Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([S:14]([OH:17])(=[O:16])=[O:15])[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:11]=2[C:12]=1[OH:13])=[O:2].C(=O)([O-])[O-:19].[Na+].[Na+].[K]>>[C:1]([C:3]1[CH:4]=[C:5]([S:14]([OH:17])(=[O:16])=[O:15])[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:11]=2[C:12]=1[OH:13])([OH:19])=[O:2]
Reactant: O=Cc1cc(S(=O)(=O)O)c2cccnc2c1O
Reactant: O=C([O-])[O-]
Agent: [K]
Agent: [Na+]
Product: O=C(O)c1cc(S(=O)(=O)O)c2cccnc2c1O
Temperature: 52 °C
Reaction time: 0.92 h
Yield: 48.5 %

Procedure:
The 7-formyl-8-hydroxyquinoline-5-sulfonic acid (15 mmol, 3.80 g) was dissolved in sodium carbonate solution (34.5 mmol, 3.66 g in 200 mL of H2O). The solution was stirred and heated at 52° C. (oil bath). Then to the hot solution potassium permaganate (37.5 mmol, 5.94 g) was added. The temperature was increased to 68° C. The stirring and heating (60°-65° C.) was continued for 55 minutes. After that time the reaction mixture was filtered, and the solid was washed with sodium carbonate solution followed by water. The filtrate was concentrated under reduced pressure, acidified with 50% sulfuric acid (pH 3) and left for crystallization. The precipitate was filtered off, washed with a small amount of water and dried to give 1.96 g of 7-carboxy-8-hydroxyquinoline-5-sulfonic acid (48.5%).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([NH:20][S:21]([C:24]1[CH:33]=[C:32]([NH:34][NH2:35])[CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27])(=[O:23])=[O:22])([CH3:19])([CH3:18])[CH3:17].[C:36]1([CH2:42][C:43](O)=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:16]([NH:20][S:21]([C:24]1[CH:33]=[C:32]([NH:34][NH:35][C:43](=[O:44])[CH2:42][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27])(=[O:23])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=C(O)Cc1ccccc1
Reactant: COC(=O)c1ccc(NN)cc1S(=O)(=O)NC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(NNC(=O)Cc2ccccc2)cc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1.5 g (7.3 mmol) of dicyclohexylcarbodiimide (DCC) are added to a solution of 2.0 g (6.6 mmol) of methyl 2-(N-tert-butylsulfamoyl)-4-hydrazinobenzoate, 0.9 g (6.6 mmol) of phenylacetic acid and 0.03 g of 4-dimethylaminopyridine (DMAP) in 20 ml of CH2Cl2 at 0° C. The mixture is stirred at 25° C. for 15 hours, the solid is filtered off with suction and the organic phase is washed successively with water, 1N HCl and NaHCO3 solution, dried and evaporated. This gives 1.6 g (58% of theory) of methyl 2-(N-tert-butylsulfamoyl)-4-(2-phenylacetyl-hydrazino)benzoate with the following nuclear magnetic resonance data:
Reaction SMILES: C[Li].[N+:3]([C:6]1[CH:49]=[CH:48][CH:47]=[CH:46][C:7]=1[CH2:8][O:9][C:10]([CH:12]([PH:27]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:13]1[CH:16]([CH2:17][C:18]([C:20]2C=CC=CC=2)=S)[CH2:15][C:14]1=[O:26])=[O:11])([O-:5])=[O:4].[NH4+].[Cl-].CC[O:54]CC>C1COCC1.C(Cl)Cl>[N+:3]([C:6]1[CH:49]=[CH:48][CH:47]=[CH:46][C:7]=1[CH2:8][O:9][C:10]([CH:12]([PH:27]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[N:13]1[CH:16]([CH2:17][C:18]([CH3:20])=[O:54])[CH2:15][C:14]1=[O:26])=[O:11])([O-:5])=[O:4]
Reactant: CCOCC
Reactant: O=C(OCc1ccccc1[N+](=O)[O-])C(N1C(=O)CC1CC(=S)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)CC1CC(=O)N1C(C(=O)OCc1ccccc1[N+](=O)[O-])[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.08 h

Procedure:
Cuprous iodide (0.380 g) is suspended in 10 ml anhydrous ether under N2, in a dry flask and cooled to 0°. Methyl lithium (3.0 ml, 1.3 Molar) is added dropwise and the mixture is stirred at 0° for 5 min to give a yellow suspension. The mixture is then cooled to -50°. 1-(o-nitrobenzyloxycarbonyl-triphenylphosphoranylmethyl)-4-(phenylthiocarbonylmethyl)-2-azetidinone (0.674 g) in 10 ml THF is added dropwise over 5 min. The mixture is stirred at -50° for 5 min and allowed to come to -20° over 20 min and stirred at -20° for 5 min. Saturated NH4Cl solution 5 ml is added and the mixture is diluted with CH2Cl2. Stirred at r.t. for 5 min. The organic phase is separated, dried and evaporated. The residue is chromatographed on silica gel using EtOAc as eluant to give 0.162 g of the product 0.112 g of recovered thio ester.
Reaction SMILES: [CH3:1][O-:2].[Na+].[SH:4][CH2:5][CH2:6][CH2:7][Si:8]([O:13][CH3:14])([O:11][CH3:12])[O:9][CH3:10].II>CO>[CH3:12][O:11][Si:8]([O:13][CH3:14])([O:9][CH3:10])[CH2:7][CH2:6][CH2:5][S:4][S:4][CH2:5][CH2:6][CH2:7][Si:8]([O:11][CH3:12])([O:9][CH3:10])[O:2][CH3:1]
Reactant: C[O-]
Reactant: CO[Si](CCCS)(OC)OC
Agent: II
Agent: [Na+]
Solvent: CO
Product: CO[Si](CCCSSCCC[Si](OC)(OC)OC)(OC)OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 28% solution of sodium methylate in methanol (97.6 g. 0.51 mole) is diluted with methanol (100 ml), and thereto is added γ-mercaptopropyltrimethoxysilane (100 g, 0.51 mole). The temperature of the mixture raises in a certain degree owing to the mixing heat but return to room temperature after about 30 minutes. To the mixture is added in portions iodine (64.6 g. 0.51 mole) with stirring. In view of exothermic reaction, the reaction vessel is cooled with ice water. After completion of the addition of iodine, the brown mixture is allowed to stand at room temperature for 3 hours to give a clean liquid having pale yellow color. The reaction mixture is moved to a flask, and the methanol solvent is distilled off under reduced pressure with a rotary evaporator. The residue containing white crystals and pale yellow liquid is filtered to separate the oily liquid (86.4 g). This liquid is subjected to analyses of IR, H-NMR and UV spectra, and thereby, it is confirmed that the liquid product is bis[γ-(trimethoxysilyl)propyl ]disulfide of the formula:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][N:3]=1.[Br:10]N1C(=O)CCC1=O>ClC1C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:10][CH2:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: Cc1cnc(Cl)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: Clc1cc(Cl)c(CBr)cn1
Temperature: 132 °C
Reaction time: 16 h
Yield: 125.3 %

Procedure:
2,4-dichloro-5-methylpyridine (13.64 g, 82.50 mmol), N-bromosuccinimide (15.42 g, 86.63 mmol) were dissolved in chlorobenzene (300 mL). 2,2′-azobis(isobutyronitrile) (1.355 g, 8.250 mmol) in chlorobenzene (160 mL) was added slowly in two times: first approximately a third of the total amount at room temperature, then the rest dropwise (over 40 min) at 132° C. The reaction mixture was stirred at 132° C. for 16 h. The reaction mixture was washed with a saturated sodium sulfite solution (organic layer at the top), then with a saturated sodium bicarbonate solution (organic layer at the bottom). The organic phase was dried with sodium sulfate, then filtered and concentrated. A crude material was obtained as a yellow oil (24.9 g). It was purified by flash chromatography (Heptanes/AcOEt gradient from 0 to 10% AcOEt) to yield pale yellow crystals (13.84 g).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:6]=1[C:7]([O-:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH:17]([O-])=O.[K+]>CCO.O.[Pd]>[C:1]([C:5]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:6]=1[C:7]([O:9][CH3:17])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C[O-]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1C(=O)[O-]
Agent: [Pd]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(N)ccc1C(C)(C)C
Temperature: 25 °C
Yield: 96.5 %

Procedure:
To a refluxing solution of 2-tert-butyl-5-nitrobenzoate (90 mg, 0.38 mmol) in EtOH (2.0 mL) was added potassium formate (400 mg, 4.76 mmol) in water (1 mL), followed by the addition of 20 mg of 10% Pd—C. The reaction mixture was refluxed for additional 40 min, cooled to room temperature and filtered through Celite. The filtrate was concentrated to give methyl 2-tert-butyl-5-aminobenzoate (E-6) (76 mg, 95%), which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.24 (d, J=8.6 Hz, 1H), 6.67 (dd, J=8.6, 2.7 Hz, 1H), 6.60 (d, J=2.7 Hz, 1H), 3.86 (s, 3H), 1.34 (s, 9H); HPLC ret. time 2.19 min, 10-99% CH3CN, 5 min run; ESI-MS 208.2 m/z (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([CH:9]=[N:10]O)[CH:5]=[CH:4][N:3]=1>C(O)(=O)C.[Zn]>[F:8][C:7]1[CH:2]=[N:3][CH:4]=[CH:5][C:6]=1[CH2:9][NH2:10]
Reactant: ON=Cc1ccnc(Cl)c1F
Agent: [Zn]
Solvent: CC(=O)O
Product: NCc1ccncc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Zinc dust (2.52 g, 38.6 mmol) was added at RT to a solution of 2-chloro-3-fluoro-pyridine-4-carbaldehyde oxime (1.34 g, 6.29 mmol) in acetic acid (30 mL). The reaction mixture was stirred at RT for 2 h, then concentrated in vacuo. The colored oily residue was partitioned between CH2Cl2 and 1N HCl. The layers were separated and the aqueous phase was extracted twice with CH2Cl2. The pH of the aqueous layer was then adjusted to pH=9 with 1N NaOH, and the resulting white suspension was extracted repeatedly with CH2Cl2. The combined organics were dried (phase separator) and concentrated in vacuo to afford the title compound as a yellow oil. MS (LC/MS): 127.0 [M+H]+; tR (HPLC conditions c): 0.50 min.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([Cl:12])=[N:6][CH:5]=1.[OH-].[Na+].Cl>CO>[Cl:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:4]([C:3]([OH:13])=[O:2])=[CH:5][N:6]=1
Reactant: COC(=O)c1cnc(Cl)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)O)cnc1Cl
Reaction time: 24 h
Yield: 74.6 %

Procedure:
To a solution of 6-chloro-5-methoxynicotinic acid methyl ester (1.3 g, 6.4 mmol) in MeOH (4 mL) at 25° C. was added 10% NaOH aqueous solution (19.3 mmol). The reaction was stirred for 24 h, then placed into an ice water bath and acidified with 2M HCl until pH=2 was achieved. The flask was then placed into a refrigerator for 3 h. The white precipitate was filtered off and rinsed with cold H2O. The solid was dissolved in acetone, dried over MgSO4 and concentrated to furnish the product 6-chloro-5-methoxynicotinic acid as a yellow solid (0.895 g, 74%); 1H NMR (400 MHz, CDCl3) δ 8.45 (d, 1H), 7.66 (d, 1H), 3.83 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][C:10]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[NH:19][C:18]=2[CH3:27])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:35][C:36]([O:38]C(C)(C)C)=[O:37]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][C:10]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[N:19]([CH2:35][C:36]([OH:38])=[O:37])[C:18]=2[CH3:27])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1[nH]c2ccc(Cl)cc2c1C1=NN(Cc2ccccc2)C(=O)C(C)(C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(C2=NN(Cc3ccccc3)C(=O)C(C)(C)C2)c2cc(Cl)ccc2n1CC(=O)O
Temperature: 80 °C

Procedure:
The product of step b) (˜0.3 mmol) was dissolved in 5 mL DMF and treated with K2CO3 (1 mmol, 138 mg) and t-butyl bromoacetate (1 mmol, 195 mg). After heating to 80° C. for ½ h, the reaction was cooled, diluted with EtOAc and washed 5× water. The reaction was concentrated, dissolved in EtOH (5 mL) and treated with 1.4 mL of 1M NaOH. After heating to 80° C. for ½ h, the reaction was acidified with 3 M HCl and extracted into DCM (3×).
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>ClCCl.N1C=CC=CC=1>[C:26]([C:25]1[CH:28]=[CH:29][C:22]([NH:21][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:21][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)=[O:13])=[CH:23][CH:24]=1)#[N:27]
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: N#Cc1ccc(N)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(NC(=O)c2ccccc2SSc2ccccc2C(=O)Nc2ccc(C#N)cc2)cc1
Yield: 12.5 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 4-aminobenzonitrile (1.38 g, 11.7 mmol) in 11 mL of pyridine. The crude product was triturated with a hot mixture of ethyl acetate and ethanol (1:1), filtered, and recrystallized from ethanol-DMF-water to yield 0.37 g of the title compound, mp 239°-241° C.
Reaction SMILES: [C:1]1([P:7](=[O:17])([O-:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[C:1]1([P:7](=[O:16])([O:17][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P([O-])(OCc1ccccc1)c1ccccc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=P(OCCN1CCOCC1)(OCc1ccccc1)c1ccccc1
Temperature: 65 °C
Reaction time: 22 h
Yield: 74.6 %

Procedure:
A mixture of monobenzyl phenylphosphonate (115 mg, 0.46 mmol), N-(2-chloroethyl)morpholine hydrochloride (95 mg, 0.51 mmol) and potassium carbonate (140 mg, 1.0 mmol) in anhydrous DMF was stirred at 65° C. for 22 hours. Following dilution with ethyl acetate (40 ml), the mixture was washed with water four times and finally brine before being dried over magnesium sulfate, filtered and concentrated to leave 124 mg (74%) of the title compound as a pale yellow oil which was used without further purification. MS: 362 m/z (M+H)+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([OH:15])[CH3:14].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:15][CH:13]([C:3]1[O:4][C:5](=[O:12])[C:6]2[C:11]([C:2]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:14]
Reactant: OB(O)c1ccccc1
Reactant: CC(O)c1oc(=O)c2ccccc2c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(O)c1oc(=O)c2ccccc2c1-c1ccccc1
Temperature: 120 °C

Procedure:
4-Bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one (Intermediate A2, 0.77 g, 2.88 mmol), phenylboronic acid (0.63 g, 5.18 mmol), Pd(PPh3)4 (0.199 g, 0.173 mmol) and Cs2CO3 (1.49 g, 4.6 mmol) were dissolved in DMF (10.7 ml) and heated under microwave irradiation at 120° C. for 20 min. The reaction mixture was then diluted with AcOEt (100 mL) and filtrate. The organic phase was washed twice with 0.5 M HClaqueous, twice with water, sat NaHCO3 and once with sat NaClaqueous. The resulting organic phase was dried over Na2SO4, filtered and concentrated. The crude was finally purified on Biotage Si 50 g Ultra with a gradient of Hexane and EtOAc. The title compound was recovered as dark pink solid (0.53 g, 1.99 mmol, 69.3%) as a dark pink solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[CH:10]=[N:9][CH:8]=1)=[O:6])[CH3:3].[CH2:20](O)CC>>[CH2:2]([O:4][C:5]([C:7]1[C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[CH:10]=[N:9][CH:8]=1)=[O:6])[CH2:3][CH3:20]
Reactant: CCCO
Reactant: CCOC(=O)c1cncc2[nH]c3ccccc3c12
Agent: Cl
Product: CCCOC(=O)c1cncc2[nH]c3ccccc3c12

Procedure:
The compound is produced by transesterification of the β-carboline-4-carboxylic acid-ethyl ester-hydrochloride with n-propanol.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:4][C:3]=1OC.[F:32]C1C=CC(C=CCBr)=CC=1>>[F:32][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C=CCBr)cc1
Reactant: COc1cc(/C=C/CN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)ccc1O
Product: Fc1ccc(/C=C/CN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)cc1

Procedure:
The same procedure was followed as in Example 11 using the compound (9) synthesized in Example 2 and 4-fluorocinnamyl bromide to produce the above.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5](Cl)=[N:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1.[CH2:14]([OH:19])[C:15]([F:18])([F:17])[F:16]>>[Br:3][C:4]1[C:5]([O:19][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1
Reactant: OCC(F)(F)F
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1cnc(OCC(F)(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
Sodium hydride (3.2 g, 80.02 mmol) was added carefully in small portions to 2,2,2-trifluroethanol (CAS Registry No. 75-89-8) (60 ml) at 0° C. under nitrogen atmosphere and stirred at 25° C. for 30 minutes. Then 3-bromo-2-chloro-5-nitropyridine (CAS Registry No. 5470-17-7) (2 g, 8.42 mmol) in trifluoroethanol was added, and the reaction mixture was refluxed for 16h. The solvent was evaporated in vacuo, and the residue was taken up in water and extracted with ethyl acetate (3×120 ml). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated to get the crude residue (3 g). The crude was purified by column chromatography (3% ethyl acetate/hexane) to give the desired product (2.4 g, 95%) as yellow liquid. MS (LC/MS): not responding, NMR is in agreement with the structure: 1H-NMR (400 MHz, CDCl3): δ 4.90 (m, 2H), 8.68 (d, 1H), 8.98 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:31])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[O:19][C:20]([CH2:23][N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[CH:21][CH:22]=3)[S:17][C:10]=12.C1(C)C=CC=CC=1.C(O)C.[C:42]1([CH2:48][C:49]([N:51]=[C:52]=[S:53])=[O:50])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:31][C:52]([NH:51][C:49](=[O:50])[CH2:48][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[S:53])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[O:19][C:20]([CH2:23][N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)=[CH:21][CH:22]=3)[S:17][C:10]=12
Reactant: CN1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(N)cc5F)c4s3)o2)CC1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=S)NC(=O)Cc6ccccc6)cc5F)c4s3)o2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
To a 5 mL round bottom flask was added 3-fluoro-4-(2-(5-((4-methylpiperazin-1-yl)methyl)furan-2-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine (32 mg, 0.0713 mmol) and 1:1 toluene/ethanol (1 mL). 2-Phenylethanoyl isothiocyanate (25.3 mg, 0.143 mmol; prepared according to the procedure described by J. Org. Chem. 1964, 29, 1115-1119) was added as a solution in toluene (0.5 mL). After stirring for 30 minutes at room temperature, the crude was concentrated in vacuo. The crude was dissolved in MeOH and purified by preparative TLC, eluting with 9:1 CH2Cl2/MeOH. The product was collected at Rf 0.4 just above the unreacted starting material at Rf 0.3 to provide the product (5 mg, 10%) as a white solid. LRMS (APCI+) m/e 626 (M+1) detected; 1H NMR (CDCl3, 400 MHz) δ 9.98 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.22 (s, 1H), 7.75 (d, J=13.7 Hz, 1H), 7.62 (s, 1H), 7.45 (m, 2H), 7.24 (m, 2H), 7.07 (t, J=8.6 Hz, 2H), 6.71 (s, 1H), 6.35 (s, 1H), 3.66 (s, 2H), 2.58 (m, 8H), 2.29 (s, 3H), 1.79 (m, 4H).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=O)[CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:30][C:26]3[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=3)[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: O=Cc1cccnc1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CC1)C1CCN(Cc2cccnc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of N-cyclopropyl-N-piperidin-4-yl-3-trifluoromethyl-benzenesulfonamide (150 mg, 0.43 mmol) and pyridine-3-carboxaldehyde (46 mg, 0.43 mmol) in dichloroethane was added sodium triacetoxyborohydride (128 mg, 0.60 mmol, 1.4 eq.). The reaction mixture was stirred at room temperature for 12 hours. After this period, the solution was decanted and purified by flash chromatography to give the title compound 19 as a yellow oil. 1H NMR (CDCl3): δ 8.55-8.48 (m, 2H), 8.15-8.11 (m, 1H), 8.08-8.02 (m, 1H), 7.87-7.81 (m, 1H), 7.71-7.59 (m, 1H), 7.25-7.20 (m, 1H), 3.92-3.81 (m, 1H), 3.48 (s, 2H), 2.91-2.81 (m, 2H), 2.10-1.87 (m, 5H), 1.56-1.45 (m, 2H), 1.01-0.94 (m, m, 2H), 0.82-0.74 (m, 2H). LC: 100%. MS (EI): m/z 440 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][Cl:20])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CO.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][Cl:20])=[C:7]([NH2:12])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCCCCCl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1cnc2cc(Br)ccc2c1NCCCCCl
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A suspension of (7-bromo-3-nitroquinolin-4-yl)-(4-chlorobutyl)amine (8.05 g, 22.5 mmol) in methanol (250 mL) was cooled to 0° C.; a solution of sodium hydrosulfite (19.5 g, 112 mmol) in water (80 mL) was added dropwise over a period of 30 minutes. The reaction was stirred at ambient temperature for two hours and then concentrated under reduced pressure. The residue was partitioned between dichloromethane (300 mL) and aqueous sodium bicarbonate (150 mL of 50%). The aqueous layer was separated and extracted with dichloromethane (2×50 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 7.25 g of crude 7-bromo-N4-(4-chlorobutyl)quinoline-3,4-diamine as a light brown semi-solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([Cl:15])[CH:9]=1)=[O:6].[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[S:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1>ClCCl.CN(C=O)C>[Cl:15][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:2]([NH:1][C:30]([NH:29][C:24]3[CH:25]=[C:26]([Cl:28])[CH:27]=[C:22]([Cl:21])[CH:23]=3)=[S:31])[CH:3]=2)[CH:13]=[CH:12][C:11]=1[CH3:14]
Reactant: COc1ccc(C(=O)Nc2ccc(C)c(Cl)c2)cc1N
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccc(C)c(Cl)c2)cc1NC(=S)Nc1cc(Cl)cc(Cl)c1
Reaction time: 16 h
Yield: 57.6 %

Procedure:
A solution of 3-amino-N-(3-chloro-4-methylphenyl)-4-methoxy-benzamide from Example 12 (0.581 g, 2.00 mmol) and 3,5-dichlorophenyl isothiocyanate (0.409 g, 2.00 mmol) in dichloromethane (40 mL) and DMF (3 mL) was allowed to stand at room temperature. After 16 hours, filtration afforded the product (0.57 g); m.p. 195-196° C.