Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[O:15][CH2:16][CH2:17][CH3:18].[Li][CH2:20]CCC.CI>C1COCC1>[CH3:14][O:13][CH2:12][O:11][C:9]1[CH:8]=[CH:7][C:6]([O:15][CH2:16][CH2:17][CH3:18])=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:10]=1[CH3:20]
Reactant: [Li]CCCC
Reactant: CCCOc1ccc(OCOC)cc1OCOC
Solvent: CI
Solvent: C1CCOC1
Product: CCCOc1ccc(OCOC)c(C)c1OCOC
Temperature: -78 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of 4b (165 mg, 0.64 mmol) in anhydrous THF (520 μL) was added dropwise to a solution of nBuLi (2.5 M in hexanes, 390 mL, 0.97 mmol) in anhydrous THF (420 μL) at room temperature. After 1 hour, the solution was cooled to −78° C. and methyl iodide (160 μL, 2.58 mmol) was added. The resulting solution was warmed to room temperature over 12 hours, and the reaction was quenched by the addition of saturated aqueous NH4Cl. Water (5 mL) was added and the solution was extracted with CH2Cl2 (3×10 mL). Combined organic fractions were dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 6:1 Hexane:EtOAc) to afford 5b as a yellow oil (166 mg, 95%): 1H NMR (CDCl3, 500 MHz) 6.66 (d, J=9.0 Hz, 1H), 6.60 (d, J=9.0 Hz, 1H), 5.02 (s, 2H), 5.00 (s, 2H), 3.80-3.77 (m, 2H), 3.49 (s, 3H), 3.47 (s, 3H), 2.14 (d, J=7.1 Hz, 3H), 1.73-1.69 (m, 2H), 0.94 (t, J=7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 148.5, 148.5, 147.3, 145.6, 126.7, 123.0, 112.8, 110.8, 110.4, 99.2, 57.7, 57.6, 21.2, 10.9, 10.0; IR (film) νmax 2957, 2924, 2853, 1738, 1597, 1487, 1468, 1391, 1335, 1231, 1157, 974, 798 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C14H22O5, 271.1545; found, 271.1558.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH:21]C(=O)OC(C)(C)C)=[N:9]3)[CH:7]=1.[CH3:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([C:38](O)=[O:39])=[N:36][CH:37]=1>>[NH2:21][C:10]1[S:11][CH2:12][C@@H:13]2[C@@H:14]([C:17]([F:20])([F:19])[F:18])[O:15][CH2:16][C@:8]2([C:6]2[CH:7]=[C:2]([NH:1][C:38](=[O:39])[C:35]3[CH:34]=[CH:33][C:32]([O:31][CH3:30])=[CH:37][N:36]=3)[CH:3]=[CH:4][C:5]=2[F:29])[N:9]=1
Reactant: COc1ccc(C(=O)O)nc1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Product: COc1ccc(C(=O)Nc2ccc(F)c([C@]34CO[C@H](C(F)(F)F)[C@H]3CSC(N)=N4)c2)nc1

Procedure:
Synthesized from tert-butyl [(4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-trifluoromethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate and 5-methoxypyridine-2-carboxylic acid according to the general procedure. 1H NMR (400 MHz, CDCl3) δ ppm 2.88 (dd, J=13.8, 3.7 Hz, 1H), 3.23 (dd, J=13.8, 2.4 Hz, 1H), 3.46 (d, J=7.3 Hz, 1H), 3.89-4.02 (m, 4H), 4.54-5.00 (m, 4H), 7.11 (dd, J=11.9, 8.8 Hz, 1H), 7.36 (dd, J=8.8, 2.8 Hz, 1H), 7.61 (dd, J=7.1, 2.8 Hz, 1H), 7.97 (dt, J=8.5, 3.6 Hz, 1H), 8.23-8.30 (m, 2H), 9.86 (s, 1H)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH2:10][CH2:11]OS(C)(=O)=O)=[CH:5][CH:4]=1)#[N:2].[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C>[N:22]([CH2:11][CH2:10][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCCC(c1ccc(C#N)cc1)n1ccnc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(CCN=[N+]=[N-])n2ccnc2)cc1
Reaction time: 4 h

Procedure:
The methanesulfonic acid 3-(4-cyano-phenyl)-3-imidazol-1-yl-propyl ester (600 mg, 2 mmol) was suspended in degassed DMF under argon and sodium azide (650 mg, 10 mmol) was added and the reaction was stirred for 4 hours. The solvent was removed in vacuo and the residue was suspended in ethyl acetate (200 mL) and extracted 2 times with saturated aqueous sodium bicarbonate (100 mL), then water (100 mL), then saturated sodium chloride solution (100 mL). The organic solvent was removed in vacuo and the residue was chromatographed on silica gel eluting with 1:2 ethyl acatate: hexanes. The desired fractions were concentrated in vacuo to give the desired product.
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Br[C:13]1C=C2C(=C[CH:21]=1)C1(CC1)CC2.[Li]CCCC.CN(C=O)C>>[C:1]12([CH2:2][CH2:3]1)[C:4]1[C:11](=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)[CH2:21][CH2:13]2
Reactant: Brc1ccc2c(c1)CCC21CC1
Reactant: O=Cc1ccc(C2CC2)cc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: O=Cc1ccc2c(c1)CCC21CC1
Yield: 56 %

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S53) using 5′-bromo-2′,3′dihydro-spiro[cyclopropane1,1′-[1H]indene] (345 mg, 1.55 mmol), n-BuLi (1.16 ml, 1.6M solution in hexane, 1.86 mmol) and DMF (481 μl, 6.19 mmol). The isolated residue was purified by flash column chromatography (1:9 ether:pentane) to give 2′,3′-dihydro-spiro[cyclopropane-1,1′-[1H]indene]-5′-carboxaldehyde (148 mg, 56%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 9.93 (s, 1H), 7.70 (m, 1H), 7.65 (m, 1H), 6.78 (d, J=8.0 Hz, 1H), 3.10 (apt t, J=8.0 Hz, 2H), 2.18 (apt t, J=8.0 Hz, 2H), 1.08-0.98 (m, 4H).
Reaction SMILES: [O:1]=[C:2]1[C@H:7]2[CH2:8][C@H:4]([CH:5]=[CH:6]2)[N:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[CH3:16][Si:17]([CH:20]=[N+]=[N-])([CH3:19])[CH3:18]>CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:12]([O:11][C:9]([N:3]1[C:2](=[O:1])[C@H:7]2[CH2:8][C@@H:4]1[C@H:5]1[C@@H:6]2[CH:16]1[Si:17]([CH3:20])([CH3:19])[CH3:18])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C=C[C@H]1C2
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1C(=O)[C@H]2C[C@@H]1[C@@H]1C([Si](C)(C)C)[C@@H]12
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.8 %

Procedure:
To a solution of (1R,4S)-tert-butyl 3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate (1.3 g, 6.2 mmol) and palladium(II) acetate (0.070 g, 0.31 mmol) in Et2O (62 mL) was added trimethylsilyldiazomethane (2 M in hexanes, 3.00 mL, 11.5 mmol) drop-wise at ambient temperature over about 1 h. The mixture was stirred at ambient temperature for about 18 h and filtered through Celite®. The Celite® pad was washed with Et2O (50 mL) and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-30% EtOAc/heptane to afford (1S,2R,4R,5R)-7-oxo-3-trimethylsilanyl-6-aza-tricyclo[3.2.1.0(2,4)]octane-6-carboxylic acid tert-butyl ester (1.7 g, 92%). 1H NMR (400 MHz, DMSO-d6) δ 4.37 (s, 1H), 2.70 (s, 1H), 1.45 (m, 10H), 1.23 (t, 1H), 0.76 (t, 1H), 0.10 (s, 2H), −0.03 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[NH:10]2)=[CH:5][CH:4]=1)#[N:2].[F:16][C:17]([F:25])([F:24])[C:18](=[O:23])[C:19]([O:21][CH3:22])=[O:20]>C(Cl)(Cl)Cl>[CH3:22][O:21][C:19](=[O:20])[C:18]([OH:23])([C:17]([F:25])([F:24])[F:16])[C:12]1[C:13](=[O:14])[N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[NH:10][C:11]=1[CH3:15]
Reactant: Cc1cc(=O)n(-c2ccc(C#N)cc2)[nH]1
Reactant: COC(=O)C(=O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COC(=O)C(O)(c1c(C)[nH]n(-c2ccc(C#N)cc2)c1=O)C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a chloroform solution (5 ml) of 1-(4-cyanophenyl)-3-methyl-5-pyrazolone (100 mg, 0.5 mmol), methyl trifluoropyruvate (78 mg, 0.5 mmol) was added at room temperature and the mixture was stirred at 80° C. for 2 hours. After removing the solvent under reduced pressure, the title compound was obtained as a pale yellow solid (174 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:16]([S:19](Cl)(=[O:21])=[O:20])([CH3:18])[CH3:17]>O>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:19]([CH:16]([CH3:18])[CH3:17])(=[O:21])=[O:20])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: O
Product: CC(C)S(=O)(=O)Nc1ccc(-c2ccc(C#N)n2C)cc1
Temperature: 70 °C
Yield: 2.2 %

Procedure:
5-(4-Aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile (0.27 g, 1.37 mmol) was dissolved in isopropyl sulfonyl chloride (0.50 mL, 2.8 mmol) and heated to 70° C. for 6 hours. The mixture was cooled and diluted with water and extracted with ethyl acetate. The organics were combined, washed with water, brine, dried over MgSO4, and concentrated. Flash chromatography (0%-100% ethyl acetate in hexane) afforded N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]propane-2-sulfonamide (0.009 g).
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:32])[CH2:7][CH:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:24]([CH3:25])=[N:23][N:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:21]=2)=[CH:14][CH:13]=1)[C:9]#[C:10][CH3:11])C.O.Cl>CCO>[CH3:25][C:24]1[C:20]([CH2:19][O:18][C:15]2[CH:14]=[CH:13][C:12]([CH:8]([C:9]#[C:10][CH3:11])[CH2:7][C:6]([OH:32])=[O:5])=[CH:17][CH:16]=2)=[N:21][N:22]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:23]=1
Reactant: CC#CC(CC(=O)OCC)c1ccc(OCc2nn(-c3ccccc3)nc2C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC#CC(CC(=O)O)c1ccc(OCc2nn(-c3ccccc3)nc2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
2N KOH(aq) (1 mL) was added to a solution of 26.2 (68 mg, 0.17 mmol) in EtOH (2 mL). The reaction was stirred at room temperature overnight and then poured into water. The aqueous mixture was acidified to pH=2 with 1N HCl(aq), and then extracted with ethyl acetate. The organic layer was washed with water, followed by brine. The organic layer was then concentrated under reduced pressure and the resulting residue was purified via radial chromatography (20% ethyl acetate in hexanes) to yield 60.3 mg (95%) of compound 26 as a colorless oil. LC/MSD m/e: 374.0 (M−H); 1H NMR (400 MHz) (acetone-d6) δ 8.05 (2H, d, J=8.0 Hz), 7.56 (2H, t, J=8.0 Hz), 7.40 (3H, t, J=8.0 Hz), 7.06 (2H, d, J=8.0 Hz), 5.28 (2H, s), 4.05 (1H, m), 2.70 (2H, m), 2.44 (3H, s), 1.80 (3H, s).
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.C[Si](Cl)(C)C.[CH2:15]([O:17][C:18](=[O:48])[CH2:19][CH2:20][N:21]([C:39]1([C:45](Cl)=[O:46])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)[S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH3:16].Cl>ClCCl>[CH2:15]([O:17][C:18](=[O:48])[CH2:19][CH2:20][N:21]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:39]1([C:45](=[O:46])[NH:2][OH:3])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)[CH3:16]
Reactant: NO
Reactant: CCOC(=O)CCN(C1(C(=O)Cl)CCOCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CCN(C1(C(=O)NO)CCOCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (19.7 mmol, 1.3 equivalents) of hydroxylamine hydrochloride in 9.2 mL (114 mmol, 7.5 equivalents) of dry pyridine at 0 ° C. is treated with 5.8 mL (45 mmol, 3.0 equivalents) of trimethylsilyl chloride, causing white solids to precipitate. The mixture is allowed to warm to ambient temperature overnight This mixture is then cooled to 0° C. aind treated with a solution of (15.1 mmol) of the product from Step F in 73 mL of dichloromethane causing an exotherm to about 8° C. This mixture is stirred at 0° C. for 30 minutes and at ambient temperature for about one hour. The reaction is then treated with 50 mL of 2N aqueous hydrochloric acid and was stirred at ambient temperature for one hour. The aqueous phase is extracted with dichloromethane and the combined organic phases are washed with 2N aqueous hydrochloric acid (2×50 mL) and water (50 mL). This solution of the title compound in dichloromethane is used in the next step.
Reaction SMILES: Cl.[C:2]1([C:8]2[N:13]=[N:12][C:11]([CH2:14][NH2:15])=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:24]=1>C(Cl)Cl>[C:2]1([C:8]2[N:13]=[N:12][C:11]([CH2:14][NH:15][S:29]([C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)(=[O:31])=[O:30])=[CH:10][CH:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: NCc1ccc(-c2ccccc2)nn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NCc1ccc(-c2ccccc2)nn1)c1cccnc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 87 %

Procedure:
To a solution of (6-phenylpyridazin-3-ylmethyl)amine hydrochloride (121 mg) (containing 0.458 mmol of a pure content) obtained in Reference Example 2-(c) in methylene chloride (1 ml) were added triethylamine (0.26 ml, 1.8 mmol) and 3-pyridylsulfonyl chloride (see The Journal of Organic Chemistry, 54, 389 (1989)) (83.2 mg, 0.468 mmol), followed by stirring at room temperature for 17 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The separated organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; ethyl acetate:acetonitrile=1:0→0:1 (V/V), then chloroform), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (130 mg) as a slightly brown solid. (Yield: 87%)
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([O:13][C:14](=[O:27])[C:15]([CH3:26])([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:16](OCC)=[O:17])[CH3:12]>C1(C)C=CC=CC=1.ClCCl>[CH2:11]([O:13][C:14](=[O:27])[C:15]([CH:16]=[O:17])([CH3:26])[CH2:21][CH2:22][CH:23]([CH3:24])[CH3:25])[CH3:12]
Reactant: CCOC(=O)C(C)(CCC(C)C)C(=O)OCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C(C)(C=O)CCC(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
Diisobutylaluminum hydride (97.5 mL of a 1.0 M solution in toluene, 97.5 mmol) was added over 10 min to a solution of rac-2-methyl-2-(3-methyl-butyl)-malonic acid diethyl ester (11.91 g, 48.7 mmol) in dichloromethane (100 mL) at −78° C. The reaction mixture was stirred at that temperature for 4 h, and then was quenched with saturated aqueous ammonium chloride (100 mL). The cold bath was removed, 1.0 M aqueous hydrochloric acid solution (300 mL) and DL-tartaric acid (12 g) were added sequentially, and the mixture was allowed to warm to 25° C. over 2 h with vigorous stirring. The biphasic mixture was then partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and dichloromethane (350 mL). The organic layer was dried over sodium sulfate and was concentrated in vacuo to afford the crude product, rac-2-formyl-2,5-dimethyl-hexanoic acid ethyl ester (8.80 g, 44 mmol, 90%).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[Br:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:30](=O)[CH:29]([NH:35][C:36]([C:38]1[O:42][N:41]=[C:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:39]=1[C:49]([F:52])([F:51])[F:50])=O)[CH2:28][CH2:27]2>C1(C)C=CC=CC=1>[Br:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:30]1[S:10][C:36]([C:38]3[O:42][N:41]=[C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:39]=3[C:49]([F:52])([F:51])[F:50])=[N:35][C:29]=1[CH2:28][CH2:27]2
Reactant: O=C(NC1CCc2cc(Br)ccc2C1=O)c1onc(-c2ccccc2)c1C(F)(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1c(-c2ccccc2)noc1-c1nc2c(s1)-c1ccc(Br)cc1CC2
Temperature: 140 °C
Yield: 85.4 %

Procedure:
To Lawesson's Reagent (1.393 g, 3.44 mmol) was added N-(6-bromo-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxamide (Preparation 82C, 1.1 g, 2.295 mmol) followed by toluene (10 mL). The reaction mixture was heated at 140° C. behind a safety shield for 15 h. The reaction mixture was cooled to room temperature, loaded onto a silica gel column (with toluene) and purified using hexane/EtOAc (9.25:0.75, 600 mL). The desired fractions were collected and concentrated to yield a pale yellow solid. The solid was triturated with acetonitrile (20 mL), filtered and washed with acetonitrile (2×5 mL) to yield 5-(7-bromo-4,5-dihydronaphtho[2,1-d]thiazol-2-yl)-3-phenyl-4-(trifluoromethyl)isoxazole (0.935 g, 1.959 mmol, 85% yield) as a pale yellow solid. LC/MS M+1=478.
Reaction SMILES: [C:1]([N:4]1[C@@H:8]([C:9]([OH:11])=[O:10])[C:7]([CH3:13])([CH3:12])[S:6][C@H:5]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:3])[CH3:2].[C:20]([N:23]1[C:27]2[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=2[S:25][CH:24]1[C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1O)(=[O:22])[CH3:21].N(C(OCC)=O)=NC(OCC)=O>CN(C=O)C>[C:20]([N:23]1[C:27]2[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=2[S:25][CH:24]1[C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[O:10][C:9]([C@H:8]1[C:7]([CH3:13])([CH3:12])[S:6][C@@H:5]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:4]1[C:1](=[O:3])[CH3:2])=[O:11])(=[O:22])[CH3:21]
Reactant: COc1ccc(O)c(C2Sc3cc(Cl)ccc3N2C(C)=O)c1
Reactant: CC(=O)N1[C@@H](C(=O)O)C(C)(C)S[C@H]1c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CN(C)C=O
Product: COc1ccc(OC(=O)[C@@H]2N(C(C)=O)[C@H](c3ccccc3)SC2(C)C)c(C2Sc3cc(Cl)ccc3N2C(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.3 %

Procedure:
A solution of (2S,4S)-3-acetyl-5,5-dimethyl-2-phenyl-4-thiazolidinecarboxylic acid [compound described in Reference Example 4 (b)] (102 g, 0.38 mol) in anhydrous DMF (500 ml) was added to a solution of 3-acetyl-6-chloro-2-(2-hydroxy-5-methoxyphenyl)-benzothiazoline (127 g, 0.38 mol) in anhydrous DMF (500 ml) at room temperature. N,N-Dimethylaminopyridine (5.58 g, 45.7 mmol) was added thereto under a nitrogen atmosphere at room temperature with stirring. After ice-cooling, diethyl azodicarboxylate (87 g, 0.50 mol) was added thereto. The mixture was stirred under ice-cooling for 15 minutes, at room temperature for one hour and further at an internal temperature of about 40° C. for three days. The reaction mixture was concentrated under reduced pressure, a 10% aqueous citric acid solution (1,000 ml) was added to the residue, and the whole was extracted with ethyl acetate (1,000 ml). The organic layer was washed with water (1,000 ml) and saturated brine (1,000 ml) successively and dehydrated with magnesium sulfate, and ethyl acetate was evaporated under reduced pressure. A mixed solvent (ethanol/diisopropyl ether=200 ml/1000 ml) was added to the residue, the residue was dissolved by heating, and then the solution was allowed to stand at room temperature overnight. The precipitated crystals were filtered off and dried to give 34.7 g of the target compound. The mother liquor was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate=1/1) to give further 43.8 g of the target compound (total 43%).
Reaction SMILES: [F-].[K+].[OH:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.F[C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[N:27]4[N:28]=[C:29]([N:32]5[CH2:36][CH2:35][CH2:34][C@@H:33]5[C:37]5[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=5)[CH:30]=[CH:31][C:26]4=[N:25][CH:24]=3)[N:18]=2)[CH:14]=[CH:13][N:12]=1>CS(C)=O>[F:43][C:39]1[CH:38]=[C:37]([C@H:33]2[CH2:34][CH2:35][CH2:36][N:32]2[C:29]2[CH:30]=[CH:31][C:26]3[N:27]([C:23]([C:19]4[N:18]=[C:17]([C:15]5[CH:14]=[CH:13][N:12]=[C:11]([N:7]6[CH2:8][CH2:9][CH:4]([OH:3])[CH2:5][CH2:6]6)[CH:16]=5)[CH:22]=[CH:21][CH:20]=4)=[CH:24][N:25]=3)[N:28]=2)[CH:42]=[CH:41][CH:40]=1
Reactant: OC1CCNCC1
Reactant: Fc1cccc([C@H]2CCCN2c2ccc3ncc(-c4cccc(-c5ccnc(F)c5)n4)n3n2)c1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: OC1CCN(c2cc(-c3cccc(-c4cnc5ccc(N6CCC[C@@H]6c6cccc(F)c6)nn45)n3)ccn2)CC1

Procedure:
In step 16-4, potassium fluoride (10 g, 175 mmol) and 4-hydroxypiperidine (10.6 g, 105 mmol) were added to a solution of crude (R)-3-(2′-fluoro-2,4′-bipyridin-6-yl)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (16-3) (16.1 g, 35 mmol) in DMSO (100 mL). The mixture was heated overnight to 120° C. (approx. 14 hours). The mixture was filtered through a celite pad and rinsed with EtOAc (1 L). The filtrate was washed with brine, dried over Na2SO4, filtered and concentrated to give a dark oil. The mixture was purified by column chromatography (silica gel, CH2Cl2/CH3OH, gradient 5% to 15%) to yield (R)-1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-2,4′-bipyridin-2′-yl)piperidin-4-ol (16-4) which was crashed out from CH2Cl2, filtered and dried under high vacuum. 1H NMR (400 MHz, DMSO, ppm): δ 8.30 (s, 1H), 8.22 (d, 1H, J=5.2 Hz), 8.10-8.24 (bs, 1H), 7.90-7.98 (m, 2H), 7.76-7.86 (bs, 1H), 7.52 (s, 1H), 7.40 (q, 1H, J=7.4 Hz), 7.34 (d, 1H, J=5.2 Hz), 7.04 (t, 1H, J=8 Hz), 6.80-6.94 (bs, 1H), 5.19 (d, 1H, J=8 Hz), 4.71 (d, 1H, J=4 Hz), 4.10-4.18 (m, 2H), 3.93-4.06 (m, 1H), 3.65-3.75 (m, 2H), 3.10-3.20 (m, 2H), 1.98-2.10 (m, 2H), 1.78-1.92 (m, 3H), LC/MS: 536.2 (M+H+), 1.34-1.45 (m, 2H). 13C NMR (400 MHz, DMSO, ppm): 163.53, 161.11, 159.53, 153.95, 151.76, 148.27 (d, J=34.7 Hz), 147.69, 147.10 (d, J=25.6 Hz), 146.92, 137.61, 133.14 (d, J=23.2 Hz), 130.34 (d, J=32.4 Hz), 126.54, 126.04, 121.56, 119.26, 118.75, 113.40 (d, J=83.6 Hz), 112.41 (d, J=86.0), 110.26, 109.86, 103.75, 66.34, 61.24, 48.37, 42.72, 35.12, 33.71, 22.65.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[CH3:16]>CN(C)C=O>[CH2:15]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1)[CH3:16]
Reactant: CCBr
Reactant: OCC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCCC(CO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of piperidin-3-ylmethanol (3.88 g) in dimethylformamide (50 mL) was added potassium carbonate (9.3 g) and ethyl bromide (2.52 mL). The reaction was stirred overnight at room temperature. The mixture was filtered and the filtrate evaporated. The residue was filtered through a short pad of silica eluting with 10% 7M NH3/MeOH in dichloromethane. The filtrate was evaporated to give the title compound as an orange oil (4.8 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8](/[CH:11]=[N:12]/[OH:13])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl:14]N1C(=O)CCC1=O>CN(C=O)C>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([CH:7]=[CH:6][C:3]=1[C:4]#[N:5])/[C:11](/[Cl:14])=[N:12]/[OH:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1c(/C=N/O)ccc(C#N)c1Cl
Solvent: CN(C)C=O
Product: Cc1c(/C(Cl)=N/O)ccc(C#N)c1Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(E)-2-chloro-4-((hydroxyimino)methyl)-3-methylbenzonitrile (0.64 g, 3.27 mmol) was dissolved in DMF (20 ml) and cooled to 0° C. N-Chlorosuccinimide (0.48 g, 3.60 mmol) was added and the mixture was allowed to warm at RT. The mixture was stirred overnight at RT and poured into ice water (100 ml), extracted twice with EtOAc, The organic phase was washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product (0.69 g) was used without purification. 1H-NMR (400 MHz; d6-DMSO): δ 2.42 (s, 3H), 7.64 (d, 1H), 7.92 (d, 1H), 12.77 (s, 1H).