Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[C:9]2[N:10]([CH:14]=[CH:15][N:16]=2)[N:11]=[CH:12][CH:13]=1.[I:17]N1C(=O)CCC1=O.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[I:17][C:14]1[N:10]2[N:11]=[CH:12][CH:13]=[C:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[N:16][CH:15]=1
Reactant: Cc1ccncc1-c1ccnn2ccnc12
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1ccncc1-c1ccnn2c(I)cnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 8-(4-methylpyridin-3-yl)imidazo[1,2-b]pyridazine, (480 mg, 1.48 mmol) in CHCl3 (15 mL) were added N-iodo succinimide (400 mg, 1.776 mmol) and TFA (0.34 g, 2.96 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated NaHCO3 and extracted with CH2Cl2. The combined organic layer was washed with water and brine, and dried over Na2SO4. The crude product was purified by BIOTAGE® (20-40% EtOAc/CH2Cl2; 1.2 L). 1H NMR (400 MHz, CDCl3) δ ppm 8.50-8.70 (3H, m), 7.90 (1H, s), 7.22-7.39 (4H, m), 7.06 (1H, d, J=4.53 Hz), 2.32 (3H, s); LC/MS: Rt=1.13 min. LC/MS (Condition A): 336.97.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([CH:9](Br)Br)[N:3]=1.C(=O)([O-])[O-:13].[Ca+2].O>CS(C)=O>[Br:1][C:2]1[N:3]=[C:4]([CH:9]=[O:13])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(C(Br)Br)nc1Br
Agent: [Ca+2]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(F)c(Br)n1
Temperature: 150 °C
Reaction time: 15.5 h
Yield: 66.5 %

Procedure:
After a solution of 2-bromo-6-(dibromomethyl)-3-fluoropyridine (615 mg) and calcium carbonate (391 mg) in dimethylsulfoxide (6.5 mL) was stirred while heating at 150° C. for 4.5 hr, the reaction mixture was reverted to room temperature and stirred for 15.5 hr. After water was added thereto, the mixtue was stirred and then extracted with ethyl acetate. The organic phase was washed with water and brine, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=98:2-82:18) to afford the title compound (240 mg).
Reaction SMILES: [CH2:1]([S:5][C:6]1[C:11]([CH2:12]Cl)=[CH:10][CH:9]=[CH:8][N:7]=1)[CH2:2]CC.C([O:16][C:17](=[O:29])[CH2:18][CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[C:22]([F:28])[CH:21]=1)C>>[CH2:1]([S:5][C:6]1[C:11]([CH2:12][O:27][C:23]2[C:22]([F:28])=[CH:21][C:20]([CH2:19][CH2:18][C:17]([OH:29])=[O:16])=[CH:25][C:24]=2[F:26])=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:2]
Reactant: CCCCSc1ncccc1CCl
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Product: CCSc1ncccc1COc1c(F)cc(CCC(=O)O)cc1F
Yield: 76 %

Procedure:
3-Chloromethyl-2-ethylsulfanyl-pyridine (0.1 g, 0.53 mmol) obtained in Step C of Preparation Example 11 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.12 g, 0.53 mmol) obtained in Step D of Preparation Example 2 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (76% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:22]=1.[CH:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24]>>[CH:23]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([CH:10]4[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]4)=[N:7][C:6]=3[CH:22]=2)=[CH:27][CH:26]=1)=[O:24]
Reactant: CC(C)OC(=O)N1CCC(c2nc3cc(Br)ccc3o2)CC1
Reactant: O=Cc1ccc(B(O)O)cc1
Product: CC(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(C=O)cc4)ccc3o2)CC1
Yield: 34.9 %

Procedure:
Following the General Procedure-1, the titled compound (100 mg) was prepared from Intermediate 13 (270 mg, 0.73 mmol) and 4-formylphenylboronic acid (132 mg, 0.88 mmol) as an off-white solid. M.P.: 167-170° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 10.07 (S, 1H), 7.96 (dd, J 1.7, 6.6, 2H), 7.93 (s, 1H), 7.76 (d, J 8.2, 2H), 7.58 (s, 2H), 4.95 (septet, J 6.2, 1H), 4.20 (d, J 11.1, 2H), 3.22-3.13 (m, 1H), 3.04 (t, J 11.3, 2H), 2.18 (dd, J 2.8, 13.3, 2H).
Reaction SMILES: C([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])=[O:12])=[O:7])(C)(C)C.Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[S:42]([NH:45][CH2:46][CH3:47])(=[O:44])=[O:43])=[CH:32][CH:31]=1>>[CH2:19]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N:16]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[S:42]([NH:45][CH2:46][CH3:47])(=[O:44])=[O:43])=[CH:32][CH:31]=2)[C:15]1=[O:25])=[O:12])=[O:7])[C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:17]=1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Reactant: CCNS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Product: CCNS(=O)(=O)c1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC(=O)OCc3ccccc3)CCc3ccccc32)cc1

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]butanamide (prepared by the method of Fisher, et al; U.S. Pat. No. 5,206,235) and 4-bromomethyl-2'-(ethylaminosulfonyl)-1,1'-biphenyl by the procedure described in Example 1, Step E. 1H NMR (400 MHz, CDCl3): δ 0.77 (t, 7Hz, 3H), 1.33 (s, 6H), 1.40 (s, 9H), 1.47 (s, 3H), 1.87 (m, 1H), 2.35-2.6 (m, 7H), 3.12 (t, 7Hz, 1H), 4.52 (m, 1H), 4.83 (d, 15 Hz, 1H), 5.17 (br s, 1H), 5.38 (d, 15 Hz, 1H), 6.66 (d, 7Hz, 1H), 7.1-7.3 (m, 7H), 7.35 (d, 8 Hz, 2H), 7.46 (m, 1H), 7.55 (m, 1H), 8.10 (d, 8 Hz, 1H). FAB-MS: calculated for C35H44N4O6S 648; found 649 (M+H, 42%).
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4](Cl)=[O:5].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]([NH2:30])=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[N:26][C:25]=23)=[CH:17][CH:16]=1>N1C=CC=CC=1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]([NH:30][C:4](=[O:5])[CH2:3][C:2]([CH3:7])([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH3:1])=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[N:26][C:25]=23)=[CH:17][CH:16]=1
Reactant: Nc1nn2cccnc2c1-c1ccc(Cl)cc1
Reactant: CC(C)(CC(=O)Cl)c1ccccc1
Solvent: c1ccncc1
Product: CC(C)(CC(=O)Nc1nn2cccnc2c1-c1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the product from Example 117A (82 mg, 0.42 mmol) was added a solution of the product from Example 99A (59 mg, 0.2 mmol) in pyridine (2.0 mL). The mixture was stirred at ambient temperature for 1 hour and then at 40° C. for 1 hour. The reaction mixture was concentrated under vacuum and purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 30-100% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.13-10.16 (bs, 1H), 9.09 (dd, J=7.0, 1.7 Hz, 1H), 8.60 (dd, J=4.1, 1.7 Hz, 1H), 7.68-7.72 (m, 2H), 7.40-7.45 (m, 4H), 7.27-7.35 (m, 2H), 7.15-7.22 (m, 1H), 7.12 (dd, J=7.0, 4.1 Hz, 1H), 2.70 (s, 2H), 1.41 (s, 6H); MS (ESI) m/z 405 (M+H)+; Anal. calculated for C23H21ClN4O.0.1H2O: C, 67.93; H, 5.25; N, 13.78. Found C, 67.65; H, 5.08; N, 13.61.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:15]=[CH:14][C:7]([C:8]([NH:12][CH3:13])=[CH:9][C:10]#[N:11])=[CH:6][CH:5]=1.O1CCCC1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:9](=[C:8]([NH:12][CH3:13])[C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:15][CH:14]=1)[C:10]#[N:11]
Reactant: CNC(=CC#N)c1ccc(Cl)cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CNC(=C(Br)C#N)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A solution of bromine (10.9 mL, 33.6 g, 0.21 mol) in carbon tetrachloride is added to a mixture of p-chloro-β-(methylamino)cinnamonitrile, (E)- or (Z)- (38.53 g, 0.2 mol) in carbon tetrachloride and tetrahydrofuran at 55°-60° C. over 30 minutes. The reaction mixture is cooled to room temperature, concentrated in vacuo to one-half of the original volume and filtered to obtain a solid. The solid is diluted with carbon tetrachloride and the resulting mixture is heated at reflux, cooled and filtered to give the title product as a yellow solid (43.6 g, mp 178°-178.5° C.) which is identified by 1H and 13CNMR spectral analyses.
Reaction SMILES: [CH3:1][PH:2](=[O:11])[C:3]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[CH3:4].[CH3:12][Si]([N-][Si](C)(C)C)(C)C.[K+].CI>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][P:2](=[O:11])([CH3:12])[C:3]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[CH3:4]
Reactant: CCOC(C)(OCC)[PH](C)=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CI
Product: CCOC(C)(OCC)P(C)(C)=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of methyl(1,1-diethoxyethyl)phosphine oxide, prepared as described in EP 0 501 702 (89.3 g, 0.5 mol) in THF (900 ml) at -78° C. under an atmosphere of argon is added a solution of potassium bis(trimethylsilyl)amide (688 ml, 0.521 mol) in toluene over 15 minutes. After stirring for 1 hour at -78° C., methyl iodide (34 ml, 0.55 mol) is added over 5 minutes and stirring at -78° C. continued for 1 hour. The reaction is then quenched by the addition of a 1% solution of NaH2PO4 (450 ml) and slow warming to room temperature. Concentration gives an aqueous suspension to which dichloromethane (600 ml) is added. The organic phase is separated and washed with 1% NaH2PO4 (500 ml), followed by water (500 ml). Drying over MgSO4, concentration and purification by flash vacuum silica column chromatography (chloroform-ethanol 40:1) gives a clear oil which is distilled to give dimethyl (1,1-diethoxyethyl)phosphine oxide. b.p. 100° C. at 0.05 mmHg.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.O.[C]=O.[CH3:16]N1CCCC1>[OH-].[Rh+3].[OH-].[OH-]>[CH2:16]([N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCCC1
Reactant: C1CCCCC1
Reactant: C1CCNCC1
Agent: [Rh+3]
Agent: [C]=O
Agent: [OH-]
Solvent: O
Product: C1CCC(CN2CCCCC2)CC1
Yield: 80 %

Procedure:
A solution of cyclohexane (0.25 mole), piperidine (0.5 mole), water (0.5 mole) and Fe(CO)5 (0.025 mole) in 60 ml N-methylpyrrolidine and rhodium hydroxide [Rh(OH)3 ] (5×10-3 mole) were charged into a stainless steel rocking autoclave of 0.5 liter capacity. The reaction chamber was pressurized by carbon monoxide at 140 atm and heated at 170° for 3 hours. On completion of the reaction period, the pressure vessel was allowed to cool and the gases vented. The reaction mixture was taken out and scrubbed 2-3 times with water in order to remove the unreacted secondary amine, its N-formyl derivative (formed in a side reaction), and the solvent, all of which are water-soluble. The aqueous phase was extracted once with pentane. The organic phase and the pentane extract were combined and dried over sodium sulfate and fractionally distilled to yield N-hexahydrobenzylpiperidine (ca. 80% yield), the product being unequivocally identified by gas-liquid chromatographic and spectroscopic (ir, nmr) comparison with an authentic sample.
Reaction SMILES: [CH:1]([NH:4][CH3:5])([CH3:3])[CH3:2].[N+](C1C=C([N+]([O-])=O)C=CC=1O[C:19](=[O:22])[CH2:20][Br:21])([O-])=O>C(Cl)Cl>[Br:21][CH2:20][C:19]([N:4]([CH:1]([CH3:3])[CH3:2])[CH3:5])=[O:22]
Reactant: O=C(CBr)Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CNC(C)C
Solvent: ClCCl
Product: CC(C)N(C)C(=O)CBr
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Isopropyl-methyl-amine (154 μL, 1.48 mmol) was added to a stirred solution of bromo-acetic acid 2,4-dinitro-phenyl ester (450 mg, 1.48 mmol) in DCM (4 mL). After stirring for 3 h at room temperature the organic layer was extracted twice with 0.1 M NaOH solution (30 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting title compound was used for the next reaction without purification. MS (m/z): 194.0 [M+H+].
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].I[C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12]>C(N(CC)CC)C.C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][Si:2]([C:5]#[C:6][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12])([CH3:4])[CH3:3]
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1cccc(I)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1cccc(C#N)c1
Reaction time: 0.07 h
Yield: 82.8 %

Procedure:
Add trimethylsilylacetylene (3.4 mL, 24.0 mmol) to a mixture of bis(triphenylphosphine)palladium (II) dichloride (766 mg, 1.1 mmol), copper (I) iodide (418 mg, 2.2 mmol) and 3-iodobenzonitrile (5 g, 21.8 mmol) in triethylamine (20 mL). Upon addition of the trimethylsilylacetylene an exothermic reaction occurs and after about 4 min the reaction mixture solidifies. Cool the reaction mixture for about 15 min, dilute with ethyl acetate (100 mL), filter through fluted filter paper using ethyl acetate and concentrate. Dissolve the residue in ethyl acetate (200 mL) and wash sequentially with an aqueous solution of 0.1 N hydrochloric acid and a saturated aqueous solution of sodium chloride. Dry (sodium sulfate), filter and concentrate. Purify the residue by silica gel chromatography, eluting with 0:100 to 5:95 ethyl acetate:hexanes, to give the title compound as a tan solid (3.6 g, 83%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[Si]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(C)C.[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([C:37]2[N:38]([CH3:42])[N:39]=[N:40][CH:41]=2)=O)=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([C:37]2[N:38]([CH3:42])[N:39]=[N:40][CH:41]=2)=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:31][CH:30]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cn1nncc1C(=O)c1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(c1ccc(OCc2ccccc2)cc1)c1cnnn1C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 95.2 %

Procedure:
To a solution of lithium bis(trimethylsilyl)amide (22 mmol, 1 M in THF) was added ethyl trimethylsilylacetate (31.5 mmol) dropwise at −78° C. After 20 minutes at −78° C., a solution of 73.3 (14.7 mmol) in THF (50 mL) was added dropwise, and the reaction was maintained at −78° C. for 4 hours. The reaction was quenched with saturated NH4Cl (aq) and warmed to room temperature. The mixture was extracted with EtOAc (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated with silica gel under reduced pressure. The residue was chromatographed (silica gel, 1:1 EtOAc/hexane) to afford compound 73.4 (5.1 g, 14 mmol). MS ESI (pos.) m/e 364.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]2[N:16]=[C:17]([CH3:24])[C:18]([C:19]([O:21]CC)=[O:20])=[C:14]2[CH:13]=[CH:12][C:11]=1[CH3:25].[OH-].[K+]>C(O)C.C1COCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]2[N:16]=[C:17]([CH3:24])[C:18]([C:19]([OH:21])=[O:20])=[C:14]2[CH:13]=[CH:12][C:11]=1[CH3:25]
Reactant: CCOC(=O)c1c(C)nn2c(-c3ccc(OC)cc3Cl)c(C)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2c(C)ccc3c(C(=O)O)c(C)nn23)c(Cl)c1
Temperature: 25 °C
Reaction time: 192 h
Yield: 78.9 %

Procedure:
A solution of ethyl 7-(2-chloro-4-methoxyphenyl)-2,6-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate (0.82 g, 2.3 mmol) in ethanol (14 mL), THF (8 mL) and H2O (8 mL) was treated with KOH (3.12 g, 55.6 mmol) and stirred at room temperature for 8 days adding more KOH periodically. The reaction was concentrated in vacuo and the residue partitioned between Et2O and H2O. The aqueous layer was acidified with concentrated HCl, extracted with ethyl aceatate, washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to give a brown solid (0.60 g, 79%) as the title compound: 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=9.0 Hz, 1H), 7.43 (d, J=9.0 Hz, 1H), 7.30 (d, J=8.5 Hz, 1H), 7.16 (d, J=2.5 Hz, 1H), 7.04 (dd, J=8.5, 2.5 Hz, 1H), 3.93 (s, 3H), 2.67 (s, 3H), 2.19 (s, 3H); HRMS (FAB) calcd for C17H15N2O3Cl+H 331.0849. found 331.0853.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[OH-].[Na+].[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>CO.O>[F:16][C:17]([F:26])([F:27])[C:18]1[CH:19]=[CH:20][C:21](/[CH:22]=[CH:12]/[C:11](=[O:13])/[CH:10]=[CH:9]/[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:24][CH:25]=1
Reactant: COc1ccc(/C=C/C(C)=O)cc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(/C=C/C(=O)/C=C/c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.4 %

Procedure:
(E)-4-(4-Methoxyphenyl)but-3-en-2-one (1 g, 5.7 mmol) was dissolved in MeOH (18 mL) and stirred for 5 min at room temperature. A solution of NaOH (500 mg, 12.5 mmol) in H2O (34 mL) was added and the reaction mixture was stirred for further 1 h. After the dropwise addition of 4-(trifluoromethyl)-benzaldehyde (822 μl, 6.0 mmol), the mixture was stirred overnight at ambient temperature. The resulting yellow precipitate was filtered and dried in vacuo to obtain NW336.2 as a pale yellow solid (1.75 g, 92%). mp: 144-146° C. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.66 (d, 3J=15.9 Hz, 1H, Hvin), 7.64 (d, 3J=15.5 Hz, 1H, Hvin), 7.63 (d, 3J=9.0 Hz, 2H, HAr), 7.58 (d, 3J=8.6 Hz, 2H, HAr), 7.50 (d, 3J=8.8 Hz, 2H, HAr), 7.06 (d, 3J=16.0 Hz, 1H, Hvin), 6.87 (d, 3J=16.0 Hz, 1H, Hvin), 6.86 (d, 3J=8.8 Hz, 2H, HAr), 3.78 (s, 3H, OCH3). 13C NMR (75 MHz, CDCl3) δ (ppm): 188.4 (C), 161.9 (C), 143.9 (CH), 140.8 (CH), 138.4 (q, 4J(C, F)=1.3 Hz, CH), 131.7 (q, 2J(C, F)=32.7 Hz, C), 130.3 (CH), 128.4 (CH), 127.6 (CH), 127.3 (C), 125.9 (q, 3J(C, F)=3.8 Hz, CH), 123.9 (q, 1J(C, F)=272.2 Hz, C), 123.2 (CH), 114.5 (CH), 55.5 (OCH3). MS (FAB) m/z: 333.1 (M+). Anal. calcd for C19H15F3O2: C, 68.67; H, 4.55. Found: C, 68.81; H, 4.63%.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[N:11]=[C:10]([OH:12])[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][CH:15]=2)=[C:8]([CH3:22])[N:7]=1>C(Cl)Cl>[ClH:3].[NH2:5][C:6]1[N:11]=[C:10]([OH:12])[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][Cl:3])=[CH:16][CH:15]=2)=[C:8]([CH3:22])[N:7]=1
Reactant: Cc1nc(N)nc(O)c1Cc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1nc(N)nc(O)c1Cc1ccc(CCl)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Thionyl chloride (6 ml) was added to a mixture of the product from step (i) (2.38 g) in DCM (80 ml) and the mixture stirred at rt under nitrogen for 18 h. The mixture was evaporated under reduced pressure to afford the subtitle compound, used crude in next step.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:29]([O:31]CC)=[CH2:30])CCC.Cl.O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:23][C:22]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][CH:18]=[N:19]2)=[CH:14][C:13]=1[CH:11]([C:8]1[N:6]2[N:7]=[C:2]([C:29](=[O:31])[CH3:30])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[CH3:12]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Agent: [Pd]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2ncc(C(C)c3cc4cccnc4cc3F)n2n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
In a flask was charged with tetrakis-(triphenylphosphine)-palladium (46 mg, 0.040 mmol) under nitrogen. A solution of 6-(1-(6-chloroimidazo[1,2-b]pyridazin-3-yl)ethyl)-7-fluoroquinoline (130 mg, 0.40 mmol) in DMF (5 mL) was added. The system was purged with nitrogen gas three times and tributyl-(1-ethoxy-vinyl)-stannane (0.14 mL, 0.42 mmol) was added. The temperature was increased to 100° C. and stirred for 2 hrs. Then the reaction mixture was cooled to room temperature, 3N HCl was added and the mixture was stirred for additional 4 hrs. Water was added and the mixture was then extracted with EtOAc, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (3% to 10% MeOH in CH2Cl2) to afford 120 mg (yield: 90) of title compound. LCMS (method B): [MH]+=335, tR=2.41 min.
Reaction SMILES: N1C=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:7]1[CH:11]=[CH:10][C:9](=[O:12])[N:8]=1.N#[C:14][C:15]#N.N1C=CC=C[CH:18]=1>>[C:15]1([N:8]2[C:9](=[O:12])[CH:10]=[C:11]([CH3:18])[NH:7]2)[CH:14]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccncc1
Reactant: N#CC#N
Reactant: O=C1C=CN=N1
Product: Cc1cc(=O)n(-c2ccccc2)[nH]1

Procedure:
Pyridine-pyrazolone reaction: Quantitative analysis of cyanogen, showing blue. PH 7→ add chlorimine T solution, and add the mixture of a solution of bis-(1-phenyl-3-methyl-5-pyrazolone) in pyridine and a solution of 1-phenyl-3-methyl-5-pyrazolone two to three minutes later, then leave for a while.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([N+:14]([O-])=O)[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH3:25][NH:26][CH2:27][CH2:28][CH3:29]>ClCCl>[CH3:18][O:17][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][C:11]=1[NH2:14])[N:5]([C:3](=[O:4])[CH2:2][N:26]([CH3:25])[CH2:27][CH2:28][CH3:29])[CH2:6][CH2:7]2
Reactant: CCCNC
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CBr)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCN(C)CC(=O)N1CCc2cc(OC)c(N)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The 1-(bromoacetyl)-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (4.0 g, 12.7 mmol) was dissolved in 50 mL of dichloromethane, then K2CO3 (4.4 g, 31.7 mmol) and N-methyl-1-propanamine (1.9 g, 25.4 mmol) in 10 mL dichloromethane were added, the reaction was stirred at RT for 3 hours. After filtration, the organic layers were washed with water (2×100 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the resulting residue was dissolved in 10 mL of EA , 25 mL of MeOH and 15 mL of THF, then 0.8 g 10% Pd/C was added and the reaction was stirred at RT overnight under H2 pressure (65 psi). The catalyst was removed via filtration and the solvent was removed under reduced pressure to afford 5-(methyloxy)-1-{[methyl(propyl)amino]acetyl}-2,3-dihydro-1H-indol-6-amine as a yellow solid, 3.0 g (96%). 1HNMR (400 MHz, DMSO-d6) δ ppm: 0.81 (t, J=7.14 Hz, 3H), 1.40 (m, 2H), 2.21 (s, 3H), 2.35(m, 2H), 2.94 (t, J=8.24 Hz, 2 H), 3.17(s, 2H), 3.70 (s, 3H), 4.07 (t, J=8.33 Hz, 2 H), 4.60 (s, 2H), 6.67 (s, 1 H), 7.52 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6](F)[CH:5]=[CH:4][N:3]=1.[CH:9]([C@H:12]1[CH2:16][O:15][C:14](=[O:17])[NH:13]1)([CH3:11])[CH3:10].[H-].[Na+]>CN(C=O)C.O>[F:1][C:2]1[N:7]=[C:6]([N:13]2[C@@H:12]([CH:9]([CH3:11])[CH3:10])[CH2:16][O:15][C:14]2=[O:17])[CH:5]=[CH:4][N:3]=1
Reactant: Fc1ccnc(F)n1
Reactant: CC(C)[C@H]1COC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(F)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.6 %

Procedure:
A solution of 2,4-difluoropyrimidine (3.5 mL, 41 mmol) and (S)-4-isopropyloxazolidin-2-one (5.3 g 41 mmol) in 30 mL DMF was cooled to 0° C. under N2 atmosphere. NaH (2.1 g of 60% suspension, 53 mmol) was slowly added. Bubbling exotherm observed. Internal temp was kept below 5° C. After 5 minutes, cold bath was removed. Reaction mixture (a sandy suspension) was allowed to warm to room temp and stir 18 h. The reaction mixture was diluted with water (100 mL) and extracted with (3×75 mL) EtOAc. Organic layer was washed with 50 mL each water, and brine. Dried over Na2SO4, and concentrated on silica gel in vacuo. Column chromatography (EtOAc/heptane 10 to 100% gradient) gave 3.1 g (S)-3-(2-fluoropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (IV) as a crystalline white solid (33%). 1H NMR (400 MHz, CDCl3) δ 8.50 (dd, J=5.8, 2.2 Hz, 1H), 8.19 (dd, J=5.8, 3.8 Hz, 1H), 4.79 (dt, J=8.1, 3.5 Hz, 1H), 4.48-4.34 (m, 2H), 2.64 (heptd, J=7.0, 3.6 Hz, 1H), 1.01 (d, J=7.0 Hz, 3H), 0.90 (d, J=6.9 Hz, 3H). MS m/z 471.8 and 471.8 (M+H)+.