H:30]([C:32]3[C:37]([Cl:38])=[CH:36][CH:35]=[C:34]([F:39])[C:33]=3[Cl:40])[CH3:31])[C:2]([NH2:1])=[N:7][CH:6]=2)[CH:9]=[N:10]1
Reactant: C[C@@H](Oc1cc(-c2cnn(C3CC4(CCN(C(=O)OC(C)(C)C)CC4)C3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](Oc1cc(-c2cnn(C3CC4(CCNCC4)C3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.2 %

Procedure:
(R)-tert-butyl 2-(4-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (105 mg, 0.178 mmol, 1.0 equiv) was dissolved in formic acid (6 mL). The solution was sonicated at room temperature for 90 min (the temperature of sonication bath reached about 40° C. after 90 min). The solution was cooled to room temperature and concentrated by rotavapor to give the residue which was dissolved in EtOAc (20 mL). A solution of Na2CO3 (2.0 M, 20 mL) was added. The mixture was stirred at room temperature for 30 min. H2O (10 mL) was added. The layers were separated. The aqueous phase was extracted with DCM (3×30 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, concentrated to give pale yellow solid which was purified by CombiFlash [12 g silica gel column; (MeOH/NH4OH=10/1)/DCM: 0-20%] to afford 77 mg (yield 88%) of (R)-5-(1-(7-azaspiro[3.5]nonan-2-yl)-1H-pyrazol-4-yl)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine as a off-white foam solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[C:24]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:11]1([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]3[C:24]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:36])[F:38])=[CH:31][CH:30]=4)=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:18][CH:19]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 4-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino)-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (11.7 g) in CH2Cl2 (50 mL) was added trifluoroacetic acid (25 mL) and the solution was stirred at room temperature for 2 hours. The mixture was then evaporated under reduced pressure and the residue was taken in water. The resulting precipitate was filtered and washed with water. The resulting solid was then suspended in water, basified with a saturated solution of Na2CO3, and extracted with CH2Cl2. The organic phase was then washed with water, dried over Na2SO4, filtered and evaporated to give the title compound (9 g) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:12][C:13]([Cl:17])=[CH:14][CH2:15][NH2:16]>C(OCC)C>[Cl:12][C:13]([Cl:17])=[CH:14][CH2:15][NH:16][C:10]([NH:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[O:11]
Reactant: NCC=C(Cl)Cl
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: CCOCC
Product: O=C(NCC=C(Cl)Cl)Nc1ccc(Cl)c(Cl)c1

Procedure:
To 0.02 mol of 3,4-dichlorophenylisocyanate, dissolved in 40 ml of ethyl ether, were admixed, at room temperature, 0.02 mol of N-(3,3-dichloroallyl)-amine (prepared starting from 3,3-trichloropropene with hexamethylentetramine--see e.g., Italian patent application No. 28,867 A/76).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH:32]=[CH:31][N:30]=[CH:29]1>>[N:28]1([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH:38]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:39][CH:40]=2)[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: Nc1ccc(Cn2ccnc2)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(Cn2ccnc2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(imidazol-1-yl-methyl)-aniline Rf value: 0.4 (silica gel, methylene chloride/methanol/ammonia=10:1:0.01) C27H22N4O3
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]2[CH:14]1[CH2:16][CH2:15]1.[C:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH:25]1[CH3:30])(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([N:24]1[CH2:29][CH2:28][N:27]([C:10]2[CH:9]=[C:8]3[C:3]([C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]3[CH:14]3[CH2:16][CH2:15]3)=[C:2]([NH2:1])[C:11]=2[F:12])[CH2:26][CH:25]1[CH3:30])(=[O:23])[CH3:22]
Reactant: Nc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC(=O)N1CCNCC1C
Solvent: c1ccncc1
Product: CC(=O)N1CCN(c2cc3c(c(N)c2F)c(=O)c(C(=O)O)cn3C2CC2)CC1C

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-acetyl-2-methylpiperazine and pyridine was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in aqueous ammonia. The solution was neutralized with an aqueous solution of acetic acid and cooled with ice. The crystals were collected by filtration to give 7-(4-acetyl-3-methyl-1-piperazinyl)-5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. It was recrystallized from ethanol/chloroform. m.p. 269°-271° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:14]2[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]2)=[N:4][C:3]=1[CH3:9]
Reactant: Cc1nc(Cl)ccc1Br
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: Cc1nc(N2CCN(C)CC2)ccc1Br

Procedure:
A solution of 3-bromo-6-chloro-2-methylpyridine (700 mg, 3.39 mmol) and 1-methylpiperazine (0.753 mL, 6.78 mmol) in DMF (4 mL) was heated in microwave reactor at 150° C. for 50 minutes. The mixture was subsequently purified via preparative HPLC, eluting with a gradient of 10-70% ACN (containing 0.035% TFA) in H2O (containing 0.05% TFA) to give the title compound.
Reaction SMILES: [OH-].[Na+].[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@H:5]([C:13]([OH:15])=[O:14])[NH:4]1.[C:16]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>O.O1CCCC1>[C:16]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:19]([S:22]([N:4]2[C@@H:5]([C:13]([OH:15])=[O:14])[CH2:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:3]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=C(O)[C@H]1Cc2ccccc2CN1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H]1Cc2ccccc2CN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
Sodium hydroxide (13.6 g) is dissolved in water (300 ml), and therein is suspended (3R)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid (30.0 g) and thereto is added tetrahydrofuran (120 ml). To the resulting solution is added 4-biphenylylsulfonyl chloride (42.9 g), and the mixture is stirred at room temperature for one hour. The reaction mixture is acidified with 10% hydrochloric acid under ice cooling, and is diluted with water, and then extracted twice with ethyl acetate. The extract is washed with water and an aqueous saturated saline solution, dried over sodium sulfate and then treated with active carbon. Undissolved materials are filtered off from the extract, and the solvent is distilled off under reduced pressure. The residue is recrystallized from ethyl acetate-hexane to give (3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid (36.5 g) as colorless crystals.
Reaction SMILES: [C:1]1([C:7](F)(F)F)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-:12].[Cl-:13].[Cl-].[C:15]1([O:21][CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:22][O:21][C:15]1[CH:20]=[CH:19][C:18]([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([Cl:13])[Cl:12])=[CH:17][CH:16]=1
Reactant: FC(F)(F)c1ccccc1
Reactant: [Cl-]
Reactant: COc1ccccc1
Agent: [Al+3]
Product: COc1ccc(C(Cl)(Cl)c2ccccc2)cc1

Procedure:
From benzotrifluoride (146 mg, 1 mmol), AlCl3 (400 mg, 3 mmol) and anisole (108 mg, 1 mmol), dark red viscous oil (352 mg, 132% crude).
Reaction SMILES: Cl[C:2]1[C:7](C2C=CC=CC=2)=[N:6][NH:5][C:4](=[O:14])[CH:3]=1.[C:15]([O-])([O-])=[O:16].[K+].[K+].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.CCOC(C)=O>CN(C=O)C.[Cl-].[Na+].O>[CH3:15][O:16][C:2]1[CH:7]=[N:6][N:5]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:4](=[O:14])[CH:3]=1
Reactant: O=c1cc(Cl)c(-c2ccccc2)n[nH]1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(CBr)cc1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2ncc(OC)cc2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 5-chloro-6-phenylpyridazin-3(2H)-one (78 mg, 0.618 mmol) in DMF (3 mL) at room temperature under argon was added K2CO3 (256 mg, 1.855 mmol), and was followed by addition of 1-(bromomethyl)-4-methoxybenzene (149 mg, 0.742 mmol). The resulting reaction mixture was stirred at room temperature overnight. EtOAc (20 mL) and brine (30 mL) were added to the reaction mixture. Layers were separated. Organic layer were washed with water (15 mL), and brine (15 mL). Organic phase was dried (MgSO4), filtered and concentrated. Crude product (117 mg) (MS (ESI) 247 (M+H)) was used directly to next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH:18][CH3:19])=[C:16]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[C:15]([C:27](=[N:29][OH:30])[NH2:28])=[N:14]1.O.[C:32]1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC)(OC)OC>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[C:17]([NH:18][CH3:19])=[C:16]([S:20]([C:23]([F:25])([F:26])[F:24])(=[O:21])=[O:22])[C:15]([C:27]2[N:28]=[CH:32][O:30][N:29]=2)=[N:14]1
Reactant: CNc1c(S(=O)(=O)C(F)(F)F)c(C(N)=NO)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: O
Product: CNc1c(S(=O)(=O)C(F)(F)F)c(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 2396.7 %

Procedure:
1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methylamino-4-trifluoromethylsulfonyl-3-pyrazolecarboxamide oxime 500 mg (1.00 mmol) was dissolved in 5 ml of trimethyl orthoformate, and then 5 mg of p-toluenesulfonic acid monohydrate was added. After the mixture was was stirred at room temperature for 6hrs, trimethyl orthoformate was distilled off in vacuo, and then added 20 ml of ethyl acetate. The ethyl acetate solution was washed once with 30 ml of aqueous saturated sodium hydrogencarbonate solution, and then four times with 30 ml of aqueous saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off. The resulting concentrated residue was purified by silica gel column chromatography [eluent: chloroform] to obtain 320 mg (0.63 mmol) of the title compound as a colorless crystal. Yield 63%.
Reaction SMILES: CC([O:5][C:6](=[O:42])[CH:7]([NH:25][CH:26]([C:31]([NH:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[CH:16]=[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=[CH:13][C:12]=2[C:11]1=[O:24])(C)C>C(O)(C(F)(F)F)=O>[O:24]=[C:11]1[C:12]2[CH:13]=[C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]3=[CH:16][C:17]=2[C:18](=[O:19])[N:10]1[CH2:9][CH2:8][C@@H:7]([NH:25][C@H:26]([C:31]([NH:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[C:6]([OH:42])=[O:5]
Reactant: CC(C)CC(NC(CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)OC(C)(C)C)C(=O)NCCN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)O)C(=O)NCCN1CCOCC1
Reaction time: 20 h

Procedure:
240 mg of 4-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)-2-[[3-methyl-1-[[(2-morpholin-4-yl-ethyl)amino]carbonyl]butyl]amino]-butanoic acid-1,1-dimethylethyl ester from part (A), was dissolved in TFA:H20 (9:1) and allowed to stand for 20 h. The solvents were removed by evaporation, and the resulting oil was purified by reverse phase H.P.L.C. The solvents were removed by lyopholization to give the title compound as a white solid; 145 mg.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:53]=[CH:54][CH:55]=1)[CH2:12][N:13]1[CH:17]=[C:16]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24]([C:27]4[CH:28]=[CH:29][C:30]([N:33]5[CH2:38][CH2:37][N:36]([CH2:39][C@@H:40]([OH:42])[CH3:41])[CH2:35][CH2:34]5)=[N:31][CH:32]=4)[CH:25]=3)[N:20]([S:43]([C:46]3[CH:52]=[CH:51][C:49]([CH3:50])=[CH:48][CH:47]=3)(=[O:45])=[O:44])[CH:19]=2)[CH:15]=[N:14]1)C1C=CC=CC=1>C1(C)C=CC=CC=1.C(O)(C(F)(F)F)=O>[OH:42][C@@H:40]([CH3:41])[CH2:39][N:36]1[CH2:37][CH2:38][N:33]([C:30]2[N:31]=[CH:32][C:27]([C:24]3[CH:25]=[C:26]4[C:18]([C:16]5[CH:15]=[N:14][N:13]([CH2:12][C:11]6[CH:10]=[C:9]([OH:8])[CH:55]=[CH:54][CH:53]=6)[CH:17]=5)=[CH:19][N:20]([S:43]([C:46]5[CH:47]=[CH:48][C:49]([CH3:50])=[CH:51][CH:52]=5)(=[O:44])=[O:45])[C:21]4=[N:22][CH:23]=3)=[CH:28][CH:29]=2)[CH2:34][CH2:35]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(OCc5ccccc5)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(O)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1

Procedure:
To the solution of (S)-1-(4-(5-(3-(1-(3-(benzyloxy)benzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-1-yl)propan-2-ol (200 mg, 0265 mmol) in toluene/TFA (10/5 mL) was heated at 100° C. for 16 hours and distilled out the solvent. This was basified with triethylamine and distilled out the solvent to get 180 mg (crude) of the titled compound. MS: m/z=664.2 (M+1).