Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)[O-].[Na+].Br[CH:7]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=[CH:8]1.[O:14]=[C:15]1[NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[NH:18][CH2:17][CH:16]1[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>CN(C)C=O>[O:14]=[C:15]1[NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]([CH:7]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=[CH:8]2)[CH2:17][CH:16]1[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2NC1=O
Reactant: BrC1C=CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CN(C2C=CCCCC2)c2ccccc2NC1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
Sodium bicarbonate (1.6 g) and 3-bromocycloheptene (3.33 g) were added to a solution of 2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (2.77 g) in N,N-dimethylformamide (20 ml), the mixture was stirred at 50° C. for one hour. After the reaction mixture was allowed to cool, ice-water was added thereto, extracted with ethyl acetate, the organic layer was washed with saturated brine. The resultant mixture was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(ethyl acetate:n-hexane=1:2), diisopropyl ether was added to the residue for crystallization, and collected by filtration, to thereby obtain 2.1 g of the title compound as the mixture of diastereomer compounds.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=3[CH3:25])=[CH:14][C:13]2=[O:26])[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:28]N(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.Cl.[OH:59][C@@H:60]([CH2:90]O)[CH2:61][N:62]1[CH:66]=[CH:65][C:64]([NH:67]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:63]1>ClCCl.C(OCC)(=O)C>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=3[CH3:25])=[CH:14][C:13]2=[O:26])[C:9]([NH:67][C:64]2[CH:65]=[CH:66][N:62]([CH2:61][C:60]([OH:59])([CH3:90])[CH3:28])[N:63]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Reactant: Cc1cccc(OC2=CC(=O)N([C@@H](CC3CCCCC3)C(=O)O)C2)c1C
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(OC2=CC(=O)N([C@@H](CC3CCCCC3)C(=O)Nc3ccn(CC(C)(C)O)n3)C2)c1C
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 30.3 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[4-(2,3-dimethyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (240 mg, 0.7 mmol) in dichloromethane (10 mL) was gradually added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (390 mg, 2.0 mmol) and N,N-diisopropylethylamine (440 mg, 3.4 mmol) at room temperature, under nitrogen. After 15 min,, 1-hydroxybenzotriazole (310 mg, 2.1 mmol) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 106 mg, 0.7 mmol) were added to the reaction mixture. The reaction mixture was then stirred at 23° C. for 48 h. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous ammonium chloride solution followed by a saturated aqueous sodium bicarbonate solution. The organic layer was then washed with a saturated aqueous sodium chloride solution, separated, dried over sodium sulfate and concentrated in vacuo to afford the crude product, which was purified by flash column chromatography (silica gel (100-200 mesh)) which afforded (S)-3-cyclohexyl-2-[4-(2,3-dimethyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (105 mg, 32%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ ppm 0.82-1.08 (m, 2H), 1.14 (br. s., 6H), 1.17-1.30 (m, 3H), 1.57-1.98 (m, 8H), 2.09 (s, 3H), 2.29 (s, 3H), 3.92 (s, 2H), 4.08 (d, J=18.0 Hz, 1H), 4.28 (d, J=18.0 Hz, 1H), 4.75 (br. s., 2H), 4.78 (br. s., 1H), 4.87 (t, J=7.6 Hz, 1H), 6.67 (d, J=2.0 Hz, 1H), 6.93 (d, J=7.8 Hz, 1H), 7.02-7.14 (m, 2H), 7.28 (d, J=2.0 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[CH2:14][C:15]3[C:20]([CH:21]=2)=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=3)=[CH:9][CH:8]=[C:7]([F:31])[C:3]=1[C:4]([NH2:6])=[O:5].[C:32]1(OS(C(F)(F)F)(=O)=O)[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O>[C:32]1([C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C:13]([CH2:12][O:11][C:10]2[C:2]([F:1])=[C:3]([C:7]([F:31])=[CH:8][CH:9]=2)[C:4]([NH2:6])=[O:5])=[CH:21]3)[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]=1
Reactant: CC1(C)OB(c2ccc3c(c2)C=C(COc2ccc(F)c(C(N)=O)c2F)C3)OC1(C)C
Reactant: O=S(=O)(OC1=CCCCC1)C(F)(F)F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1c(F)ccc(OCC2=Cc3cc(C4=CCCCC4)ccc3C2)c1F
Temperature: 80 °C
Yield: 22.3 %

Procedure:
To a solution of 2,6-Difluoro-3-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-inden-2-ylmethoxy]-benzamide (0.10 g, 0.20 mmol) in 3 ml of anhydrous DMF and water (1.5 ml) was added trifluoromethanesulfonic acid cyclohex-1-enyl ester (0.15 g, 0.60 mmol) and potassium phosphate (0.057 g, 0.20 mmol). The reaction mixture was degassed for 10 minutes followed by addition of dichlorobis(triphenyl phosphine) palladium (II) (0.02 g, 0.03 mmol). The reaction mixture was heated at 80° C. for 1 h under the nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 45% EtOAc-Hexane) to get the desired product (0.017 g, 19%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 1.63 (m, 4H), 2.20 (m, 2H), 2.45 (m, 2H), 5.67 (s, 2H), 6.29 (m, 1H), 7.12 (m, 1H), 7.37 (m, 1H), 7.57 (m, 2H), 7.90 (br s, 1H), 8.03 (d, J=8.40 Hz, 1H) and 8.18 (br s, 1H). MS ES+ (401.16), HPLC (method II) Rt=14.13 min.
Reaction SMILES: [O-][CH2:2][CH3:3].[Na+].C([C:7](CC)([C:11]([O-:13])=O)[C:8]([O-:10])=[O:9])C.[NH2:16][C:17]1[N:21]([CH3:22])[N:20]=[CH:19][C:18]=1[C:23]([O:25]CC)=O>C(O)C>[OH:25][C:23]1[C:18]2[CH:19]=[N:20][N:21]([CH3:22])[C:17]=2[NH:16][C:11](=[O:13])[C:7]=1[C:8]([O:10][CH2:2][CH3:3])=[O:9]
Reactant: CCOC(=O)c1cnn(C)c1N
Reactant: CC[O-]
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(O)c2cnn(C)c2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.3 %

Procedure:
Sodium ethoxide (95%, 83 g, 1.18 moles) was dissolved in 175 mL of absolute ethanol, following the protocol described in J. Heterocyclic Chem. (1978) 15:319 with some modifications. Diethylmalonate 2 (184.6 g, 1.18 moles) was added and stirred at room temperature for 10 minutes. Ethyl 5-amino-1-methylpyrazole-4-carboxylate 1 (50 g, 0.295 moles) was added slowly and the resulting solution refluxed overnight at 100° C. During the reflux period, an off-white solid began to form. The solution was evaporated to dryness on a rotary evaporator and the residue dissolved in a minimum amount of water. Upon acidification (pH 2) of the aqueous solution with concentrated hydrochloric acid, the resulting precipitate was filtered and recrystallized from acetic acid-water to give 3 as a white solid (˜45 g, 64%). NMR (trifluoroacetic acid): δ 1.60 (t.3H.J=7 Hz, CH3 of ester), 4.22 (s, 3H, N—CH3), 4.80 (q, 2H, J=7 hz, CH2), 8.49 (s, 1H, H-3)
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].C(O)C>[Fe].O>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[N:25]=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=3)[CH2:22][CH2:23]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Temperature: 70 °C
Yield: 69.6 %

Procedure:
1-Benzyl-4-[4-(5-nitro-pyridin-2-yl)-piperazin-1-yl]-phthalazine (500 mg, 1.17 mmol), iron powder (523 mg, 9.38 mmol), ammonium chloride (125 mg, 0.234 mmol), ethanol (6 mL) and water (1.5 mL) are all combined in 50 mL round bottom flask with stir bar. The mixture is stirred and heated to 70° C. for 4 h. Material is filtered through a pad of Celite and washed with CH2Cl2. Concentrate to remove all ethanol and residual water. The residue is purified by flash chromatography on silica gel (0-18% MeOH/CH2Cl2) to afford the title compound (323 mg, 70%).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14](OC)(OC)(OC)C>>[CH3:14][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: O=C(O)c1ccc(I)c([N+](=O)[O-])c1
Reactant: COC(C)(OC)OC
Product: COC(=O)c1ccc(I)c([N+](=O)[O-])c1
Yield: 99 %

Procedure:
A solution of 4-iodo-3-nitrobenzoic acid (3 g, 10 mmol) in trimethyl orthoacetate (30 ml) is refluxed (˜110° C.) for 15 hours and then solvent is evaporated under reduced pressure. The 4-iodo-3-nitrobenzoic acid methyl ester is obtained as a yellow solid (3.11 g, 99% yield, 97.5% HPLC).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@H:13]([C:22]([O:24]CC=C)=O)[CH2:14][CH2:15][C:16]([O:18]CC=C)=[O:17].[CH3:28][C:29]1[CH:30]=CC(S(O)(=O)=O)=CC=1.N[C@H](C([O:51][CH2:52]C=C)=O)CCC(OCC=C)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C([N:69](CC)CC)C>C1(C)C=CC=CC=1>[CH2:28]([N:12]([CH2:11][CH:1]=[CH2:6])[C@H:13]([C:22]([N:69]=[C:52]=[O:51])=[O:24])[CH2:14][CH2:15][C:16](=[O:17])[OH:18])[CH:29]=[CH2:30]
Reactant: C=CCOC(=O)CC[C@H](N)C(=O)OCC=C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCN(CC)CC
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: C=CCN(CC=C)[C@@H](CCC(=O)O)C(=O)N=C=O
Reaction time: 0.5 h

Procedure:
To diallyl L-glutamate p-toluene sulfonate (the TsOH salt of diallyl L-glutamate) (1.08 g, 2.7 mmol, NovaBiochem) and triphosgene (0.30 g, 1.03 mmol) in 20 mL toluene, stirred at −78° C., trietylamine (0.86 mL, 6.2 mmol) was added. After 30 min, the reaction mixture was allowed to reach room temperature and was used without further purification. A typical IR spectrum was obtained v=2253 cm−1 (NCO, v. intense).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[F:6][C:7]([F:17])([F:16])[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[N+:18]([CH2:21][CH2:22][CH2:23][C:24]([O:26]C)=O)([O-:20])=[O:19]>C(O)C>[N+:18]([C@H:21]1[C@H:12]([C:11]2[CH:14]=[CH:15][C:8]([C:7]([F:17])([F:16])[F:6])=[CH:9][CH:10]=2)[NH:5][C:24](=[O:26])[CH2:23][CH2:22]1)([O-:20])=[O:19]
Reactant: COC(=O)CCC[N+](=O)[O-]
Reactant: [NH4+]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: CC(=O)[O-]
Solvent: CCO
Product: O=C1CC[C@@H]([N+](=O)[O-])[C@H](c2ccc(C(F)(F)F)cc2)N1
Temperature: 25 °C

Procedure:
Ammonium acetate (21.21 g), 4-trifluoromethylbenzaldehyde (19.61 ml) and methyl 4-nitrobutyrate (17.5 ml) in ethanol (150 ml) was stirred and heated under reflux for 3.5 h. After cooling to room temperature, an orange solid was formed which was filtered, washed with ethanol (2×100 ml) and dried in vacuo to give the title compound (30.56 g). Mass spectrometry. For C12H11F3N2O3, m/z 5.77 (2M+H+), 306 (M+NH4), 289 (MH+).
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=O.O.[NH2:20][NH2:21]>C(O)C.C(OCC)(=O)C>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[C:7]1[C:6]2[CH:5]=[CH:4][S:3][C:2]=2[NH:20][N:21]=1
Reactant: O=C(c1ccc2ccccc2c1)c1ccsc1Cl
Reactant: NN
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: c1ccc2cc(-c3n[nH]c4sccc34)ccc2c1

Procedure:
To a solution of 0.61 g of (2-chlorothiophen-3-yl)-(naphthalen-2-yl)-methanone in 6 mL of ethanol was added 0.12 mL of hydrazine monohydrate at room temperature and heated under reflux for 2 days. The reaction solution was diluted with ethyl acetate, and the organic layer washed successively with saturated aqueous ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The resultant crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:30-1:5), to afford 32 mg of the title compound as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([SH:11])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].BrC[CH2:21][C:22]1[CH:26]=[CH:25][S:24][CH:23]=1>[OH-].[Na+]>[NH2:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:4]([S:11][CH2:21][C:22]2[CH:26]=[CH:25][S:24][CH:23]=2)[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Nc1cc(C(=O)O)cc(S)c1Oc1ccccc1
Reactant: BrCCc1ccsc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(C(=O)O)cc(SCc2ccsc2)c1Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-amino-3-mercapto-4-phenoxybenzoic acid (2.5 g) in 0.5 N sodium hydroxide (100 ml), a solution of 3-bromoethylthiophene (3.5 g in benzene (20 ml)) is added. The reacton mixture is stirred for 2 hours at room temperature. After extraction with additional benzene, the aqueous layer is acidified by addition of 4 N hydrochloric acid to precipitate 5-amino-4-phenoxy-3-(3-thienylmethylthio)benzoic acid. After collection by filtration, recrystallisation from aqueous ethanol and drying, the compound is obtained with a melting point of 153°-155°C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:13])[C:8](=[CH:11][CH:12]=1)[O:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[C:14]([O-:17])(O)=O.[Na+].C(Cl)(Cl)=O.[N-]=C=O.[NH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([N:37]2[C:45]3[CH:44]=[CH:43][N:42]=[CH:41][C:40]=3[CH:39]=[CH:38]2)=[CH:29][CH:28]=1>ClCCl.C1COCC1>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[C:7]([NH:13][C:14]([NH:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([N:37]3[C:45]4[CH:44]=[CH:43][N:42]=[CH:41][C:40]=4[CH:39]=[CH:38]3)=[CH:29][CH:28]=2)=[O:17])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])O
Reactant: Nc1ccc(-n2ccc3cnccc32)c2ccccc12
Reactant: COc1ccc(C(C)(C)C)cc1N
Agent: O=C(Cl)Cl
Agent: [N-]=C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)C)cc1NC(=O)Nc1ccc(-n2ccc3cnccc32)c2ccccc12
Temperature: 0 °C

Procedure:
4-tert-Butyl-o-anisidine (54 mg, 0.301 mmol, 1 equiv.) was dissolved in 15 mL dichloromethane and 15 mL of saturated aqueous NaHCO3 solution was added. The biphasic mixture was cooled to 0° C. and phosgene (˜2 M solution in toluene, 0.75 mL) was added to the organic layer via syringe in one portion, without stirring. The mixture was then stirred vigorously for 10 min, then the layers were separated. The aqueous layer was extracted once with dichloromethane and the combined organics were dried (Na2SO4), filtered and most of the dichloromethane was removed in vacuo, leaving the toluene. To this isocyanate residue was then added 1-(4-aminonaphthalen-1-yl)pyrrolo[3,2-c]pyridine (Example 1) (77 mg, 0.297 mmol, 1 equiv.) dissolved in 5 mL anhydrous THF. The mixture was left to stir at room temperature for 2 h, then the solvents were removed in vacuo. The residue was purified by column chromatography on SiO2 using dichloromethane/MeOH eluent mixtures. The isolated enriched fraction was further purified by reverse-phase preparative HPLC to provide 20 mg of the title compound as a white foam.
Reaction SMILES: [CH:1](=O)[CH3:2].[NH2:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7]>>[CH3:1][CH:2]1[NH:4][CH:5]([C:8]([OH:10])=[O:9])[CH2:6][S:7]1
Reactant: N[C@@H](CS)C(=O)O
Reactant: CC=O
Product: CC1NC(C(=O)O)CS1

Procedure:
Acetaldehyde (0.27 g) and L-cysteine (0.75 g) were reacted in aqueous solution 10 ml at room temperature for 1.5 hours, followed by solvent evaporation evaporated in vacuo. The resulting product was recrystallized from methanol to yield the title compound. Melting Point: 161°-163° centigrade Optical Rotation [α]26D: -148°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH2:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH:9]([CH3:11])[CH3:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)c1cc(Br)ccc1O
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.1 %

Procedure:
A mixture of 32 g of 4-bromo-2-isopropylphenol, 25.7 g of benzyl bromide, 23 g of potassium carbonate and 300 ml of N,N-dimethylformamide was stirred at room temperature for 24 hours. The reaction solution was poured into ice-water, acidified by adding 10% hydrochloric acid and then extracted with 500 ml of diethyl ether. There, the ether layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 30 g of 4-bromo-2-isopropylphenyl benzyl ether (yield, 65%).
Reaction SMILES: [CH3:1][NH:2][C:3]1(NC)[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:11])=[O:10])=[C:5]([N+:23]([O-])=O)[CH2:4]1.Cl[Sn]Cl.Cl.[CH3:32]CO>>[NH2:23][C:5]1[CH:4]=[C:3]([N:2]([CH3:32])[CH3:1])[CH:8]=[CH:7][C:6]=1[S:9]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2)(=[O:10])=[O:11]
Reactant: CCO
Reactant: CNC1(NC)C=CC(S(=O)(=O)Nc2cccc3cccnc23)=C([N+](=O)[O-])C1
Agent: Cl
Agent: Cl[Sn]Cl
Product: CN(C)c1ccc(S(=O)(=O)Nc2cccc3cccnc23)c(N)c1
Yield: 74 %

Procedure:
In a similar fashion using route 2 general procedure 4,4-dimethylamino-2-nitro-N-quinolin-8-yl-benzenesulfonamide 500 (140 mg, 0.37 mmol), SnCl2 (210 mg, 1.12 mmol), 6N HCl (1 ml) and EtOH (5 ml) at 80° C. for 6 h gave the title compound (95 mg, 74%) which was used in the next step without further purification.
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].[C:5]([N:9]=[N:10][C:11](Cl)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])([CH3:8])([CH3:7])[CH3:6].O>C(O)(C)C>[C:5]([N:9]=[N:10][C:11]([N:3]=[C:2]=[S:1])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:12])([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(C)(C)N=NC(C)(Cl)c1ccccc1
Reactant: N#C[S-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)N=NC(C)(N=C=S)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 26.0 grams (0.32 moles) of sodium thiocyanate in 150 ml of 75% aqueous isopropanol cooled to 5° C. in a 500 ml erlenmeyer flask was added 71.4 grams (0.32 moles) of 1-t-butylazo-1-chloro-1-phenylethane over 3 minutes holding the temperature at 5°-10° C. with an ice bath. The reaction mixture was stirred for 90 minutes at room temperature, poured into 300 ml water and the product extracted with 100 ml of pentane. The pentane extract was washed twice with 100 ml water, once with 10% NaHCO3 solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure. The product was a light brown liquid which weighed 43.3 grams (54.6% crude yield). The infrared spectrum of the product had a very strong broad band at 1960-2175 cm-1 which is indicative of the α-isothiocyanate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)=[O:7].C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[CH2:42]([NH:44][CH2:45][CH3:46])[CH3:43]>C(Cl)Cl>[CH2:42]([N:44]([CH2:45][CH3:46])[C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([C:6](=[O:7])[C:5]2[CH:17]=[CH:18][CH:19]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:16][CH:15]=1)[CH3:43]
Reactant: CCNCC
Reactant: COc1cccc(C(=O)c2ccc(C(=O)O)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(C(=O)c2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A mixture of 0.23 grams of acid (3.1b), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.2 equivalents with respect to the acid) and 1-hydroxy benzotriazol hydrate (1.2 equivalents) in anhydrous CH2Cl2 (2 ml) is stirred at room temperature for 30 minutes. A solution of diethylamine (1.5 equivalents) in anhydrous CH2Cl2 (8 ml) is then dropwise added. The obtained mixture is stirred at room temperature for 14 hours and washed in a first step with saturated aqueous sodium bicarbonate and in a second step with water. The organic phase is dehydrated with sodium sulphate, filtered and evaporated under vacuum. The residue that is recovered is purified by flash chromatography (ligroin/ethyl acetate 1/1 v/v). N,N-diethyl-4-(3′-methoxybenzoyl)benzamide (3.1c) is obtained. Yield: 98%. IR (nujol) (λ=cm−1) 1690 (C═O); 1H-NMR (CDCl3) δ 1.00-1.38 (m, 6H); 3.20-3.38 (m, 2H); 3.50-3.70 (m, 2H); 3.86 (s, 3H); 7.10-7.40 (m, 4H); 7.48 (d, 2H, J=8.4 Hz); 7.84 (d, 2H, J=8.4 Hz). Anal. calc. for C19H21NO3: C, 73.29; H, 6.80; N, 4.50. Found: C, 73.11; H, 6.78; N, 4.49.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[C:12]2[N:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH2:28][C:29]1[CH:30]=[C:31]([NH:35][C:36](=[O:39])[CH:37]=[CH2:38])[CH:32]=[CH:33][CH:34]=1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[C:12]2[N:13]=[CH:14][N:15]=[C:16]([NH:28][C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:39])[CH:37]=[CH2:38])[CH:32]=[CH:33][CH:34]=3)[N:17]=2)=[CH:4][CH:3]=1
Reactant: C=CC(=O)Nc1cccc(N)c1
Reactant: Clc1ccc2c(c1)N(c1ncnc(Cl)n1)CCC2
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cccc(Nc2ncnc(N3CCCc4ccc(Cl)cc43)n2)c1
Temperature: 100 °C

Procedure:
To a slurry of 7-chloro-1-(4-chloro-[1,3,5]triazin-2-yl)-1,2,3,4-tetrahydro-quinoline (Step 2)(70 mg, 0.249 mmol) in IpOH (2.0 ml) was added DIEA (0.20 mL, 1.15 mmol) and N-(3-aminophenyl)acrylamide (100 mg, 0.192 mmol). The heated at 100° C. for 18 h, then cooled to RT. The organics were concentrated under reduced pressure then purified by column chromatography (elution with CH2Cl2 followed by 99:1 CH2Cl2/MeOH followed by 97:3 CH2Cl2/MeOH) to give N-{3-[4-(7-chloro-3,4-dihydro-2H-quinolin-1-yl)-[1,3,5]triazin-2-ylamino]-phenyl}-acrylamide: MS m/z=407 [M+H]+. Calc'd for C21H19ClN6O: 406.13.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][O:13][C:14]1[N:15]=[N:16][CH:17]=[CH:18][C:19]=1[Sn](CCCC)(CCCC)CCCC>[Cu]I.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.CN(C=O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:19]3[CH:18]=[CH:17][N:16]=[N:15][C:14]=3[O:13][CH3:12])=[CH:3][N:4]=2)[N:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1OC
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1nnccc1-c1cnc2ccc(Cl)nn12
Temperature: 100 °C
Reaction time: 20 h
Yield: 64.2 %

Procedure:
A mixture of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (Preparation 1b, 182 mg, 0.78 mmol), 3-methoxy-4-(tributylstannyl)pyridazine (Preparation 8b, 313 mg, 0.78 mmol), copper(I) iodide (15 mg, 0.08 mmol) and dry N,N′-dimethylformamide (4 mL) in a Schlenk vial was subjected to three cycles of evacuation backfilling with argon. Tetrakis(triphenylphosphine)palladium(0) (91 mg, 0.08 mmol) was then added and the resulting mixture was subjected to three further cycles of evacuation backfilling with argon before being stirred at 100° C. for 20 hours. The reaction mixture was cooled down, the solvent was removed under reduced pressure and the residue was purified by flash chromatography (1:1 hexanes/ethyl acetate to 100% ethyl acetate) to give the title compound (131 mg, 64%) as a beige solid.