Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([NH2:12])[CH:6]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[N:4]=1.[H-].[Na+].[C:25]([C:29]1[C:30]([Cl:38])=[C:31]([C:35](O)=[O:36])[N:32]([CH3:34])[N:33]=1)([CH3:28])([CH3:27])[CH3:26].C(Cl)(=O)C(Cl)=O>C1COCC1.C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([NH:12][C:35]([C:31]2[N:32]([CH3:34])[N:33]=[C:29]([C:25]([CH3:27])([CH3:26])[CH3:28])[C:30]=2[Cl:38])=[O:36])[CH:6]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])[N:4]=1
Reactant: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)O
Reactant: COc1nc(-c2ccccc2C(F)(F)F)cc(N)c1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1nc(-c2ccccc2C(F)(F)F)cc(NC(=O)c2c(Cl)c(C(C)(C)C)nn2C)c1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
A solution of 2-methoxy-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-ylamine (162 mg, 0.517 mmol, prepared as described in Example 5, Step B above) in THF (10 mL) was treated with NaH (62.1 mg, 1.55 mmol, 60% dispersion in oil) at room temperature, and the mixture was allowed to stir for 1 h. Simultaneously, a solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (168 mg, 0.776 mmol, prepared as described in Example B above) in anhydrous DCM (10 mL) was treated with oxalyl chloride (67.7 μL, 0.776 mmol) and DMF (2 drops), and the mixture was stirred at room temperature for 1 h. Volatile components were removed in vacuo, and the residue was taken up in anhydrous THF (6 mL). The above-prepared acid chloride solution was added to the sodium anilide solution above, and the mixture was stirred at room temperature for 1 h. The mixture was quenched with saturated aqueous NH4Cl (20 mL) and extracted twice with EtOAc (25 mL). The residue was purified on a 12-g SEPRA Si 50 SPE column (Flow rate=15 mL/min; Eluent=EtOAc-hexanes, 1:99 for 10 min, then 1:99 to 3:17 over 40 min) to yield 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [2-methoxy-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-yl]-amide as a white solid. Mass Spectrum (LCMS, APCI pos.): Calculated for C22H21N5O4ClF3: 512.1 (M+H); Measured: 512.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:31])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][C:16]=2[O:17][CH2:18][C:19](OCC)=[O:20])(=[O:11])=[O:10])[CH:8]=1)#[N:2].O.[NH2:33][NH2:34]>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:31])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][C:16]=2[O:17][CH2:18][C:19]([NH:33][NH2:34])=[O:20])(=[O:10])=[O:11])[CH:8]=1)#[N:2]
Reactant: NN
Reactant: CCOC(=O)COc1cc(C(C)C)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1O
Solvent: CCO
Solvent: O
Product: CC(C)c1ccc(CCNS(=O)(=O)c2cc(C#N)ccc2O)c(OCC(=O)NN)c1

Procedure:
Ethyl [2-[2-(5-cyano-2-hydroxybenzenesulfonylamino)-ethyl]-5-isoproylphenoxy]acetate (0.266 g) was dissolved in 5 mL of ethanol. To the solution was added 0.087 mL of hydrazine monohydrate at room temperature, and the mixture was refluxed for 1 hour. The solvent was removed under reduced pressure to give 0.258 g of 5-cyano-N-[2-(2-hydrazinocarbonylmethoxy-4-isopropylphenyl)ethyl]-2-hydroxybenzenesulfonamide.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][C@H:18]3[CH3:30])=[O:16])[CH2:11][CH2:10]2)[C:5]([N+:31]([O-:33])=[O:32])=[CH:4][N:3]=1.[N:34]1([CH2:40][CH2:41][OH:42])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH3:30][C@H:18]1[N:17]([C:15]([C@H:12]2[CH2:13][CH2:14][C@@H:9]([NH:8][C:6]3[C:5]([N+:31]([O-:33])=[O:32])=[CH:4][N:3]=[C:2]([O:42][CH2:41][CH2:40][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)[CH:7]=3)[CH2:10][CH2:11]2)=[O:16])[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Reactant: OCCN1CCCCC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)[C@H]1CC[C@@H](Nc2cc(OCCN3CCCCC3)ncc2[N+](=O)[O-])CC1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-tert-butyl 4-(cis-4-(2-chloro-5-nitropyridin-4-ylamino)cyclohexanecarbonyl)-3-methylpiperazine-1-carboxylate (0.4 g, 0.830 mmol) in toluene (8.30 mL) was added 2-(piperidin-1-yl)ethanol (0.536 g, 4.15 mmol), 18-crown-6 (0.329 g, 1.245 mmol), and cesium carbonate (0.811 g, 2.490 mmol). The reaction was purged with argon and stirred at 75° C. overnight. The mixture was diluted with EtOAc to about 50 mL total volume and washed sequentially with water (50 mL), brine (50 mL), and aqueous NH4Cl (2×50 mL). The organic layer was dried over sodium sulfate and concentrated to afford an orange residue. The residue was purified by silica gel chromatography (1-5% MeOH/DCM, 1% NH4OH) to afford (R)-tert-butyl 3-methyl-4-(cis-4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarbonyl)piperazine-1-carboxylate as a tan solid (0.33 g, 69.2% yield). MS m/z=575.4 [M+H]. Calc'd for C29H46N6O6: 574.4.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=[CH:6][CH:5]=1)(=O)[NH2:2].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[C:1]([C:4]1[N:9]=[C:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])[CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(N)=O)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)Nc1cccc(C#N)n1
Temperature: 0 °C
Yield: 62 %

Procedure:
To a round bottom flask charged with tert-butyl (6-carbamoylpyridin-2-yl)carbamate (0.940 g, 3.96 mmol) in dichloromethane (7.92 ml) was added triethylamine (1.380 ml, 9.90 mmol). The reaction mixture was cooled to 0° C. and trifluoroacetic anhydride (0.671 ml, 4.75 mmol) was added dropwise. The reaction mixture was stirred at 0° C. 90 min. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and transferred to a separatory funnel. The aqueous layer was extracted with dichloromethane (2×). The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography on the Isco system (40 g, 0-15% EtOAc/Hex) to provide tert-butyl (6-cyanopyridin-2-yl)carbamate (0.538 g).
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[Cl:21][C:22]1[C:27]([CH3:28])=[C:26](Cl)[N:25]=[CH:24][N:23]=1>C1COCC1>[Cl:21][C:22]1[N:23]=[CH:24][N:25]=[C:26]([O:7][CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)[C:27]=1[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cc1c(Cl)ncnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 30 °C
Reaction time: 17.5 h

Procedure:
Potassium tert-butoxide (3.4 gm, 0.0306 moles) was added to a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (6.8 gm, 0.0368 moles) and 4,6-dichloro-5-methylpyrimidine (5.0 gm, 0.0368 moles) in dry THF at 0° C. and the reaction mixture was stirred for 15-20 hours at 30° C. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The organic extract was washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure to collect 5.1 gm off-white solid product.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#N)[CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[Mg]Br.Cl.C1C[O:26]CC1>>[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)=[O:26]
Reactant: COc1ccc([Mg]Br)c(OC)c1
Reactant: Cc1cccc(C#N)n1
Reactant: C1CCOC1
Agent: Cl
Product: COc1ccc(C(=O)c2cccc(C)n2)c(OC)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
6-Methylpyridine-2-carbonitrile (4.88 g, 41.3 mmol) was dissolved in THF (50 mL), cooled to 0° C. and 2,4-dimethoxyphenylmagnesium bromide (20.5 mL, 10.24 mmol, 0.5 M in THF) was added. The reaction aged at rt for 3 h and was quenched with HCl (45.4 mL, 91 mmol, 2 M diethyl ether). The reaction was concentrated and extracted with EtOAc. The aq layer was basified to pH 10 and extracted with EtOAc. The combined organic portions were washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel gradient eluted with 0 to 50% EtOAc/hexane, affording the title compound. HPLC/MS: 258.3 (M+1); Rt=1.96 min.
Reaction SMILES: [Na+].[S:2]1[C:6]2[CH:7]=[C:8]([S:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.N1C=CC=CC=1.Br[C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C>[CH2:25]([O:24][C:22](=[O:23])[C:21]([S:11]([C:8]1[CH:9]=[CH:10][C:5]2[N:4]=[CH:3][S:2][C:6]=2[CH:7]=1)(=[O:13])=[O:12])([CH3:28])[CH3:27])[CH3:26]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=S([O-])c1ccc2ncsc2c1
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)S(=O)(=O)c1ccc2ncsc2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
The crude 1,3-benzothiazol-6-sulfinic acid sodium salt (1.1 g, 4.97 mmol) is suspended in DMF (15 mL). Pyridine (0.33 mL) and ethyl α-bromoisobutyrate (0.61 mL) are added. The reaction is stirred at 50° C. under nitrogen for 2 h. The reaction mixture is cooled to room temperature and the solvent is removed under reduced pressure. The residue is dissolved in ethyl acetate (20 mL) and washed with 2M aqueous HCl solution (20 mL). The acidic aqueous layer is back-extracted with ethyl acetate (2×20 mL). The combined organic extracts are washed with brine (20 mL) and dried over Na2SO4. Filtration, concentration under reduced pressure, followed by column chromatography of the residue (silica, eluent DCM, 30-40% ethyl acetate) afforded 0.85 g of 2-(benzothiazole-6-sulfonyl)-2-methyl-propionic acid ethyl ester. Yield: 66%, ES-MS: m/z 314 [M+H]; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.19 (3H, t, J=7.16 Hz), 1.67 (6H, s), 4.15 (2H, q, J=7.13 Hz), 7.99 (1H, dd, J=8.68, 1.79 Hz), 8.28 (1H, d, J=8.68 Hz), 8.54 (1H, d, J=1.48 Hz), 9.26 (1H, s);
Reaction SMILES: [CH2:1]([CH2:8][NH:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[NH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:21]([O:23][CH3:24])=[O:22]>C(COC)OC.N1C=CC=CC=1>[CH2:1]([CH2:8][NH:9][C:10]1[CH:11]=[C:12]([NH:13][C:21](=[O:22])[O:23][CH3:24])[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc([N+](=O)[O-])c(NCCc2ccccc2)c1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: COCCOC
Product: COC(=O)Nc1ccc([N+](=O)[O-])c(NCCc2ccccc2)c1
Temperature: 20 °C
Yield: 84 %

Procedure:
A stirred solution of 3-(N-benzylmethylamino)-4-nitroaniline (2.2 g, 8.5 mM) in dry dimethoxyethane (15 ml) and pyridine (4 ml) was treated dropwise with methyl chloroformate (10 mM) at 0° C. The mixture was allowed to warm slowly to 20° C. and after 3 h was quenched with water (5 ml). Volatile solvents were removed under vacuum and the residue was extracted with ethyl acetate. After successive washings with aqueous methanesulfonic acid, water, aqueous KHCO3 and brine the organic layer was dried over Na2SO4. Removal of the solvent and chromatography of the residue on silica gel in ethyl acetate-petroleum ether (3:7) gave the product as a bright red oil (2.25 g, 84% yield).
Reaction SMILES: C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:46])[NH:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[C:28]([F:47])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10](OC2C=CC=CC=2)=[O:11])C=CC=CC=1.Cl.Cl.Cl.[CH3:52][N:53]([CH3:64])[CH:54]1[CH2:57][N:56]([CH:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH2:55]1.C(N(CC)CC)C>CN(C)C=O>[CH3:52][N:53]([CH3:64])[CH:54]1[CH2:55][N:56]([CH:58]2[CH2:63][CH2:62][N:61]([C:10]([NH:9][C:19]3[CH:24]=[C:23]([O:25][C:26]4[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]5([C:38]([NH:39][C:40]6[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=6)=[O:46])[CH2:36][CH2:37]5)=[O:34])=[C:28]([F:47])[CH:27]=4)[CH:22]=[CH:21][N:20]=3)=[O:11])[CH2:60][CH2:59]2)[CH2:57]1
Reactant: CN(C)C1CN(C2CCNCC2)C1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccccc4)CC3)c(F)c2)ccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C1CN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccccc6)CC5)c(F)c4)ccn3)CC2)C1
Reaction time: 120 h
Yield: 25.2 %

Procedure:
To a solution of [4-(3-fluoro-4-{[1-(phenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (100 mg) in N,N-dimethylformamide (2.0 ml) were added 4-(3-dimethylaminoazetidin-1-yl)piperidine trihydrochloride (181 mg) and triethylamine (0.259 ml) at room temperature, followed by stirring for 5 days. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether to the resultant residue. The solid was collected by filtration. The solid was dried under aeration to provide the titled compound as white powder (24.0 mg, 25%).
Reaction SMILES: [F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[C:6]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.P(Br)(Br)(Br)=O.CCN(C(C)C)C(C)C.[CH3:40][C:41]1[NH:45][N:44]=[C:43]([NH2:46])[CH:42]=1>CN(C=O)C.C1(C)C=CC=CC=1>[F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[N:12]=[C:11]([NH:46][C:43]2[CH:42]=[C:41]([CH3:40])[NH:45][N:44]=2)[C:10]2[C:5](=[C:6]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: CS(=O)(=O)c1cccc2c(O)nc(C(F)(F)c3ccc(F)cn3)nc12
Agent: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3c(S(C)(=O)=O)cccc23)n[nH]1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-(methylsulfonyl)quinazolin-4-ol (100 mg, 0.27 mmol) were added phosphoryl tribromide (1.25 g) and toluene (0.5 mL) and DIEA (0.094 mL, 0.54 mmol), and the mixture was heated at 100° C. for 20 min. The mixture was cooled and partitioned between EtOAc and saturated aq sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. To the residue was added a solution of 5-methyl-1H-pyrazol-3-amine (67 mg, 0.69 mmol) in DMF (3 mL) and the mixture was stirred at rt for 0.5 h. The crude mixture was purified by preparative HPLC (Phenomenex C-18 reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O) to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)-8-(methylsulfonyl)quinazolin-4-amine (72 mg, 69%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.21 (s, 3H) 3.47 (s, 3H) 6.14 (s, 1H) 7.83 (t, J=7.91 Hz, 1H) 7.97-8.09 (m, 2H) 8.44 (d, J=7.35 Hz, 1H) 8.68 (s, 1H) 9.03 (d, J=8.10 Hz, 1H) 11.11 (s, 1H) 12.24-12.36 (m, 1H); LC-MS (ESI) m/z 449 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]([CH2:18]O)=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]([CH2:18][Br:23])=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(CO)ccc1CCc1ccc(F)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(CBr)ccc1CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.3 %

Procedure:
A mixture of methyl 2-(4-fluorophenethyl)-5-hydroxymethylbenzoate (13.10 g., 45.43 mmol), carbon tetrabromide (18.08 g, 54.52 mmol) and triphenylphosphine (14.30 g, 54.52 mmol) in dichloromethane (400 ml) was stirred at ambient temperature for 4 hours. More carbon tetrabromide (7.54 g, 23.00 mmol) and triphenylphosphine (5.96 g, 23.00 mmol) in dichloromethane (50 ml) were added and then stirred for a further 2 hours. The reaction was applied directly to a silica flash column and eluted with iso-hexane/ethyl acetate (92.5:7.5) to give as a clear gum methyl 2-(4-fluorophenethyl)-5-bromomethylbenzoate (9.30 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[O:16][CH:15](NC)[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.[CH:20]([N:23]([CH:26](C)C)CC)(C)[CH3:21].C(OC(=O)C)(=[O:31])C>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:26][NH:23][C:20](=[O:31])[CH3:21])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)OC(C)=O
Reactant: CNC1Cc2cccc(-c3ccccc3Cl)c2O1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)NCC1Cc2cccc(-c3ccccc3Cl)c2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
[7-(2-Chloro-phenyl)-2,3-dihydro-benzofuran-2-yl]-methylamine hydrochloride (0.050 g, 0.17 mmol) was suspended in 5.0 mL of methylene chloride and diisopropylethylamine (0.072 g, 0.56 mmol) and acetic anhydride (0.029 g, 0.28 mmol) added. The mixture was stirred at room temperature for 30 min, diluted to 100 mL with methylene chloride, washed with 50 mL portions of 2 N HCl (aqueous), saturated aqueous sodium bicarbonate and saturated brine. The solution was dried over sodium sulfate, filtered and concentrated in vacuum to give 0.047 g of the title compound as an oil which slowly hardened to a white solid in vacuum. 1H-NMR (CDCl3): doublet of doublets 7.48 δ (1H); multiplet 7.33 δ (2H); doublet 7.2 δ (1H); doublet 7.06 δ (1H); triplet 6.93 δ (1H); broad singlet 5.95 δ (1H); multiplet 4.9 δ (1H); doublet of doublets 3.7 δ (1H); doublet of doublets 3.45 δ (1H); doublet of doublets 3.35 δ (1H), doublet of doublets 3.0 δ (1H), singlet 1.95 δ (3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]3[CH2:14][C@H:15]([NH:18][C:19](=[O:39])[C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29](CC6C=CC=CC=6)[CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH2:16][O:17][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[C:13]3[CH2:14][C@H:15]([NH:18][C:19](=[O:39])[C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)=[CH:24][CH:25]=4)[CH2:16][O:17][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCN(Cc5ccccc5)CC4)cc2)CO3)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCNCC4)cc2)CO3)CC1
Temperature: 50 °C
Reaction time: 19 h
Yield: 93.3 %

Procedure:
(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-4-(4-benzylpiperazin-1-yl)benzamide (1.7 g, 3.2 mmol) was dissolved in methanol (100 mL). Palladium (10%) on activated carbon (510 mg) and ammonium formate (1.6 g, 26 mmol) were added and the reaction mixture was stirred at 50° C. for 19 h. The catalyst was filtered off and the solvent was evaporated in vacuo to give 1.3 g (92% yield) of the title compound as a pale yellow solid: mp>102° C. sinters; EIMS (70 eV) m/z (relative intensity) 435 (8, M+); [α]22D−102° (c 0.15, chloroform).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=O.[C:13](C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:15][CH2:16][CH3:17])=[O:14].[C:38]1(C)C=CC=CC=1>>[N+:10]([C:7]1[CH:8]=[CH:9][C:4](/[C:2](/[CH3:38])=[CH:1]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: Cc1ccccc1
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)/C=C(\C)c1ccc([N+](=O)[O-])cc1
Yield: 29 %

Procedure:
A toluene (90 ml) solution of 4-nitroacetophenone (2.0 g) and (carbethoxymethylidene)triphenylphosphorane (6.33 g) was stirred while refluxing under heating for 10 hours. After the solution was allowed to cool, the solvent was distilled off. The obtained residue was purified by column chromatography (6.25% ethyl acetate/n-hexane) to obtain Compound 19a (829 mg, 29%) as a white solid.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]#[N:10].[ClH:11].CCOCC>C(Cl)Cl>[ClH:11].[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([S:3][CH2:1][CH3:2])=[NH:10]
Reactant: N#Cc1cccs1
Reactant: CCS
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCSC(=N)c1cccs1
Temperature: 25 °C

Procedure:
To a stirred solution of ethanethiol (28.4 g, 0.45 mols) in methylene chloride (500 ml) at 10° C. under nitrogen was added 2-thiophenecarbonitrile (50.0 g, 0.45 mols). This solution was treated with a slow stream of HCl gas for 6 h. The reaction mixture was then allowed to warm to room temperature for 18 h. Ether (200 ml) was added and a white solid crystallized. The solid 2-thiophenecarboximidothioic acid, ethyl ester, hydrochloride was collected by filtration and air dried (65.8 g), m.p. 196-197° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26](=[O:31])[CH2:27][CH2:28][CH2:29]Cl)[CH:20]=3)=[CH:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.O>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH2:29][CH2:28][CH2:27][C:26]4=[O:31])[CH:20]=3)=[CH:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(CCCCl)Nc1cc(Oc2ccc(NC(=O)Nc3ccc(F)cc3)cc2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(Oc2ccnc(N3CCCC3=O)c2)cc1
Yield: 40.9 %

Procedure:
N-(4-Fluorophenyl)-N′-(4-{[2-(4-chlorobutyrylamino)-4-pyridyl]oxy}phenyl)urea (56 mg), potassium carbonate (46 mg) and dimethylformamide (2 ml) were stirred at 150° C. for 15 minutes. Water and ethyl acetate were added for extraction, and the extract was passed through a glass filter coated with silica gel. The silica gel was washed with ethyl acetate, and the organic layer was distilled off under reduced pressure. Ethyl acetate and hexane were added to the residue, and the precipitated solid was filtered out to obtain 21 mg of a faint brown powder.