Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23](O)=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([Br:22])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[N:33]1[CH2:38][C@H:37]([C:39]([F:42])([F:41])[F:40])[CH2:36][C@H:35]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:34]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:22][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:13]([C:23]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][C:32]=3[N:33]3[CH2:38][C@H:37]([C:39]([F:41])([F:40])[F:42])[CH2:36][C@H:35]([NH:43][C:44]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:50])[CH2:34]3)=[O:24])=[N:14]2)=[CH:19][CH:18]=1
Reactant: O=C(Nc1cc2ccc(Br)cc2nc1C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2ccncc2N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2ccncc2NC(=O)c2nc3cc(Br)ccc3cc2NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.1 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylic acid (0.50 g, 1.2 mmol), tert-butyl [(3S,5R)-1-(3-aminopyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate (0.45 g, 1.2 mmol) and HATU (1.2 g, 3.1 mmol) in DMF (4.9 mL), DIPEA (0.65 mL, 3.7 mmol) was added. The mixture was stirred at room temperature for 2 h, then quenched with 50 mL of EtOAc and 30 mL of 1 M NaOH. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organics were concentrated under reduced pressure. The residue was purified by flash chromatography on a 40 g silica gel column, eluting with 0-100% EtOAc in hexanes, to give the sub-title compound (0.492 g, 53%). LCMS calc. for C34H35BrF3N6O5 [M+H]+: m/z=743.2. found: 743.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12](=[N:20]S(C3C=CC(C)=CC=3)(=O)=O)[N:13]([CH:15]([CH3:19])[C:16]([NH2:18])=O)[CH:14]=2)=[CH:5][CH:4]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH-].[Na+].O>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([CH3:19])=[C:16]([NH2:18])[N:20]=3)[CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COc2ccc(=NS(=O)(=O)c3ccc(C)cc3)n(C(C)C(N)=O)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc3nc(N)c(C)n3c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
To a suspension of 2-[5-[(4-methoxybenzyl)oxy]-2-{[(4-methylphenyl)sulfonyl]imino}pyridin-1(2H)-yl]propanamide (2.6 g, 5.71 mmol) in tetrahydrofuran (25 mL) was added trifluoroacetic acid anhydride (2.35 mL, 17.1 mmol) at 0° C., and the mixture was stirred at room temperature for 1 hr. 8N Aqueous sodium hydroxide solution was added to the reaction mixture until it reached pH 12 to 13, and the mixture was stirred at 50° C. for 5 hr. Water and ethyl acetate were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was washed with ethyl acetate and collected by filtration to give the title compound (1.0 g, 68%) as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:38])[C@:4]1([OH:37])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@:18]([F:24])([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:25])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:26][CH2:27][C:28]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)C[O:29]1.I(O)(=O)(=O)=O>O1CCCC1.O>[Cl:1][CH2:2][C:3](=[O:38])[C@:4]1([OH:37])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@:18]([F:24])([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:25])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:26][CH2:27][C:28](=[O:29])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](OCC4(c5ccccc5)CO4)[C@](O)(C(=O)CCl)[C@@]3(C)C[C@H](O)[C@@]12F
Agent: [O-][I+3]([O-])([O-])O
Solvent: O
Solvent: C1CCOC1
Product: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](OCC(=O)c4ccccc4)[C@](O)(C(=O)CCl)[C@@]3(C)C[C@H](O)[C@@]12F
Yield: 51.3 %

Procedure:
A solution of 4.8 g of 21-chloro-9-fluoro-11β,17-dihydroxy-16α-[(2-phenyloxiranyl)methoxy]pregna-1,4-diene-3,20-dione in 150 ml of tetrahydrofuran is stirred with a solution of 10 g of periodic acid in 40 ml of water for 4 hours. The resulting slurry is diluted with 1 liter of water and filtered. The solid is dried in vacuo and recrystallized from methanol-chloroform to give 2.4 g of 21-chloro-9-fluoro-11β,17-dihydroxy-16α-(2-oxo-2-phenylethoxy)pregna-1,4-diene-3,20-dione, melting point 266°-268°C, dec.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[CH:8]([N:14]([CH:16]3[CH2:18][CH2:17]3)[CH3:15])[CH2:7][CH2:6][C:5]([CH3:20])([CH3:19])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:16]1([N:14]([CH3:15])[CH:8]2[CH2:7][CH2:6][C:5]([CH3:20])([CH3:19])[C:4]3[C:3]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])=[CH:2][CH:11]=[C:10]([O:12][CH3:13])[C:9]2=3)[CH2:18][CH2:17]1
Reactant: COc1cc(Br)cc2c1C(N(C)C1CC1)CCC2(C)C
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COc1ccc(C#C[Si](C)(C)C)c2c1C(N(C)C1CC1)CCC2(C)C
Yield: 76.5 %

Procedure:
Following General Procedure D and using 2-bromo-5-(cyclopropyl-methyl-amino)-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene (Intermediate 79, 1.08 g, 3.2 mmol), triethyl amine (5 mL), copper(I)iodide (0.061 g, 0.32 mmol), trimethylsilyl acetylene (3 mL, 21.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (225 g, 0.32 mmol) followed by flash column chromatography over silica gel (230–400 mesh) using hexane-10% ethyl acetate in hexane as the eluent, the title compound (0.87 g, 80%) was obtained.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[OH:15][C:16]1[CH:27]=[CH:26][CH:25]=[CH:24][C:17]=1[O:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[CH3:11][O:10][CH2:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([N+:12]([O-:14])=[O:13])=[C:2]([CH:7]=1)[O:15][C:16]1[CH:27]=[CH:26][CH:25]=[CH:24][C:17]=1[O:18][CH2:19][C:20]([O:22][CH3:23])=[O:21]
Reactant: COCOc1ccc([N+](=O)[O-])c(F)c1
Reactant: COC(=O)COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc([N+](=O)[O-])c(Oc2ccccc2OCC(=O)OC)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 21.5 %

Procedure:
A mixture of 2-fluoro-4-(methoxymethoxy)-1-nitrobenzene (9.25 g, 0.046 mol), methyl (o-hydroxyphenoxy)acetate (8.5 g, 0.047 mol) and potassium carbonate (6.44 g, 0.047 mol) in N,N-dimethylformamide is stirred at 100° C. for 18 hours, cooled to room temperature, poured into water and extracted with ether. The organic extract is washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain an orange gum. Flash chromatography of the gum using silica gel and a 35% ethyl acetate in hexanes solution gives the title product as a yellow oil (3.6 g) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][C:11]1[NH:15][N:14]=[C:13]([NH2:16])[CH:12]=1.C(N(CC)CC)C>CCO>[Br:1][C:2]1[C:3]([NH:16][C:13]2[CH:12]=[C:11]([CH3:10])[NH:15][N:14]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: Cc1cc(N)n[nH]1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(Cl)ncc2Br)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine (1.29 g, 5.66 mmol) in EtOH (15 ml) at room temperature was added a solution of 5-methyl-1H-pyrazol-3-amine (549 mg, 5.66 mmol) in EtOH (3 ml) and triethylamine (628 mg, 6.22 mmol) and the reaction mixture was stirred at room temperature overnight. The suspension was filtered and washed with water and dried to give the desired product as a white solid (1.27 g, 78%). NMR (CDCl3) 2.24 (s, 3H), 6.24 (s, 1H), 8.41 (s, 1H), 9.29 (s, 1H), 12.32 (s, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([N:14]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[CH2:18][O:17][CH2:16][C@H:15]2[CH2:26][C:27](O)=[O:28])(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.O=S(Cl)Cl.[NH2:34][CH2:35][C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:37].C(N(CC)CC)C>C(Cl)Cl.O>[O:37]=[C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:35][NH:34][C:27](=[O:28])[CH2:26][C@H:15]1[N:14]([S:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)(=[O:12])=[O:13])[CH2:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[CH2:18][O:17][CH2:16]1
Reactant: O=C(O)C[C@@H]1COCc2ccccc2CN1S(=O)(=O)c1cccc2cccnc12
Reactant: NCC(=O)c1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(C[C@@H]1COCc2ccccc2CN1S(=O)(=O)c1cccc2cccnc12)NCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
A mixture of compound 21a (412 mg, 1 mmol) and SOCl2 (3 mL) was stirred at rt for 1 h and concentrated. 2-Amino-1-phenylethanone (342 mg, 2 mmol) and triethylamine (303 mg, 3 mmol) in DCM (5 mL) were added to the above residue. The mixture was stirred at rt for 1 h. The reaction was taken up in H2O (10 mL) and extracted with DCM (30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by CC to give compound 28a (400 mg, 75% yield).
Reaction SMILES: Cl.O=[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:13]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH:23]([O:30][CH2:31][CH3:32])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:18][CH2:17]3)(=[O:15])=[O:14])[CH:11]=2)[N:6]=[CH:5][NH:4]1.S(Cl)([Cl:35])=O.CN(C)C=O.C(Cl)(Cl)Cl>O>[Cl:35][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:13]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH:23]([O:30][CH2:31][CH3:32])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:18][CH2:17]3)(=[O:15])=[O:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: CCOC(CN1CCN(S(=O)(=O)c2ccc3nc[nH]c(=O)c3c2)CC1)c1ccccc1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(CN1CCN(S(=O)(=O)c2ccc3ncnc(Cl)c3c2)CC1)c1ccccc1
Yield: 80 %

Procedure:
To 9.57 g of 1-(3,4-dihydro-4-oxo-6-quinazolinesulfonyl)-4-(2-ethoxy-2-phenylethyl)piperazine hydrochloride were added 40 ml of thionyl chloride and 4.8 ml of N,N-dimethylformamide, and the mixture was refluxed under heating. To the residue thus obtained were added 60 ml of chloroform and 30 ml of a mixture of ice and water, and the mixture was stirred under cooling with ice. Then the chloroform layer was separated therefrom and the aqueous layer was extracted with chloroform and the chloroform layer obtained was combined with the one previously separated. The chloroform layer was washed with, in order, water, a saturated sodium bicarbonate solution and water, and then dried with Glauber's salt. The chloroform layer thus obtained was condensed under reduced pressure to give 7.33 g of 1-(4-chloro-6-quinazolinesulfonyl)-4-(2-ethoxy-2-phenylethyl)piperazine as an oily substance in a yield of 80%.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2.[CH3:18][C:19]1[C:20](=[O:26])[NH:21][CH:22]=[C:23]([CH3:25])[CH:24]=1.Br[C:28]1[S:32][C:31]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[CH:35][CH:34]=2)=[N:30][CH:29]=1>CS(C)=O.[Cu]I>[CH2:40]([O:39][C:36]1[CH:35]=[CH:34][C:33]([C:31]2[S:32][C:28]([N:21]3[CH:22]=[C:23]([CH3:25])[CH:24]=[C:19]([CH3:18])[C:20]3=[O:26])=[CH:29][N:30]=2)=[CH:38][CH:37]=1)[CH3:41]
Reactant: CCOc1ccc(-c2ncc(Br)s2)cc1
Reactant: Cc1c[nH]c(=O)c(C)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: CCOc1ccc(-c2ncc(-n3cc(C)cc(C)c3=O)s2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
A mixture of CuI (0.038 g, 0.20 mmol), Cs2CO3 (0.98 g, 3.00 mmol) and 8-hydroxyquinoline ligand (0.029 g, 0.20 mmol) in DMSO (2 mL) was stirred at rt for 30 min under N2. Then to the reaction mixture was added a solution of 3,5-dimethylpyridin-2(1H)-one (0.30 g, 2.40 mmol) and 5-bromo-2-(4-ethoxyphenyl)thiazole (0.57 g, 2.00 mmol) in DMSO (2 mL) via syringe. The reaction mixture was heated at 130° C. for 12 h, then cooled to rt and filtered. The filtrate was diluted with H2O (10 mL) and extracted with CH2Cl2 (20 mL×3). The combined organic phases were concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:10) to give the title compound (0.17 g, 26%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])(=[O:15])=[O:14])[CH:11]=[C:10]([CH:23]=O)[CH:9]=1.CO.[CH3:27][NH2:28].[BH4-].[Na+].[ClH:31].C(=O)([O-])O.[Na+]>CO>[ClH:31].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:23][NH:28][CH3:27])[CH:9]=1
Reactant: O=Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2ccccc2F)c1
Reactant: CN
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CNCc1cc(-c2ccccc2F)n(S(=O)(=O)c2ccccc2F)c1
Reaction time: 0.5 h
Yield: 70 %

Procedure:
5-(2-Fluorophenyl)-1-[(2-fluorophenyl)sulfonyl]-1H-pyrrole-3-carbaldehyde (330 mg) was dissolved in methanol (33 mL), 40% methylamine methanol solution (370 mg) was added at room temperature, and the mixture was stirred for 30 min. Sodium borohydride (108 mg) was added at room temperature, and the mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (50 mL) was added, and the mixture was stirred for 5 min. The reaction mixture was alkalized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-methanol=1:0→7:3), and dissolved in methanol (5 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 266 mg, 70%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].CCN(CC)CC.[S:25](Cl)([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26].C(OCC)C>C(Cl)Cl>[CH3:32][C:31]1[CH:33]=[CH:34][C:28]([S:25]([O:1][CH2:2][C@@H:3]2[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])(=[O:27])=[O:26])=[CH:29][CH:30]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
To phenylmethyl(2S)-2-(hydroxymethyl)-1-pyrrolidinecarboxylate (0.78 g, 3.32 mmol) in CH2Cl2 (10 mL) was added Et3N (0.92 mL, 6.63 mmol) followed by TsCl (0.664 g, 3.48 mmol) and the reaction mixture was stirred overnight at room temperature. The mixture was poured onto water and diethyl ether (Et2O). The aqueous layer was separated and the organic layer was washed with saturated aqueous NaHCO3 followed by brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% hexanes to 20% EtOAc/hexanes) afforded the title compound (0.85 g, 66%) as a colorless oil. LC-MS (ES) m/z=390 [M+H]+.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[C:11]([N+:18]([O-:20])=[O:19])[CH:10]=2)[CH2:5][CH2:4]1.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:37]([C:39]3[CH:44]=[C:43]([F:45])[CH:42]=[C:41]([F:46])[CH:40]=3)=[O:38])[CH:35]=2)[N:30]([C:47]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:29]=1.C(N(CC)C(C)C)(C)C>O1CCCC1.CN(C)C=O>[F:46][C:41]1[CH:40]=[C:39]([CH:44]=[C:43]([F:45])[CH:42]=1)[C:37]([C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][CH:33]=1)[N:30]([C:47]([C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[N:29]=[C:28]2[NH:27][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([N:6]2[CH2:5][CH2:4][N:3]([CH3:2])[CH2:8][CH2:7]2)=[CH:10][C:11]=1[N+:18]([O-:20])=[O:19])=[O:38]
Reactant: Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(C(=O)c3cc(F)cc(F)c3)cc12
Reactant: CN1CCN(c2ccc(C(=O)O)c([N+](=O)[O-])c2)CC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(C(=O)Nc3nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c4ccc(C(=O)c5cc(F)cc(F)c5)cc34)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
To a suspension of 4-(4-methyl-piperazin-1-yl)-2-nitro-benzoic acid hydrochloride (1.5 g, 4.97 mmol) in dry tetrahydrofuran (80 mL) were added oxalyl chloride (1.4 mL, 19.9 mmol) and N,N-dimethylformamide (1-2 drops). The mixture was stirred at room temperature overnight and then evaporated to dryness. The resulting crude acyl chloride was taken-up with toluene and evaporated again then dissolved in dry tetrahydrofuran (180 mL). A solution of (3-amino-1-trityl-1H-indazol-5-yl)-(3,5-difluoro-phenyl)-methanone (1.83 g. 3.55 mmol) and N,N-diisopropylethylamine (2.5 mL, 14.22 mmol) in dry tetrahydrofuran (15 mL) was added to the reaction mixture. The mixture was stirred at room temperature overnight and then at 75° C. for 2 hours. The volatiles were evaporated and the residue taken up with dichloromethane and washed with brine. The organic phase was dried over sodium sulfate and evaporated to dryness. Purification of the crude by chromatography over silica gel (DCM/MeOH) afforded 2.51 g of the title compound as yellow powder (92% yield).
Reaction SMILES: [OH:1][C:2]1[N:7]([C:8]#[C:9][C:10]2[CH:29]=[CH:28][C:13]([C:14]([NH:16][C@H:17]([C:24]([O:26][CH3:27])=[O:25])[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:15])=[CH:12][CH:11]=2)[CH:6]=[N:5][C:4]2=[N:30][CH:31]=[CH:32][C:3]=12>CO.C(Cl)Cl.[Pd]>[OH:1][C:2]1[N:7]([CH2:8][CH2:9][C:10]2[CH:29]=[CH:28][C:13]([C:14]([NH:16][C@H:17]([C:24]([O:26][CH3:27])=[O:25])[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:15])=[CH:12][CH:11]=2)[CH:6]=[N:5][C:4]2=[N:30][CH:31]=[CH:32][C:3]=12
Reactant: COC(=O)CC[C@H](NC(=O)c1ccc(C#Cn2cnc3nccc-3c2O)cc1)C(=O)OC
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CC[C@H](NC(=O)c1ccc(CCn2cnc3nccc-3c2O)cc1)C(=O)OC
Reaction time: 24 h
Yield: 60.4 %

Procedure:
A mixture of 1.1 g of dimethyl N-[4-(4-hydroxypyrrolo[2,3-d]pyrimidin-3-ylethynyl)benzoyl]-L-glutamate in 100 mL of 50% methanol in methylene chloride and 0.8 g of 3% palladium-on-carbon is hydrogenated at 50 p.s.i. for 24 hours, filtered, and concentrated under reduced pressure. Ether is added to the residue and the solid is collected by filtration and dried to yield 0.67 g of dimethyl N-{4-[2-(4-hydroxypyrrolo[2,3-d]pyrimidin-3-yl)ethyl]benzoyl}-L-glutamate. mp 170-172° C. 1NMR (d6 -DMSO) δ1.94-2.14 (m, 2H), 2.44 (t, J=7.4 Hz, 2H), 2.93-3.02 (m, 2H), 3.57 (s, 3H), 3.63 (s, 3H), 4.40-4.70 (m, 1H), 6.71 (s, 1H), 7.29 (d, J=8.2 Hz, 2 H), 7.77 (m, 3 H), 8.66 (d, J=7.4 Hz, 1H), 11.52 (s, 1H), 11.71 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Br:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:12]([Mg]Cl)([CH3:14])[CH3:13].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.O>C1COCC1>[CH:12]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:8][Br:9])([CH3:14])[CH3:13]
Reactant: CC(C)[Mg]Cl
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1cc(CBr)ccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 35.4 %

Procedure:
A solution of 4-nitrobenzyl bromide (432 mg, 2 mmol) in THF (5 mL) at −70° C., was treated dropwise with isopropylmagnesium chloride (1 mL, 2-M in Et2O, 2 mmol), stirred for 1 h, treated with DDQ (499 mg, 2.2 mmol) and stirred at room temperature for 16 h. The reaction mixture was poured into water (10 mL), extracted with EtOAc (2×10 mL), dried (MgSO4), concentrated in vacuo and filtered. The resulting solid was purified by chromatography [SiO2; EtOAc:Heptane (1:4)] to give the title compound (183 mg, 35%) as a pale yellow solid which was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21])(=[O:12])=[O:11])[CH3:2].[N:24]1([CH2:33][C:34](O)=[O:35])[CH:32]=[C:30]([CH3:31])[C:28](=[O:29])[NH:27][C:25]1=[O:26]>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21])(=[O:12])=[O:11])[C:34](=[O:35])[CH2:33][N:24]1[CH:32]=[C:30]([CH3:31])[C:28](=[O:29])[NH:27][C:25]1=[O:26])[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1ccc(F)cc1[N+](=O)[O-]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Product: CCOC(=O)CN(CCNS(=O)(=O)c1ccc(F)cc1[N+](=O)[O-])C(=O)Cn1cc(C)c(=O)[nH]c1=O
Yield: 91.2 %

Procedure:
The title compound (2.35 g, 91%) was synthesized by the reaction of N-[2-(4-fluoro-2-nitro-benzenesulfonylamino)-ethyl]-glycine ethyl ester (1.76 g, 5 mmol) and (thymin-1-yl)-acetic acid (0.92 g, 5 mmol) as per the procedure of example 46. 1H-NMR (500 MHz; DMSO-d6) δ 11.30 (s, 0.6H), 11.27 (s, 0.4H), 8.28˜8.05 (m, 2.8H), 7.78 (m, 1.2H), 7.31 (s, 0.6H), 7.23 (s, 0.4H), 4.65 (s, 1.2H), 4.47 (s, 0.8H), 4.30 (s, 0.8H), 4.16 (q. 0.8H), 4.07 (q. 1.2H), 4.00 (s, 1.2H), 3.49 (t, 1.2H), 3.22 (q, 1.2H), 3.12˜3.01 (m, 1.6H), 1.75 (s, 3H), 1.23 (t, 1.2H), 1.18 (t, 1.88H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:34])[CH:14]=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=O>C(Cl)(Cl)Cl.C(OC(C)C)(C)C>[Cl:1][C:2]1[CH:11]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:12][C:13](=[O:34])[CH:14]=[C:7]2[O:9][CH3:10]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(C)OC(C)C
Solvent: ClC(Cl)Cl
Product: COc1cc(=O)[nH]c2ccc(Cl)cc12
Yield: 67.4 %

Procedure:
Methyl 5-chloro-2-(2-(triphenyl-λ5-phosphanyliden)-acetylamino)benzoate (3.8 g) was heated at 180° C. for 1 h. The reactant was suspended in chloroform and diisopropyl ether. Solids were collected by filtration and dried to obtain 6-chloro-4-methoxyquinoline-2(1H)-one (1.1 g). (3) A mixture of 6-chloro-4-methoxyquinoline-2(1H)-one (1.1 g), N,N-dimethylaniline (1 mL), and phosphorus oxychloride (4 mL) was stirred at 80° C. to 90° C. for 10 h. The reaction solution was added dropwise to ice water and extracted with chloroform. The organic layer was dried with anhydrous magnesium sulfate, followed by addition of silica gel. The desiccant and silica gel were removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 2,6-dichloro-4-methoxyquinoline (1.2 g) as pale yellow crystals.