Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:31][CH3:32])=[C:6]([CH:30]=1)[C:7]([N:9]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)=[O:8].Br[CH2:34][CH:35]([OH:40])[C:36]([F:39])([F:38])[F:37].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:31][CH3:32])=[C:6]([CH:30]=1)[C:7]([N:9]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:34][CH:35]([OH:40])[C:36]([F:39])([F:38])[F:37])=[CH:27][CH:28]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=1)=[O:8]
Reactant: CNc1ccc(Cl)cc1C(=O)N(CCc1cccc(C(F)(F)F)c1)Cc1ccc(O)cc1
Reactant: OC(CBr)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNc1ccc(Cl)cc1C(=O)N(CCc1cccc(C(F)(F)F)c1)Cc1ccc(OCC(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 65 h
Yield: 59.3 %

Procedure:
A suspension of 80 mg (0.17 mmol) of 5-chloro-N-(4-hydroxy-benzyl)-2-methylamino-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide, 40 mg (0.21 mmol) 3-bromo-1,1,1-trifluoro-2-propanol and 57 mg (0.41 mmol) of potassium carbonate in 3 ml DMF was stirred at RT for 65 hours. The reaction mixture was then diluted with 15 ml water and 15 ml brine, and extracted twice with ethylacetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel; DCM/EtOAc 97:3) to give 58 mg of 5-chloro-2-methylamino-N-[4-(3,3,3-trifluoro-2-hydroxy-propoxy)-benzyl]-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide (55%) as a light yellow viscous oil. MS (ISP) 575.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[O:11])=O)=[CH:4][CH:3]=1.[H-].[Na+].[C:21](#[N:24])[CH:22]=[CH2:23]>CN(C)C=O>[C:21]([CH2:22][CH2:23][C:9]1[N:8]=[C:6]([C:5]2[CH:17]=[CH:18][C:2]([F:1])=[CH:3][CH:4]=2)[O:11][C:10]=1[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)#[N:24]
Reactant: C=CC#N
Reactant: O=C(NCC(=O)c1cccs1)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCCc1nc(-c2ccc(F)cc2)oc1-c1cccs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-[(4-fluorobenzoylamino)acetyl]thiophene (527 mg) in N,N-dimethylformamide (10 ml) was added sodium hydride (88 mg, 60% mineral oil) under ice-cooling, and the mixture was stirred under argon atmosphere at room temperature for one hour. After ice-cooling, acrylonitrile (127 ml) was added to the mixture and the mixture was stirred at room temperature for 3 hours. After addition of ice-water, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was dissolved in N,N-dimethylformamide (10 ml), and phosphoryl chloride (240 μl) was added to the solution under ice-cooling. The mixture was stirred under argon atmosphere at room temperature for 3 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: hexane:ethyl acetate=9:1→7:1), and triturated with hexane and ethyl acetate to obtain 4-(2-cyanoethyl)-2-(4-fluorophenyl)-5-(2-thienyl)oxazole (132 mg) as colorless powder.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[N:15]([C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@@H:24]4[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]4)[N:18]=2)[CH:14]=[CH:13][S:12]3)=[CH:5][C:4]=1[O:30][CH3:31].CCN(C(C)C)C(C)C.[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([S:48](Cl)(=[O:50])=[O:49])=[CH:44][CH:43]=1>C(Cl)Cl>[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([S:48]([N:26]2[CH2:27][CH2:28][CH2:29][C@@H:24]([NH:23][C:19]3[N:18]=[C:17]([C:16]4[N:15]5[C:11]([S:12][CH:13]=[CH:14]5)=[N:10][C:9]=4[C:6]4[CH:7]=[CH:8][C:3]([F:2])=[C:4]([O:30][CH3:31])[CH:5]=4)[CH:22]=[CH:21][N:20]=3)[CH2:25]2)(=[O:50])=[O:49])=[CH:44][CH:43]=1
Reactant: COc1cc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCNC3)n2)ccc1F
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
The 4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[(3R)-piperidin-3-yl]pyrimidin-2-amine hydrochloride (0.25 g, 0.50 mmol) in methylene chloride (DCM) (12 ml) was cooled to 0° C. and was treated with Hunig's base (440 μl, 2.5 mmol). The mixture was kept at 0° C. for 30 minutes then the 4-chlorophenylsulfonyl chloride (0.128 g, 0.60 mmol) was added. The reaction mixture was stirred at room temperature for one hour. The mixture was diluted with methylene chloride (10 ml) and was washed water (2×10 ml) and a saturated aqueous sodium chloride solution (10 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient (ethyl acetate/hexanes, 50-75%), affording 0.281 g (94%) of the title compound as a pale yellow solid. M.p.: 142-143° C. 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 8.71 (br. s, 1H), 8.15 (d, J=5.5 Hz, 1H), 7.80-7.74 (m, 2H), 7.70-7.64 (m, 2H), 7.42 (d, J=4.5 Hz, 1H), 7.36 (dd, J=8.6, 2.3 Hz, 1H), 7.27 (dd, J=11.3, 8.2 Hz, 1H), 7.19-7.12 (m, 2H), 6.43 (d, J=5.5 Hz, 1H), 4.00-3.90 (m, 1H), 3.84 (s, 3H), 3.77-3.70 (m, 1H), 3.52-3.44 (m, 1H), 2.56-2.42 (m, 1H), 2.34 (t, J=10.0 Hz, 1H), 1.95-1.80 (m, 2H), 1.66-1.52 (m, 1H), 1.45-1.33 (m, 1H). LCMS: 599 [M+H]. Calc. for C27H24N6O3S2FCl.0.16 water.0.74 diethyl ether: C, 53.94; H, 4.57; N, 12.60. Found C, 53.94; H, 4.19; N, 12.59.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][C@@H:8]([O:14][CH2:15][O:16][CH2:17]COC)[CH2:9][CH2:10][CH2:11]CO)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CS(C)=O.CCN(CC)CC.Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][C@H:8]2[O:14][CH:15]([O:16][CH3:17])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COCCOCO[C@@H](CCCCO)COc1ccc(F)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC1CCC[C@@H](COc2ccc(F)cc2)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution of (2S)-1-(4-fluorophenoxy)-2-(methoxyethoxymethyloxy)-hexan-6-ol (1.25 g, 3.9 mmol) and oxalyl chloride (0.7 ml, 7.9 mmol) in dry CH2Cl2 was added dry DMSO (1.12 ml, 15.8 mmol) slowly at −78° C. The stirring was continued for a further 30 min. at −78° C. and quenched with dry Et3N (3.15 ml, 23.7 mmol). The reaction mixture was extracted with CH2Cl2 and dried (Na2SO4) to afford the crude aldehyde (1.1 g, 85%). A 20% methanolic HCl solution was added to the aldehyd and stirred for 5 h. at room temperature. The reaction mixture was neutralised with aqueous NaHCO3, extracted with ethyl acetate, dried (Na2SO4) and concentrated under vacuum. The crude product was purified by silica gel column chromatography to give a cis-trans mixture (2RS, 6S)-6-(4-fluorophenoxymethyl)-2-methoxytetrahydropyran (0.6 g, 80%) as a yellow syrup. TLC:ethyl acetate-light petroleum (1:3), Rf=0.8. 1H NMR (CDCl3, 200 MHz): δ 1.6-2.0 (m, 6H), 3.45 (s, 3H), 3.9-3.96 (m, 2H), 4.0-4.15(m, 1H), 4.8 (s, 1H), 6.8-7.01 (m, 4H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1Br)(=[O:3])[CH3:2].[C:25]1([S:31]([O-:34])(=[O:33])=[S:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Na+].C(OCC)(=O)C>C(#N)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:25]1([S:31]([O:34][C@@H:6]2[O:7][C@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:5]2[O:4][C:1](=[O:3])[CH3:2])(=[O:33])=[S:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=S([O-])(=S)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](OS(=O)(=S)c2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 70 °C
Yield: 89.2 %

Procedure:
2,3,4,6-Tetra-O-acetyl-α-D-glucopyranosyl bromide (207 mg, 0.5 mmol) was dissolved in anhydrous acetonitrile (5 mL). To this sodium phenylthiosulfonate (201 mg, 1 mmol) and tetrabutylammonium bromide (16 mg, 0.05 mmol) were added. The resulting mixture was stirred under argon at 70° C. After a 4.5 h period, thin layer chromatography (t.l.c.) (petrol:ethyl acetate, 1:1) indicated the formation of a product (Rf 0.5) with complete consumption of the starting material (Rf 0.3). The solution was concentrated in vacuo. The crude solid was partitioned between dichloromethane (DCM, 20 mL) and water (20 mL), and the aqueous layer re-extracted with DCM (2×20 mL). The combined organics were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (petrol:ethyl acetate, 1:1) to afford the title product (225 mg, 88%) as a white crystalline solid; mp 129-130° C.; [α]D25+51.2 (c, 1.0 in CHCl3); νmax (KBr) 1754 (s, C═O), 1376 (s, C═C) cm−1; δH; (400 MHz, C6D6) 1.68, 1.72, 1.73, 1.75 (4×3H, 4×s, 4×OAc), 3.09 (1H, ddd, J4,5 10.2 Hz, J5,6 2.4 Hz, J5,6′ 4.2 Hz, H-5), 3.83 (1H, dd, J5,6 2.4 Hz, J6,6′ 12.7 Hz, H-6),4.08 (1H, dd, J5,6′ 4.2 Hz, J6,6′ 12.6 Hz, H-6′), 5.17-5.23 (2H, m, H-2, H -4), 5.40 (1H, d, J1,2 10.2 Hz, H-1), 5.44 (1H, at, J9.4 Hz, H-3), 6.98-7.03 (3H, m, Ar—H), 7.90-7.92 (2H, m, Ar—H). The structure of the product was further confirmed by single crystal X-ray diffraction.
Reaction SMILES: Cl.CC(C)(CC1C=CC(CCN)=CC=1)C(OCC)=O.[C:20]([NH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:22])[CH3:21].[Cl-].[CH3:33][O:34][C:35](=[O:42])[C:36]([CH3:41])([CH3:40])[C:37](O)=[O:38]>>[CH3:40][C:36]([CH3:41])([C:37](=[O:38])[C:29]1[CH:30]=[CH:31][C:26]([CH2:25][CH2:24][NH:23][C:20](=[O:22])[CH3:21])=[CH:27][CH:28]=1)[C:35]([O:34][CH3:33])=[O:42]
Reactant: COC(=O)C(C)(C)C(=O)O
Reactant: CC(=O)NCCc1ccccc1
Agent: CCOC(=O)C(C)(C)Cc1ccc(CCN)cc1
Agent: Cl
Agent: [Cl-]
Product: COC(=O)C(C)(C)C(=O)c1ccc(CCNC(C)=O)cc1

Procedure:
The ethyl α,α-dimethyl-β-[4-(2-aminoethyl)-phenyl]-propionate hydrochloride (m.p. 113°-117° C.) used as starting material is prepared in the following manner: N-acetylphenethylamine is reacted with dimethylmalonic acid methyl ester chloride according to Friedel-Crafts method to give methyl α,α-dimethyl-β-oxo-β-[4-(2-acetamidoethyl)-phenyl]-propionate (b.p. 215°-220° C./0.1 mm.Hg.), this then reduced, via methyl α,α-dimethyl-β-hydroxy-β-[4-(2-acetamidoethyl)-phenyl]-propionate (m.p. 120°-123° C.) to give methyl α,α-dimethyl-β-[4-(2-acetamidoethyl)-phenyl]-propionate (b.p. 180°-190° C./0.1 mm Hg.), saponified to give α,α-dimethyl-β-[4-(2-aminoethyl)-phenyl]-propionic acid hydrochloride (m.p. 230°-235° C.) and thereafter esterified to give the desired ethyl ester hydrochloride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][C:12]([CH:13]=[CH:14][CH:15]=O)=[CH:11][C:10]=1[O:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29]>>[CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][C:12]([CH:13]=[CH:14][CH:15]=[C:27]2[S:23][C:24](=[O:29])[NH:25][C:26]2=[O:28])=[CH:11][C:10]=1[O:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: COc1cc(C=CC=O)cc(OC)c1OCc1ccccc1
Product: COc1cc(C=CC=C2SC(=O)NC2=O)cc(OC)c1OCc1ccccc1
Yield: 57 %

Procedure:
According to the same manner as that described in Example 1, 4-benzyloxy-3,5-dimethoxycinnamaldehyde was condensed with 2,4-thiazolidinedione to give 5-(4-benzyloxy-3,5-dimethoxycinnamylidene)-2,4-thiazolidinedione (yield: 57%). This product was recrystallized from chloroform-ethanol. Yellow prisms, mp: 217-218° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:44]=[CH:43][C:11]2[CH2:12][CH2:13][CH2:14][CH:15]([N:17]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:18][C@H:19]([O:28][Si:29]([CH2:34][CH3:35])([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:16][C:10]=2[CH:9]=1.Br[CH2:46][F:47].C(=O)([O-])O.[Na+]>C(#N)C.CN(C)C=O>[F:47][CH2:46][O:7][C:8]1[CH:44]=[CH:43][C:11]2[CH2:12][CH2:13][CH2:14][CH:15]([N:17]([C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[CH2:18][C@H:19]([O:28][Si:29]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH2:34][CH3:35])[CH2:20][O:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:16][C:10]=2[CH:9]=1
Reactant: FCBr
Reactant: CC[Si](CC)(CC)O[C@H](COc1ccccc1)CN(C(=O)OC(C)(C)C)C1CCCc2ccc(O)cc2C1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)O[C@H](COc1ccccc1)CN(C(=O)OC(C)(C)C)C1CCCc2ccc(OCF)cc2C1
Reaction time: 0.5 h

Procedure:
Under nitrogen, to a suspension of potassium carbonate (76 mg) in a mixture of acetonitrile (5 ml) and N,N-dimethylformamide (2 ml) was added N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine (150 mg) at room temperature. After being stirred at the same temperature for 30 minutes, to this one was an excessive amount of bromofluoromethane, and the mixture was stirred for 12 hours. The resulting solution was poured into saturated aqueous sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=10:1) to give N-(3-fluoromethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine (130 mg).
Reaction SMILES: C1N(P(N2CC2)(NC(C2C(I)=CC=CC=2)=O)=O)C1.[CH3:19][N:20]([CH3:30])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[CH2:29])=[CH:24][CH:23]=1.I[C:32]1[C:40]2[C:35](=[CH:36][C:37]([CH:41]=[O:42])=[CH:38][CH:39]=2)[N:34]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[N:33]=1>>[CH3:19][N:20]([CH2:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:32]2[C:40]3[C:35](=[CH:36][C:37]([CH:41]=[O:42])=[CH:38][CH:39]=3)[N:34]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[N:33]=2)=[CH:24][CH:23]=1)[CH3:30]
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Reactant: C=Cc1ccc(CN(C)C)cc1
Agent: O=C(NP(=O)(N1CC1)N1CC1)c1ccccc1I
Product: CN(C)Cc1ccc(/C=C/c2nn(COCC[Si](C)(C)C)c3cc(C=O)ccc23)cc1

Procedure:
The title compound was synthesized according to the method of Example A103, utilizing N,N-dimethyl-1-(4-vinylphenyl)methanamine (42 mg, 0.26 mmol) and 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (70 mg, 0.17 mmol). Purified by prepTLC (SiO2 10% MeOH/DCM) to provide the title compound to as a pale orange gum (33.4 mg, 44%). 1H NMR (400 MHz, CD3OD) δ ppm 10.13 (s, 1H), 8.27 (m, 2H), 7.81 (d, J=9.29 Hz, 1H), 7.69 (d, J=8.28 Hz, 2H), 7.61 (d, J=16.6 Hz, 1H), 7.50 (d, J=16.6 Hz, 1H), 7.43 (d, J=8.28 Hz, 2H), 5.86 (s, 2H), 3.82 (s, 2H), 3.62 (t, J=8.03 Hz, 1H), 2.50 (s, 6H), 0.87 (t, J=8.03 Hz, 2H), −0.09 (s, 9H); MS ESI 436.3 [M+H]+, calcd for [C25H33N3O2Si+H]+ 436.6.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([Cl:14])=[C:11]([OH:13])[CH:12]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[O:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]1[O:44][CH2:45][CH2:46][CH2:47]O.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:15]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:8]=[CH:9][C:10]([Cl:14])=[C:11]([O:13][CH2:47][CH2:46][CH2:45][O:44][CH:39]3[CH2:40][CH2:41][CH2:42][CH2:43][O:38]3)[CH:12]=2)[N:5]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(Cl)c(O)c2)n1
Reactant: OCCCOC1CCCCO1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(N)n(-c2ccc(Cl)c(OCCCOC3CCCCO3)c2)n1
Temperature: 0 °C
Yield: 96 %

Procedure:
To a solution of 5-(5-amino-3-tert-butyl-pyrazol-1-yl)-2-chloro-phenol (WO20111154734A1, which is incorporated herein by reference in it is entirety; 500 mg, 1.88 mmol), and Ph3P (986 mg, 3.76 mmol) in dry THF (10 mL) was added 3-(tetrahydro-pyran-2-yloxy)-propan-1-ol (Can. J. Chem. Vol. 73, 1195, pp 1682, which is incorporated herein by reference in it is entirety; 452 mg, 2.82 mmol). The resulting mixture was cooled to 0° C. using an ice bath and diethylazodicarboxylate (0.69 mL, 3.76 mmol) was added to the chilled mixture which was allowed to warm up to RT. The volatiles were removed under reduced pressure. The residue was purified by FCC, using 0-50% EtOAc in cyclohexane, to give the title compound (739 mg, 96%). LCMS (Method 1): Rt 3.63 min, m/z 408 [MH+].
Reaction SMILES: C([N:8]1[C:13](=[O:14])[C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[CH:10]=[N:9]1)C1C=CC=CC=1.[Al](Br)(Br)Br>C1(C)C=CC=CC=1>[F:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:12]2[C:13](=[O:14])[NH:8][N:9]=[CH:10][C:11]=2[C:23]2[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=2)=[CH:21][CH:20]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(Cc3ccccc3)c(=O)c2Oc2ccc(F)cc2)cc1
Agent: Br[Al](Br)Br
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared by treating 2-benzyl-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 75) with AlBr3 in toluene according to the procedure in Example 11 (yield: 1.8 g, 95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23](O)=[O:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:26].ON1C2C=CC=CC=2N=N1.Cl.[CH3:39][O:40][C:41](=[O:47])[C@H:42]([CH:44]([CH3:46])[CH3:45])[NH2:43].C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([NH:43][CH:42]([CH:44]([CH3:46])[CH3:45])[C:41]([O:40][CH3:39])=[O:47])=[O:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:26]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: Cc1cc(-c2cc(C(=O)O)on2)ccc1NC(=O)Nc1c(F)cccc1F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(NC(=O)c1cc(-c2ccc(NC(=O)Nc3c(F)cccc3F)c(C)c2)no1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-(4-(3-(2,6-difluorophenyl)ureido)-3-methylphenyl)isoxazole-5-carboxylic acid (1.0 equiv.) was dissolved in 25 ml of DMF, N,N′-dicyclocarbodiimide (1.2 equiv.) and 1-hydroxybenzotriazole (1.0 equiv.) was added and stirred at room temperature for 10 min. L-valine methyl ester hydrochloride (1.5 equiv.) was neutralized with triethylamine (1.5 equiv.) in 10 ml of DMF and was added to the above mixture and the resulting reaction mixture was stirred at room temperature for 48 hours. DMF was evaporated and then diluted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in a chloroform and methanol mixture, adsorbed on silica (100-200 mesh) and purified by flash chromatography on silica gel, and then eluted with 0-2% methanol in chloroform to obtain a crude product.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[CH:30]=O>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:30][C:21]4[CH:22]=[CH:23][C:24]5[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=5)[N:20]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1ccc2ccccc2n1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc5ccccc5n4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with quinoline-2-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 2-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]quinoline.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17]([C:27]([F:30])([F:29])[F:28])=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>CO>[N:11]1([C:14]2[N:15]=[N:16][C:17]([C:27]([F:29])([F:28])[F:30])=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[CH:19]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: Cc1ccccc1-c1cc(N2CCN(C(=O)OC(C)(C)C)CC2)nnc1C(F)(F)F
Solvent: CO
Product: Cc1ccccc1-c1cc(N2CCNCC2)nnc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.4 %

Procedure:
To a solution of 4-[5-(2-tolyl)-6-trifluoromethyl-pyridazin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (D11) (0.089 g, 0.21 mmol) in methanol (7 ml) was added Amberlyst® 15 ion exchange resin, acidic form (4.1 mmol/g) (0.257 g, 1.05 mmol) and the reaction mixture was shaken at room temperature for 18 h. After this period, the mixture was filtered and then a saturated solution of ammonia in methanol was added. The mixture was shaken for 1 h, filtered and the filtrate evaporated in vacuo. The residue was purified by HPLC and the desired fractions were collected and evaporated in vacuo to yield E8 (0.026 g, 50%) as a white solid. C16H17F3N4 requires 322; Found 323 (MH+).
Reaction SMILES: [OH-:1].[Li+].OO.[O-]O.[Li+].C([C@@H]1COC(=O)N1[C:21](=[O:40])[C@@H:22]([C:29]1[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:31]([Cl:39])[CH:30]=1)[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)C1C=CC=CC=1>O.O1CCCC1>[Cl:39][C:31]1[CH:30]=[C:29]([C@@H:22]([CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)[C:21]([OH:40])=[O:1])[CH:34]=[CH:33][C:32]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: [OH-]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1Cl
Agent: OO
Agent: [Li+]
Agent: [O-]O
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84.6 %

Procedure:
A solution of lithium hydroxide (215 mg, 9.0 mmol) in water (2.8 mL) was treated with a 30% aqueous solution of hydrogen peroxide (2.0 mL, 18 mmol). This lithium hydroperoxide solution was cooled to 0° C. and was then slowly added to a solution of 4(R)-benzyl-3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionyl]-oxazolidin-2-one (2.20 g, 4.5 mmol) in tetrahydrofuran (18 mL) and water (5.8 mL) cooled to 0° C. The reaction was stirred at 0° C. for 1.5 h. At this time, the reaction was quenched with a 1.5N aqueous sodium sulfite solution (25 mL) and was further diluted with water (150 mL). This solution was extracted with diethyl ether (3×50 mL). The aqueous layer was then acidified to pH=2 with a 1N aqueous hydrochloric acid solution and extracted with ethyl acetate (3×50 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate plus 1% acetic acid) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (1.26 g, 85%) as a white solid: mp 106.1-108.8° C.; [α]23589=−43.0° (c=0.172, chloroform); EI-HRMS m/e calcd for C15H19ClO4S (M+) 330.0692, found 330.0690.