Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.Cl.[CH:55]([C:58]1[O:62][N:61]=[CH:60][C:59]=1[NH2:63])([CH3:57])[CH3:56]>CN(C)C=O.O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([NH:63][C:59]2[CH:60]=[N:61][O:62][C:58]=2[CH:55]([CH3:57])[CH3:56])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: CC(C)c1oncc1N
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1oncc1NC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.6 %

Procedure:
To a solution (15 ml) of 3-cyclopentyl-2-[4-(methylsulfonyl)phenyl]propanoic acid (2.00 g) in N,N-dimethylformamide were added N,N-diisopropylethylamine (3.49% mL), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo(4,5-b)pyridinium 3-oxide hexafluorophosphate (2.82 g) and 5-isopropylisoxazol-4-amine hydrochloride (1.15 g), and the mixture was stirred at room temperature for 48 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-100:0, volume ratio) to give the title compound (2.50 g, 92%) as colorless amorphous crystals. MS: 405 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=O.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.[I-].[CH2:47]([N+:51]1[N:55]=[C:54]([CH3:56])[S:53][C:52]=1[CH3:57])[CH2:48][CH2:49][CH3:50]>>[CH2:47]([N:51]1[N:55]=[C:54]([CH3:56])[S:53]/[C:52]/1=[CH:57]\[C:6]([C:5]1[CH:9]=[CH:10][C:11]([CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:8])[CH2:48][CH2:49][CH3:50]
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: COc1cc(C(=O)O)ccc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1ccc(C)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-methoxy-4-methylbenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89-0.94 (m, 3 H) 1.29-1.37 (m, 2 H) 1.71-1.79 (m, 2 H) 2.20 (s, 3 H) 2.48 (s, 3H) 3.85 (s, 3 H) 4.23 (t, 2 H) 6.67 (s, 1 H) 7.22 (d, 1 H) 7.48 (s, 1 H) 7.53 (d, 1 H); MS (ESI) m/z 319 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[CH2:5][CH2:4]1)[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[C:25]1[C:34]2[N:33]=[CH:32][CH:31]=[N:30][C:29]=2[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.ClC1C=C(OC)C=CC=1B(O)O>>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:10]=[C:11]([NH:12][C:35]([C:28]3[C:29]4[N:30]=[CH:31][CH:32]=[N:33][C:34]=4[C:25]([C:18]4[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=4[Cl:16])=[CH:26][CH:27]=3)=[O:36])[CH:13]=[CH:14][CH:15]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2cccc(N)c2)CC1
Reactant: COc1ccc(Cl)c(-c2ccc(C(=O)O)c3nccnc23)c1
Agent: COc1ccc(B(O)O)c(Cl)c1
Product: CCN1CCN(c2cccc(NC(=O)c3ccc(-c4cc(OC)ccc4Cl)c4nccnc34)c2)CC1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 3-(4-ethyl-piperazin-1-yl)-aniline (Step 2.1) and 8-(2-chloro-5-methoxy-phenyl)quinoxaline-5-carboxylic acid. The latter compound was synthesized as described in Steps 1.2-1.7 but using 2-chloro-4-methoxyphenylboronic acid in Step 1.4. Title compound: ESI-MS: 502.1 [M]+; tR=3.57 min (System 3).
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[N+:14]([O-:16])=[O:15])[CH2:5][CH2:4][S:3]1.[C:17](Cl)(=[O:19])[CH3:18].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:17]([N:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[N+:14]([O-:16])=[O:15])[CH2:5][CH2:4][S:3]1)(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: N=C1SCCN1c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)N=C1SCCN1c1ccc(Cl)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
0.52 g (2 mmoles) of 2-imino-3-(4'-chloro-2-nitrophenyl)-thiazolidine is dissolved in 20 ml of anhydrous chloroform. 0.24 g (0.21 ml, 3 mmoles) of acetyl chloride and 0.4 ml (0.3 g, 3 mmoles) of triethylamine are added to the solution and it is boiled for 30 minutes. The solution is then evaporated in vacuo, the oily residue is dissolved in 30 ml of dichloromethane and extracted twice with 10 ml of saturated aqueous sodium chloride solution each. The solution is dried and evaporated, the oily residue is crystallized from ethyl acetate.
Reaction SMILES: [NH:1]([C:8](=[O:42])[CH:9]([C:19]1[CH:41]=[CH:40][C:22]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:24])=[CH:21][CH:20]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[B-](F)(F)(F)[F:50].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C1COCC1.C(OCC)(=O)C>[NH:1]([C:8](=[O:42])[C:9]([C:19]1[CH:41]=[CH:40][C:22]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:24])=[CH:21][CH:20]=1)([C:10]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:11])[F:50])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: F[B-](F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(F)(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Reaction time: 0.08 h
Yield: 18 %

Procedure:
tert-Butyl [2-({(4-[2-anilino-1-(anilinocarbonyl)-1-fluoro-2-oxoethyl]benzoyl}amino)phenyl]carbamate. To a solution of tert-butyl [2-({4-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]benzoyl}amino)phenyl]carbamate (59 mg, 0.10 mmol) in THF (2 mL) at room temperature was added potassium tert-butoxide (110 μL, 1 M in THF, 0.11 mmol). The solution was stirred for 5 min and Selectfluor™ (40 mg, 0.11 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 18 h, diluted with ethyl acetate, washed with saturated NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by reverse phase HPLC (30% to 100% MeCN in water) gave tert-butyl [2-({-4-[2-anilino-1-(anilinocarbonyl)-1-fluoro-2-oxoethyl]benzoyl}amino)phenyl]carbamate (11 mg, 18%) as a white solid: 1H NMR (600 MHz, CDCl3) δ 9.42 (s br, 1H), 9.11 (s br, 2H), 8.02 (d, J=8.2 Hz, 2H), 7.86 (d, J=8.5 Hz, 2H), 7.77 (d, J=7.9 Hz, 1H), 7.58 (d, J=7.6 Hz, 4H), 7.37 (t, J=7.6 Hz, 4H), 7.25-7.16 (m, 5H), 6.78 (s br, 1H); ESIMS calcd 605.2 (M++H), found 605.2 (M++Na).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([OH:12])[C:3]=1[Cl:13].[CH2:14]1CCN2C(=NCCC2)CC1.CI.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:1][C:2]1[C:3]([Cl:13])=[C:4]([O:12][CH3:14])[C:5]([O:10][CH3:11])=[CH:6][C:7]=1[CH:8]=[O:9]
Reactant: COc1cc(C=O)c(Br)c(Cl)c1O
Reactant: C1CCC2=NCCCN2CC1
Solvent: CI
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(C=O)c(Br)c(Cl)c1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 71 %

Procedure:
Into 50 ml of acetonitrile were suspended 5.39 g (20.3 mmol), of 6-bromo-5-chlorovanillin, and 3.04 ml (20.3 mmol) of 1.8-diazabicyclo[5,4,0]-7-undecene and 2.53 ml (40.6 mmol) of methyl iodide were added dropwise under cooling with ice. After stirred for 5 hours at room temperature, 3.9 ml (22.33 mmol) if diisopropylethylamine and 2.53 ml (40.6 mmol) of methyl iodide were added under cooling with ice and the mixture was stirred for 20 hours at room temperature. After distilled off the solvent, 200 ml of dichloromethane were added to the residue, which was washed with water. After dried over anhydrous magnesium sulfate, the concentrated residue was purified by means of silica gel column chromatography (hexane-AcOEt 5:1) to obtain 4.04 g (yield 71%) of title compound as colorless needle-like crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1>[Pd].CO>[CH3:1][O:2][C:3](=[O:21])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)COc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)COc1ccc(-c2ccc(N)cc2)cc1
Yield: 34.6 %

Procedure:
A mixture of (4′-nitro-biphenyl-4-yloxy)-acetic acid methyl ester (2.26 g, 7.86 mmol), prepared in the previous step, and 10% palladium on carbon in methanol was hydrogenated under a hydrogen atmosphere at room temperature. The reaction was filtered and the filtrate concentrated under reduced pressure. Purification of the residue on silica gel using 20% ethyl acetate hexanes as the eluent gave (4′-amino-biphenyl-4-yloxy)-acetic acid methyl ester (700 mg. 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].Cl[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:19]>>[CH2:21]([O:20][C:18]([N:14]1[C:13](=[O:16])[CH:12]=[CH:11][C:10]([C:4]2[CH:5]=[C:6]([Cl:9])[C:7]([CH3:8])=[C:2]([Cl:1])[CH:3]=2)=[N:15]1)=[O:19])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCOC(=O)Cl
Reactant: Cc1c(Cl)cc(-c2ccc(=O)[nH]n2)cc1Cl
Product: CCCCOC(=O)n1nc(-c2cc(Cl)c(C)c(Cl)c2)ccc1=O
Temperature: 25 °C
Yield: 92.9 %

Procedure:
A mixture of 2.55 g of 6-(3,5-dichloro-4-methylphenyl)-3-pyridazone and 6.8 g of butyl chloroformate was heated under reflux for 1 hour. The reaction mixture was then left to cool at room temperature and the precipitate produced was collected by filtration, washed with hexane and dried under reduced pressure, giving 3.3 g (93%) of the desired Compound No. 32 in the form of colourless plates melting at 153°-157° C.
Reaction SMILES: [CH:1]1([N:7]2[C:11](=[O:12])[C:10](=[CH:13][C:14]([O:16]C)=[O:15])[S:9][C:8]2=[N:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Li+].Cl>CN(C)C=O.O>[CH:1]1([N:7]2[C:11](=[O:12])[C:10](=[CH:13][C:14]([OH:16])=[O:15])[S:9][C:8]2=[N:18][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)C=C1SC(=NC2CCCCC2)N(C2CCCCC2)C1=O
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)C=C1SC(=NC2CCCCC2)N(C2CCCCC2)C1=O
Yield: 67.9 %

Procedure:
A mixture of methyl [3-cyclohexyl-2-(cyclohexylimino)-4-oxo-5-thiazolidinylidene]acetate (5.0 g, 14 mmoles) and anhydrous lithium iodide (7.6 g, 57 mmoles) in N,N-dimethylformamide (30 mls) is heated under argon to reflux. After six hours the mixture is cooled, diluted with water, acidified with 4N HCl, and extracted twice with dichloromethane. The combined extracts are washed with brine and dried over MgSO4. The solvent is removed to afford a syrupy residue which evenually crystallizes. Recrystallization from acetonitrile gave the product (3.2 g), mp 189°-190° C.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=O)=[C:4]([Cl:13])[CH:3]=1.[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(OCC)(=O)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:8](=[O:10])[CH2:7][O:6][C:5]2[CH:11]=[CH:12][C:2]([Br:1])=[CH:3][C:4]=2[Cl:13])[CH:18]=1
Reactant: O=C(O)COc1ccc(Br)cc1Cl
Reactant: COC(=O)c1ccnc(N)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccnc(NC(=O)COc2ccc(Br)cc2Cl)c1
Temperature: 25 °C
Yield: 55.6 %

Procedure:
To solution of (4-bromo-2-chloro-phenoxyacetic acid (100 mg, 0.378 mmol), 2-amino isonicotinic acid methyl ester (86.42 mg, 0.568 mmol) and DMAP (69.43 mg, 0.568 mmol) in DMF 2 mL was added PyBOP (295 mg, 0.568 mmol) at room temperature. Reaction mixture was stirred at room temperature. Resulting mixture poured onto ice cold water, was diluted by ethyl acetate. The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by flash silica gel column chromatography (EtoAC:Hexane=1:9˜4:6) to give 2-[2-(4-bromo-2-chloro-phenoxy)-acetylamino]-isonicotinic acid methyl ester as a colorless solid (0.084 g, 56% yield).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:17]=2)=[O:15])[CH:8]=1)C.O[Li].O>>[C:26]1([C:18]2[CH:17]=[C:16]([C:14]([NH:13][C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[O:6][CH2:5][C:4]([OH:32])=[O:3])=[O:15])[C:25]3[C:20]([CH:19]=2)=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)COc1cccc(NC(=O)c2cc(-c3ccccc3)cc3ccccc23)c1
Agent: [Li]O
Solvent: O
Product: O=C(O)COc1cccc(NC(=O)c2cc(-c3ccccc3)cc3ccccc23)c1

Procedure:
Compound 9a was synthesized from 8a (0.21 mmol) and LiOH.H2O (0.63 mmol) using the procedure according to the above Method E.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[O:14][C@@H:13]([O:15][CH:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[CH2:17]Br)[CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1.[I-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[O:14][C@@H:13]([O:15][CH:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[CH2:17][N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)[CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: c1c[nH]cn1
Reactant: Clc1ccc(COC[C@H]2CCC[C@H](OC(CBr)c3ccc(Cl)cc3Cl)O2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(COC[C@H]2CCC[C@H](OC(Cn3ccnc3)c3ccc(Cl)cc3Cl)O2)cc1
Reaction time: 6 h
Yield: 56 %

Procedure:
A solution of 121 mg of trans-6-(4-chlorobenzyloxymethyl)-2-[2-bromo-1-(2,4-dichlorophenyl)ethoxy]tetrahydropyran, 73 mg of imidazole and 81 mg of sodium iodide in 3 ml of dimethylformamide was heated, with stirring, at 130°-140° C. for 6 hours, after which the mixture was treated and the product purified essentially as described in Example 34(b)(i), to give 66 mg of the title compound, in the form of a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C([Li])(CC)C.CN(C)CCN(C)C.[Cl:24]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:24][C:3]1[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cccc(F)c1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: O=C(O)c1cccc(F)c1Cl
Temperature: -90 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A solution of 3-fluorobenzoic acid (8.0 g, 64.3 mmol) in 40 mL of THF was added dropwise to a solution of sec-butyllithium (90 mL, 128.6 mmol) and N,N,N′,N′-tetramethylethylenediamine (20.0 mL, 147.9 mmol) in THF (100 mL) at −90° C. After addition, the reaction mixture was stirred at −90° C. for 30 minutes. Hexachloroethane (54 g, 257.2 mmol) in THF (100 mL) was added to reaction mixture dropwise. Then the reaction mixture was stirred at −78° C. to room temperature for 16 hours. The solvent was evaporated and the water was added to the residue. The reaction mixture was acidifed to PH=1 by added conc. hydrochloric acid. Then the reaction mixture was extracted with ether (3×). The combined organic phase was dried and conc. The crude product was washed with hexane for 3 times. Then it was filtered to get pure product (9.2 g, 93%). EI-MS m/z 172.89 (M−).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1.C(O)(=O)C>Br(O)(=O)=O.C(OCC)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:7][CH:8]=1
Reactant: CCC(=O)c1ccc(OC)cc1
Agent: [O-][Br+2]([O-])O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCC(=O)c1ccc(O)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 69891.1 %

Procedure:
While 20 g (0.121 mmol) of 1-(4-methoxyphenyl)-1-propanone (7) prepared in Example 1-2 were added to 139 ml (2.4 mol) of acetic acid and stirred, 270 ml (2.4 mmol) of 48% bromic acid were added. Subsequently, the temperature was gradually increased to 100° C. and stirring under reflux was continued for 18 hr. The temperature was decreased to room temperature, and ethyl acetate was added, and organic layer was washed with water. Thereafter, the organic layer was washed with a saturated aqueous solution of potassium carbonate, then concentrated under reduced pressure, after which the precipitated solid was recrystallized with ethyl acetate/n-hexane system, and filtered, thus obtaining 12.7 g (yield: 70%) of a title compound (8) as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(-c2ccnc(Cl)n2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2ccnc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
To a solution of 17 (3.7 g, 16.8 mmol) in dry dichloromethane (42 mL) at 0° C. was added boron tribromide (3.17 mL, 33.5 mmol). The mixture was stirred vigorously at room temperature for 16 h, cooled down to 0° C. Ice-water was poured-in and the stirring was continued for 30 min. The reaction mixture was concentrated to form a precipitate which was collected by filtration, washed with water, dried and purified by flash chromatography on silica gel (MeOH/CH2Cl2: 2/98) to afford the title compound 18 (3.28 g, 15.9 mmol, 94% yield). 1H NMR: (400 MHz, DMSO-d6) δ (ppm): 10.26 (s, 1H), 8.66 (d, J=5.6 Hz, 1H), 8.05 (td, J=8.4, 1.6 Hz, 2H), 7.96 (d, J=5.6 Hz, 1H), 6.90 (td, J=8.4, 1.6 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([CH2:12][CH2:13][CH2:14][N:8]3[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:26]([N:33]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:34][CH2:35]Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:26]([N:33]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:34][CH2:35][O:16][C:15]([C:6]1[C:5](=[O:18])[C:4]2[C:9]3=[C:10]([CH2:12][CH2:13][CH2:14][N:8]3[CH:7]=1)[CH:11]=[C:2]([O:1][CH2:35][CH2:34][N:33]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH:3]=2)=[O:17])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: ClCCN(Cc1ccccc1)Cc1ccccc1
Reactant: O=C(O)c1cn2c3c(cc(O)cc3c1=O)CCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCCN(Cc1ccccc1)Cc1ccccc1)c1cn2c3c(cc(OCCN(Cc4ccccc4)Cc4ccccc4)cc3c1=O)CCC2
Temperature: 60 °C
Yield: 88.1 %

Procedure:
9-Hydroxy-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid (GB1417129) (0.905 g, 3.69 mmol) was suspended in dry DMF (50 mL). To this was added potassium carbonate (3.06 g, 22 mmol) and dibenzyl-(2-chloroethyl)amine hydrochloride (2.37 g, 8 mmol). The mixture was heated at 60° C. for 16 h, then more potassium carbonate (0.55 g) and dibenzyl-(2-chloroethyl)amine hydrochloride (1.18 g, 4 mmol) were added. After a further 25 h at 75° C. the mixture was evaporated. The residue was diluted with water and extracted with ethyl acetate (×3). The combined organic extracts were washed with brine, dried and evaporated under reduced pressure. The crude product (4.0 g) was purified by chromatography on silica gel (100 g), eluting with 0-4% methanol in dichloromethane, to give the title compound (2.25 g, 89%); ESMS m/z 692 [M+H]+ (100%).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[N:12]1([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CC(=O)OCC>>[N:11]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH2:2][N:15]1[CH2:14][CH2:13][N:12]([C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)[CH2:17][CH2:16]1
Reactant: ClCc1nc2cccnc2s1
Reactant: Oc1ccc(N2CCNCC2)cc1
Solvent: CCOC(C)=O
Product: Oc1ccc(N2CCN(Cc3nc4cccnc4s3)CC2)cc1

Procedure:
The product from Example 38A (150 mg, 0.81 mmol), 4-(1-piperazinyl)phenol (160 mg, 0.98 mmol), and D1 EA (280 μL, 1.6 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.73 (m, 4H) 3.02 (m, 4H) 4.03 (s, 2H) 6.72 (m, 4H) 7.56 (dd, J=8.14, 4.75 Hz, 1H) 8.33 (dd, J=8.14, 1.70 Hz, 1H) 8.59 (dd, J=4.58, 1.53 Hz, 1H): (ESI) m/z 327 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:4][N:3]=1.O.NN>[Ni].CO>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1nccc(OCc2ccccc2)c1N
Yield: 85.4 %

Procedure:
A mixture of 0.88 g of 2-amino-4-benzyloxy-3-nitropyridine (starting material M2), 0.81 ml of hydrazine hydrate and 0.100 g of Raney nickel in 25 ml of methanol is heated under reflux until no starting material is detectable by TLC. After filtration and evaporation of the solvent the residue is chromatographed on silica gel (dichloromethane/methanol 20:1+1% triethylamine). Concentration of the pure fractions and drying in vacuo gives 0.66 g of the title compound as a brownish solid of m.p. 135–136° C. The mass spectrum shows the molecular peak MH+ at 216.1 Da.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[C:38]1([O:44][C:45](Cl)=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl>[CH3:24][N:21]1[C:22]([CH3:23])=[C:18]([C:16]([NH:15][C:12]2[N:13]=[CH:14][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:45](=[O:46])[O:44][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:7]=3)=[CH:10][CH:11]=2)=[O:17])[C:19](=[O:31])[N:20]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cn2)c(=O)n(-c2ccccc2)n1C
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)cn2)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
To a suspension of N-(5-((2-aminopyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (0.25 g, 0.6 mmol) in DCM (20 mL) was added pyridine (0.65 mL, 6 mmol). The suspention was cooled to 0° C., followed by slowly addition of a solution of phenylcarbonochloridate (98 mg, 0.63 mmol) in DCM (5 mL). The reaction was stirred at rt for 2 hours, diluted with DCM (20 mL), and then washed with water (25 mL×2), followed by washing with brine (25 mL). The organic solution was dried over anhydrous Na2SO4, then concentrated in vacuo, and the residue was purified by a silica gel column chromatography (DCM/MeOH (v/v)=100/1) to give the title compound as a white solid (134 mg, 42%).