Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[N:15][C:14]([O:17][CH2:18][C:19](=[O:21])[NH:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[N:13][CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: Nc1cccnc1
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)Nc1cccnc1
Yield: 27 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 3-aminopyridine (20 mg, 0.21 mmol) as the coupling partner. Concentration (no chromatography) yielded 17 mg (27%) of the titled compound. ESI-MS m/z 368 (MH+), 366 (M−H−).
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:12]=1.C(O)(=O)C>COCCOC>[CH3:27][C:25]1[NH:24][N:23]=[C:22]([NH:21][C:13]2[N:12]=[C:11]([S:9][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:20]3[C:15]([CH:14]=2)=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:26]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COCCOC
Product: Cc1cc(Nc2cc3ccccc3c(Sc3ccccc3)n2)n[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.6 %

Procedure:
NaH (155 mg) was added to a solution of benzenethiol (500 mg) in DME (2 ml) and the mixture was stirred for 1 hour at room temperature. (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (100 mg) was then added, and the resulting mixture was heated at 150° C. for 30 minutes under microwave irradiation. The reaction mixture was acidified to pH=7 with acetic acid and purified by preparative LC-MS to give 20 mg of (5-methyl-1H-pyrazol-3-yl)-(1-phenylsulfanyl-isoquinolin-3-yl)-amine as a yellow solid. LC-MS: m/e 333(MH+).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:14]=[CH:15][N:16]=2)[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[CH3:17][C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23]1[N:28]=[C:27]([NH2:29])[CH:26]=[CH:25][CH:24]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:17][C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23]1[N:28]=[C:27]([NH:29][C:2]2[C:3]3[N:4]([CH:14]=[CH:15][N:16]=3)[N:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:7]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: C[C@@H]1CCCN1c1cccc(N)n1
Reactant: Brc1cc(-c2ccccc2)nn2ccnc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C[C@@H]1CCCN1c1cccc(Nc2cc(-c3ccccc3)nn3ccnc23)n1
Temperature: 100 °C
Reaction time: 16 h
Yield: 35.1 %

Procedure:
A mixture of 8-bromo-6-phenylimidazo[1,2-b]pyridazine (166 mg, 0.6 mmol), (R)-6-(2-methylpyrrolidin-1-yl)pyridin-2-amine (160 mg, 0.9 mmol), Pd2(dba)3 (36 mg, 0.06 mmol), BINAP (152 mg, 0.24 mmol), Cs2CO3 (593 mg, 1.8 mmol) and dioxane (10 mL) was heated to 100° C. with stirring for 16 h under N2. The solvent was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give (R)—N-(6-(2-methylpyrrolidin-1-yl)pyridine-2-yl)-6-phenylimidazo[1,2-b]pyridazin-8-amine (78 mg, 35%) as a white solid. 1H NMR (300 MHz, DMSO): δ 8.76 (s, 1H), 7.95-7.87 (m, 3H), 7.55-7.35 (m, 5H), 6.23 (d, 1H, J=7.5 Hz), 6.02 (d, 1H, J=8.1 Hz), 4.22-4.18 (m, 1H), 3.57-3.53 (m, 1H), 3.41-3.36 (m, 1H), 2.09-1.98 (m, 3H), 1.72 (brs, 1H), 1.16 (d, 3H, J=6.0 Hz). LC-MS: [M+H]+, 371, tR=1.994 min, HPLC: 99.27% at 214 nm, 99.26% at 254 nm, tR=4.72 min.
Reaction SMILES: [ClH:1].O1CCOCC1.[C:8]1([C:14]2[N:19]=[C:18]([C:20]([N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH:23]3[CH2:35][O:36][C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)=[O:21])[CH:17]=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[ClH:1].[ClH:1].[C:8]1([C:14]2[N:19]=[C:18]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH:23]3[CH2:35][O:36][C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)=[O:21])[CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(-c3ccccc3)n2)C(COc2cccnc2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(c1cccc(-c2ccccc2)n1)N1CCNCC1COc1cccnc1
Reaction time: 8 h
Yield: 99 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(6-phenylpicolinoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (143 mg, 0.231 mmol) in MeOH (1 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure, yielding 102.1 mg (99%) of the title compound. LC-MS: RT=4.36 min, [M+H]+=375.6.
Reaction SMILES: C(N(CC)CC)C.C1(O[C:15](=[O:34])[NH:16][C:17]2[N:18]=[C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[CH:21][N:20]3[CH:33]=2)C=CC=CC=1.Cl.[CH:36]([N:39]1[N:43]=[N:42][C:41]([CH2:44][CH2:45][NH2:46])=[N:40]1)([CH3:38])[CH3:37].O>CN1C(=O)CCC1>[CH:36]([N:39]1[N:43]=[N:42][C:41]([CH2:44][CH2:45][NH:46][C:15]([NH:16][C:17]2[N:18]=[C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[CH:21][N:20]3[CH:33]=2)=[O:34])=[N:40]1)([CH3:38])[CH3:37]
Reactant: CC(C)n1nnc(CCN)n1
Reactant: COc1ccc(-c2ccc3nc(NC(=O)Oc4ccccc4)cn3c2)cn1
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2ccc3nc(NC(=O)NCCc4nnn(C(C)C)n4)cn3c2)cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Triethylamine (0.54 ml, 3.26 mmol) is added to a stirred mixture of [6-(6-methoxy-pyridin-3-yl)-imidazo[1,2-a]pyridin-2-yl]carbamic acid phenyl ester (Intermediate C) (0.587 g, 1.63 mmol) and 2-(2-isopropyl-2H-tetrazol-5-yl)-ethylamine hydrochloride (Intermediate D1)(0.275 g, 1.96 mmol) in NMP (5 ml). The resulting mixture is stirred at 80° C. for 2 hours and then allowed to cool to room temperature. Water (100 ml) is added and the resulting grey suspension is collected by filtration and dried in a vacuum oven to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH:12]=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]([S:18]([NH2:20])=[O:19])([CH3:17])[CH3:16]>C(Cl)Cl.[O-]S([O-])(=O)=O.[Cu+2]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10](/[CH:12]=[N:20]/[S:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)S(N)=O
Reactant: CC(C)(C)OC(=O)N1CC(C=O)C1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(/C=N/S(=O)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
To a solution of 3-formyl-azetidine-1-carboxylic acid tert-butyl ester (1.0 g, 5.4 mmol) and 2-methylpropane-2-sulfinamide (654 mg, 5.4 mmol) in dry CH2Cl2 (10 mL) was added anhydrous CuSO4 (1.9 g, 11.9 mmol). The heterogeneous reaction mixture was stirred at room temperature overnight then filtered over Celite, rinsing with CH2Cl2. The filtrate was concentrated and the resultant residue was absorbed onto SiO2 and purified by column chromatography with 20% to 40% EtOAc/hexanes to provide 1.26 g (81%) of 3-{[(E)-2-methyl-propane-2-sulfinylimino]-methyl}-azetidine-1-carboxylic acid tert-butyl ester as a white solid.
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(C(C)C)CC)(C)C.[C:13]1([P:19](Cl)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[NH2:2][O:3][P:19](=[O:20])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NO
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NOP(=O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
To a suspension of hydroxylamine hydrochloride (29.4 g) in dichloromethane (200 mL) was added diisopropylethylamine (54.6 g) over 3 minutes in a methanol-ice bath under a nitrogen atmosphere. A white precipitate was formed upon the addition. After stirring for 1 hour under the bath, a solution of diphenylphosphinic chloride (20.0 g) in dichloromethane (20 mL) was added over 60 minutes. A white crystal was formed upon the addition. The mixture was warmed to 0° C. over 1 hour with stirring. The reaction was quenched by adding water (200 mL) over 3 minutes. After stirring the mixture for 0.5 hour, the crystal was collected by filtration. The crystal was washed with water (50×3 mL) followed by diisopropyl ether (50×3 mL). The collected crystal was dried overnight in the air and 3 hours under a reduced pressure with slight warming (4° C.) to give a crude product. The crude product was triturated in EtOH (ethanol) to give (aminooxy)(diphenyl)phosphine oxide as a white crystal (15.3 g).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43](C=O)[CH:42]=5)[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N:51]1([C:57](OC(C)(C)C)=O)[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:57][N:51]6[CH2:52][CH2:53][NH:54][CH2:55][CH2:56]6)[CH:42]=5)[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(C=O)c3)ccc2OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(CN4CCNCC4)c3)ccc2OC)c1
Reaction time: 3 h
Yield: 63.1 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-formyl-4-(methyloxy)-3-biphenylyl]methyl}-1,3-benzenedicarboxamide (54 mg, 0.00008 mol) in DCM with 1,1-dimethylethyl 1-piperazinecarboxylate (23.3 mg, 0.00012 mol) and sodium triacetoxyborohydride (34 mg., 0.00016 mol) and AcOH (6 μL) were agitated overnight on a shaker. LC-MS was used to monitor the reaction. The reaction was quenched with sat. aq. NaHCO3, then extracted with DCM (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. The residue was taken up in DCM (10 mL) containing 25% TFA and allowed to stand at room temperature for 3 h. LC-MS showed the reaction to be complete. Solvent was stripped off. Purification was carried out on a Gilson instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as a white solid [37.6 mg (63%)]. LC-MS m/z 745.4 (M+H)+.
Reaction SMILES: Cl.Cl.[CH3:3][CH:4]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)=[O:18]>>[CH3:3][CH:4]([N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[CH:27]=[CH:26][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=2)=[O:18])[CH2:15][CH2:16]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCCCCCC(C)N1CCNCC1
Agent: Cl
Product: CCCCCCC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1

Procedure:
Prepared from the product of Example 9 and 4-formylbenzoic acid.
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][O:23][C:24]([C@:26]1([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:31][C:30](=[O:32])[C@@H:29]2[C@H:27]1[C@H:28]2[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[F:43])=[O:34])=[O:25].FC1C=CC=CC=1COC([C@]1(NC(OC(C)(C)C)=O)C[C@@H](O)[C@@H]2[C@H]1[C@H]2C(OCC1C=CC=CC=1F)=O)=O>O1CCCC1>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][O:23][C:24]([C@:26]1([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:31][C@H:30]([OH:32])[C@@H:29]2[C@H:27]1[C@H:28]2[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[F:43])=[O:34])=[O:25]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OCc2ccccc2F)CC(=O)[C@H]2[C@H](C(=O)OCc3ccccc3F)[C@H]21
Agent: CC(C)(C)OC(=O)N[C@@]1(C(=O)OCc2ccccc2F)C[C@@H](O)[C@H]2[C@H](C(=O)OCc3ccccc3F)[C@H]21
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)OCc2ccccc2F)C[C@H](O)[C@H]2[C@H](C(=O)OCc3ccccc3F)[C@H]21
Reaction time: 0.75 h

Procedure:
Add 1M L-selectride solution in THF (6.78 mL, 6.78 mmol) dropwise to a stirred solution of bis[(2-fluorophenyl)methyl](1S,2S,5R,6R)-2-(tert-butoxycarbonylamino)-4-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylate (2.33 g, 4.52 mmol) in tetrahydrofuran (20.3 mL) at −78° C. Stir the resulting orange mixture under nitrogen for 1 hour 45 minutes. Quench with a saturated solution of sodium hydrogen carbonate at −78° C. Dilute with water and ethyl acetate. Separate the layers and wash the organic phase with brine and water. Dry over sodium sulfate, filter and concentrate to dryness to give the crude material as pale yellow oil contaminated with approximately 6% of the minor isomer bis[(2-fluorophenyl)methyl](1S,2S,4R,5R,6R)-2-(tert-butoxycarbonylamino)-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate as detected by MS. Combine the crude material with a second batch similarly prepared from bis[(2-fluorophenyl)methyl](1S,2S,5R,6R)-2-(tert-butoxycarbonylamino)-4-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylate (0.23 g, 0.44 mmol). Purify the combined material by flash chromatography eluting with ethyl acetate:hexane (20:80 to 50:50) to give the title product as a single isomer (2.49 g, 4.81 mmol). MS (m/z): 540 (M+23).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[SH:11].Br[C:13]1[C:14]2[C:19]([CH:20]=[C:21]3[C:26]=1[CH:25]=[CH:24][CH:23]=[CH:22]3)=[CH:18][CH:17]=[CH:16][CH:15]=2.C([O-])([O-])=O.[K+].[K+].C(O)CO>C(O)(CC)(C)C.[Cu]I.ClCCl>[CH:15]1[C:14]2[C:19](=[CH:20][C:21]3[C:26]([C:13]=2[S:11][C:2]2[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[CH:17][CH:16]=1
Reactant: Sc1ccc2ccccc2c1
Reactant: Brc1c2ccccc2cc2ccccc12
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: OCCO
Solvent: CCC(C)(C)O
Product: c1ccc2cc(Sc3c4ccccc4cc4ccccc34)ccc2c1
Yield: 50.6 %

Procedure:
A mixture of 2-naphthalenethiol (15.5 g, 0.097 mol), 9-bromoanthracene (25.0 g, 0.0.097 mol), CuI (19.1 g, 0.1 mol), K2CO3 (15.0 g, 0.11 mol), KI (16.6 g, 0.1 mol) and ethylene glycol (10 mL) in tert-amyl alcohol (500 mL) were refluxed for 48 h under N2. After cooling, dichloromethane was added and the mixture washed with 2N NaOH and water, and filtered through an alumina plug. Solvent was removed by rotary evaporation under vacuum and the residue purified by column chromatography (silica/hexanes) to yield 16.5 g (50.5%) of the sulfide. 1H NMR (CDCl3) δ 7.13 (dd, J=8.7, 1.85 Hz, 1H) 7.28-7.35 (m, 3H), 7.43-7.47 (m, 1H), 7.49-7.56 (m, 4H), 7.58 (d, J=8.7 Hz, 1H), 7.66-7.70 (m, 1H), 8.06-8.10 (m, 2H), 8.64 (s, 1H), 8.84-8.89 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][C:3]=1[CH3:11].ClN1C(=O)CCC1=O.[Cl:20][C:21]1[CH:26]=[C:25]([C:27]([C:29]([F:32])([F:31])[F:30])=[CH2:28])[CH:24]=[C:23]([Cl:33])[CH:22]=1.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[CH2:28][C:27]([C:25]3[CH:24]=[C:23]([Cl:33])[CH:22]=[C:21]([Cl:20])[CH:26]=3)([C:29]([F:30])([F:32])[F:31])[O:8][N:7]=2)=[CH:4][C:3]=1[CH3:11]
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: Cc1cc(C=NO)ccc1Br
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Temperature: 70 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a solution of 4-Bromo-3-methyl-benzaldehyde oxime (2.600 g, 12.15 mmol) in DMF (40 mL) was added N-chloro succinimide (1.700 g, 12.73 mmol) and the mixture was heated at 70° C. (bath temperature) for 1 h. After cooling to 0° C., a solution of 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (2.900 g, 12.03 mmol) in DMF (8 mL), followed by triethylamine (2.00 g, 2.75 mL, 19.8 mmol) was added. After 1 h at this temperature, the cooling bath was removed and the mixture was stirred over night. The mixture was separated between MTBE and aqueous NH4Cl solution. The organic layer was separated and the solvent was removed in vacuum. Column chromatography on SiO2 with heptane/CH2Cl2 gave the title compound (2.95 g, 54%).
Reaction SMILES: C([Li])=C.[Li]C[CH2:6][CH2:7][CH3:8].C([Sn](C=C)(C=C)C=C)=C.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[N:22]=C[N:20]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(OCC)C>[CH:7]([C:6]1[N:20]=[C:19]([Cl:18])[CH:24]=[C:23]([Cl:25])[N:22]=1)=[CH2:8]
Reactant: Clc1cc(Cl)ncn1
Reactant: [Li]CCCC
Agent: C=C[Sn](C=C)(C=C)C=C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]C=C
Solvent: CCOCC
Product: C=Cc1nc(Cl)cc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Vinyl lithium (10 mmol; generated from the reaction of nBuLi with tetravinyltin in diethyl ether) was added to a solution of 4,6-dichloropyrimidine (1.49 g, 10 mmol) in diethyl ether (70 mL) under an argon atmosphere at −30° C. The reaction mixture was quenched with acetic acid (600 mL) and water (200 mL) after stirring for 60 min. DDQ (2.27 g, 10 mmol) was added and the reaction mixture was warmed to 0° C. and stirred for 2 hr. The brownish slurry was then washed three times with 1M NaOH, once with brine and dried over MgSO4. Filtration followed by removal of volatiles under reduced pressure afforded a dark brown tar from which 2-vinyl-4,6-dichloropyrimidine was isolated by flash chromatography (10% ethyl acetate in hexane).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:8]=1)=O.[C:22]1([NH:28]N)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[F:20][C:17]1[CH:18]=[CH:19][C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)=[CH:15][CH:16]=1
Reactant: NNc1ccccc1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccc(F)cc2)ccc1=O
Solvent: CO
Product: O=c1ccn(-c2ccc(F)cc2)nc1-c1ccnn1-c1ccccc1
Yield: 27 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(4-fluorophenyl)pyridazin-4(1H)-one (crude 840 mg, 2.93 mmol) in 20 mL of methanol was added phenylhydrazine (474 mg, 4.39 mmol) The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-(4-fluorophenyl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (260 mg, 27% for two steps) as a brown solid.
Reaction SMILES: COC1C=C(C(Cl)=O)C=CC=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.[CH3:34][O:35][C:36]1[CH:37]=[C:38]([C:42]([N:44]=[C:45]=[S:46])=[O:43])[CH:39]=[CH:40][CH:41]=1>C1(C)C=CC=CC=1.C(O)C>[CH3:34][O:35][C:36]1[CH:37]=[C:38]([C:42]([N:44]=[C:45]=[S:46])=[O:43])[CH:39]=[CH:40][CH:41]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:45]([NH:44][C:42](=[O:43])[C:38]2[CH:39]=[CH:40][CH:41]=[C:36]([O:35][CH3:34])[CH:37]=2)=[S:46])=[CH:29][CH:28]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: COc1cccc(C(=O)Cl)c1
Agent: COc1cccc(C(=O)N=C=S)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cccc(C(=O)NC(=S)Nc2ccc(Oc3ncnc4cc(OC)c(OC)cc34)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
3-Methoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-methoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-methoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (67 mg, yield 81%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[NH2:52][C:53]1[CH:58]=[CH:57][C:56]([OH:59])=[CH:55][C:54]=1[F:60]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:52][C:53]3[CH:58]=[CH:57][C:56]([OH:59])=[CH:55][C:54]=3[F:60])=[O:16])[CH2:12][CH2:13]2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: Nc1ccc(O)cc1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2ccc(O)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 38.9 %

Procedure:
To a solution of 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (1.02 g) in N,N-dimethylformamide (5.0 ml) were added triethylamine (1.28 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.03 g), followed by stirring at room temperature for 5 min. To this was added 4-amino-3-fluorophenol hydrochloride (500 mg), followed by stirring at room temperature for 3 days. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with a 1N aqueous solution of sodium hydroxide. To the aqueous layer was added 5N hydrochloric acid to make it acidic, this was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=2:3 to 1:2). Fractions containing the target compound were concentrated under reduced pressure to provide the titled compound as a pale red solid (395 mg, 39%).