Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28])(=[O:20])=[O:19])[CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])(=O)=O.C([O-])([O-])=O.[K+].[K+].O[C:37]1[CH:42]=[C:41]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[N:40]=[C:39]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH:38]=1>CN(C=O)C>[C:14]([O:13][C:11]([CH2:10][CH2:9][N:8]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28])(=[O:20])=[O:19])[CH2:7][CH2:6][O:5][C:37]1[CH:38]=[C:39]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[N:40]=[C:41]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:42]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)CCN(CCOS(C)(=O)=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)c1cc(O)cc(C(=O)OCC)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCCN(CCC(=O)OC(C)(C)C)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc(C(=O)OCC)n1
Temperature: 60 °C
Yield: 47 %

Procedure:
To a solution of 10.6 g of tert-butyl 3-[(2-methanesulfonyloxy-ethyl)-(2-nitro-benzenesulfonyl)-amino]-propionate in 220 ml of DMF was added 16.2 g of K2CO3 and 5.6 g of diethyl 4-hydroxy-pyridine-2,6-dicarboxylate. The mixture was heated for 20 hours at 60° C. and then concentrated under reduced pressure and taken up in 200 ml of water and 200 ml of EtOAc. The aqueous phase was extracted 2× with EtOAc. The organic phases were combined, washed with saturated NaCl solution, dried over MgSO4, concentrated under reduced pressure and purified by flash chromatography on silica (Merck EasyVarioPrep 600 g column, Si60 15-40 μm), using a gradient of 0 to 20% EtOAc in DCM. The fractions containing the desired product were combined and concentrated under reduced pressure. 6.56 g of diethyl 4-{2-[(2-tert-butoxycarbonyl-ethyl)-(2-nitro-benzenesulfonyl)-amino]-ethoxy}-pyridine-2,6-dicarboxylate were obtained. LC/MS (C): tr=4.14 min; [M+H]+: m/z 596.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]([C:23]1[CH:27]=[C:26]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([N:52]5[CH2:57][CH2:56][CH2:55][CH2:54][C@@H:53]5[CH3:58])=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:25]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([O:65][CH2:66][CH2:67][OH:68])[CH:60]=2)[N:24]=1)([CH3:22])[CH3:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:78][S:79](Cl)(=[O:81])=[O:80]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:78][S:79]([O:68][CH2:67][CH2:66][O:65][C:61]1[CH:62]=[CH:63][CH:64]=[C:59]([N:25]2[C:26]([NH:28][C:29](=[O:30])[NH:31][C@@H:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[C@H:35]([O:42][C:43]4[CH:44]=[CH:45][C:46]5[N:47]([C:49]([N:52]6[CH2:57][CH2:56][CH2:55][CH2:54][C@@H:53]6[CH3:58])=[N:50][N:51]=5)[CH:48]=4)[CH2:34][CH2:33]3)=[CH:27][C:23]([C:20]([CH3:21])([CH3:22])[CH2:19][O:18][Si:1]([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:24]2)[CH:60]=1)(=[O:81])=[O:80]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)CO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)CO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Yield: 57.6 %

Procedure:
A solution of Intermediate 153h (214 mg, 0.23 mmol) in DCM (2.3 mL) was treated with DIPEA (0.12 mL, 0.69 mmol) then methanesulfonyl chloride (0.037 mL, 0.48 mmol). After 30 mins the mixture was diluted with DCM and saturated aqueous sodium bicarbonate solution. The phases were separated and the aqueous layer was extracted with DCM (×2). The combined organic phase was washed with water, saturated aqueous sodium bicarbonate solution and brine, dried (Na2SO4) and concentrated in vacuo to an orange gum. The gum was purified by FCC, using 0-8% MeOH in DCM, to give the title compound as a pale brown glass (134 mg, 58%). LCMS (Method 3): Rt 5.18 min, m/z 1011.7 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[CH2:26][C:25](=[N:28][OH:29])[CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.Br[CH2:31][CH2:32][CH2:33][CH2:34][N:35]([CH2:42][CH2:43][S:44]([CH3:47])(=[O:46])=[O:45])[C:36](=[O:41])[C:37]([F:40])([F:39])[F:38].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[CH2:26][C:25](=[N:28][O:29][CH2:31][CH2:32][CH2:33][CH2:34][N:35]([CH2:42][CH2:43][S:44]([CH3:47])(=[O:45])=[O:46])[C:36](=[O:41])[C:37]([F:39])([F:38])[F:40])[CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CS(=O)(=O)CCN(CCCCBr)C(=O)C(F)(F)F
Reactant: ON=C1C=Cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)CCN(CCCCON=C1C=Cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2C1)C(=O)C(F)(F)F
Temperature: 60 °C
Reaction time: 13 h
Yield: 29.9 %

Procedure:
In N,N-dimethylacetamide (1.5 ml) were dissolved 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(hydroxyimino)quinazoline (V-2, 84 mg) and N-(4-bromobutyl)-N-(2-methanesulfonylethyl)-2,2,2-trifluoroacetamide (71 mg), and potassium carbonate (41 mg) was added, followed by stirring at 60° C. for 13 hours with heating. Thereafter, the reaction mixture was poured into 0.5M citric acid, followed by extraction with ethyl acetate. The organic layer was washed with water and aqueous sodium chloride solution, and dried over magnesium sulfate. The crude product was purified by silica gel chromatography (eluting with hexane:ethyl acetate=1:4) to obtain 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(4-(N-(2-(methanesulfonyl)ethyl)-2,2,2-trifluoroacetamido)butyloxyimino)quinazoline (V-14, 41 mg) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8]([O:10]CC)=O.[NH2:22][C@H:23]([C:25]([OH:27])=[O:26])[CH3:24].[O-]CC.[Na+].Cl>CN(C=O)C.O>[OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8]([NH:22][C@H:23]([CH3:24])[C:25]([OH:27])=[O:26])=[O:10]
Reactant: CCOC(=O)c1ncc2c(-c3ccccc3)noc2c1O
Reactant: C[C@H](N)C(=O)O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1ncc2c(-c3ccccc3)noc2c1O)C(=O)O
Temperature: 25 °C
Yield: 48 %

Procedure:
Ethyl 7-hydroxy-3-phenylisoxazolo[4,5-c]pyridine-6-carboxylate (0.1 g, 0.35 mmol) was dissolved in 10 mL of DMF. L-Alanine (0.627 g, 7.04 mmol) and sodium ethoxide (0.36 g, 5.28 mmol) were added and the mixture was refluxed for 3 h. The mixture was cooled to room temperature and diluted with 70 mL of water. Concentrated hydrochloric acid was added dropwise until pH was 2. The resulting suspension was filtered and the solid was dried under vacuum to give 55 mg of the title compound. MS: (+) m/z 328.00 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:12]1[S:25][C:15]2[C:16]3[CH:24]=[N:23][CH:22]=[CH:21][C:17]=3[O:18][CH2:19][CH2:20][C:14]=2[CH:13]=1)=[N:10][NH2:11].C1N=CN([C:31](N2C=NC=C2)=[O:32])C=1>CN(C)C=O>[S:25]1[C:15]2[C:16]3[CH:24]=[N:23][CH:22]=[CH:21][C:17]=3[O:18][CH2:19][CH2:20][C:14]=2[CH:13]=[C:12]1[C:9]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:31](=[O:32])[NH:11][N:10]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NN=C(Nc1ccccc1Cl)c1cc2c(s1)-c1cnccc1OCC2
Solvent: CN(C)C=O
Product: O=c1[nH]nc(-c2cc3c(s2)-c2cnccc2OCC3)n1-c1ccccc1Cl
Temperature: 65 °C
Yield: 32.1 %

Procedure:
A mixture of N-(2-chlorophenyl)-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepine-2-carbohydrazonamide (42 mg, 0.11 mmol) from Example 230 and 92 mg (0.57 mmol) of N,N-carbonyldiimidazole in 3 ml of dimethylformamide was heated at 65° C. for 18 hours. The mixture was concentrated in vacuum and triturated with diethylether. The precipitate was collected, washed with ethyl ether and purified by flash chromatography eluting with 5% of methanol in methylene chloride to give 321 (14 mg, 31%). MS: (ESI+) 397.0
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[O:11][CH:12]=2)=[CH:4][CH:3]=1.[C:18]1([C:24](O)([CH3:26])[CH3:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][C:15]([O:17][C:24]([CH3:26])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:25])=[O:16])[O:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(O)c1ccccc1
Reactant: O=C(O)CCc1nc(-c2ccc(Cl)cc2)co1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(OC(=O)CCc1nc(-c2ccc(Cl)cc2)co1)c1ccccc1
Temperature: 25 °C
Reaction time: 65 h
Yield: 40.4 %

Procedure:
To a solution of 4-(4-chlorophenyl)-2-oxazolepropionic acid (0.5 g) in acetonitrile (20 ml) were added 2-phenyl-2-propanol (0.325 g), dicyclohexylcarbodiimide (0.49 g) and 4-dimethylaminopyridine (0.025 g), followed by stirring for 65 hours at room temperature. 2-Phenyl-2-propanol (0.325 g), dicyclohexylcarbodiimide (0.49 g) and 4-dimethylaminopyridine (0.025 g) were further added to the reaction mixture, followed by stirring for 2 hours at 50° C. The reaction mixture was filtered to remove an insoluble substance, and the filtrate was then concentrated. The oily residue was subjected to a silica gel column chromatography. Crystals of 1-methyl-1-phenylethyl 4-(4-chlorophenyl)-2-oxazolepropionate (0.297 g, 38%) were obtained from the fraction eluted with ethyl acetate-hexane (1:4, V/V). Recrystallization from hexane gave colorless prism crystals of mp 94°-95° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Br:8][C:9]1[CH:10]=[C:11]([C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=2[C:31]#[N:32])=[N:17]S(C(C)(C)C)=O)[CH:12]=[CH:13][C:14]=1[F:15]>>[Br:8][C:9]1[CH:10]=[C:11]([C:16]2([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[C:24]3[C:25](=[C:26]([F:30])[CH:27]=[CH:28][CH:29]=3)[C:31]([NH2:32])=[N:17]2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: Ic1ccncc1
Reactant: CC(C)(C)S(=O)N=C(c1ccc(F)c(Br)c1)c1cccc(F)c1C#N
Product: NC1=NC(c2ccncc2)(c2ccc(F)c(Br)c2)c2cccc(F)c21
Yield: 37 %

Procedure:
The title compound was synthesized as described for example 11i in 37% yield, starting from 4-iodopyridine (0.530 g, 2.59 mmol) and N-((3-bromo-4-fluorophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (1.00 g, 2.35 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[CH2:8][CH:9]([C:11]1[C:16]2[CH2:17][C:18]([CH3:21])([CH3:20])[O:19][C:15]=2[C:14]([O:22][CH3:23])=[CH:13][CH:12]=1)O.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[CH2:8][CH2:9][C:11]1[C:16]2[CH2:17][C:18]([CH3:21])([CH3:20])[O:19][C:15]=2[C:14]([O:22][CH3:23])=[CH:13][CH:12]=1
Reactant: COc1ccc(C(O)Cc2c(Cl)cncc2Cl)c2c1OC(C)(C)C2
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CCc2c(Cl)cncc2Cl)c2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.7 %

Procedure:
Under an argon atmosphere, a solution (80 ml) of Compound 45a (3.0 g) obtained in Step A in methylene chloride was cooled to −78° C., and then boron trifluoride ether complex (2.0 ml) and triethylsilane (3.9 ml) were successively added thereto, followed by stirring at room temperature for 3 hours. The reaction solution was poured into a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with chloroform. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=20/1) to give Compound 45 (1.57 g, 54.7%) as colorless crystals.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=N1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O-]S([O-])(=O)=O.[Na+].[Na+].O1CCC[CH2:27]1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][OH:12])=[CH:9][C:4]=2[N:3]=[CH:27]1
Reactant: O=C(O)c1ccc2[nH]nnc2c1
Reactant: C1CCOC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Product: OCc1ccc2[nH]cnc2c1
Temperature: 70 °C
Reaction time: 90 h
Yield: 16 %

Procedure:
To a solution of 1H-benzotriazole-5-carboxylic acid (1.00 g, 6.13 mmol) in 30 mL of dry tetrahydrofuran was added lithium aluminum hydride (0.47 g, 12 mmol) under nitrogen at 0° C. After the reaction mixture was stirred at 70° C. for 90 h, saturated Na2SO4 aqueous solution was added carefully at 0° C. After the solution was stirred at room temperature for 30 min, a sufficient amount of Na2SO4 was added with additional stirring for drying. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (chloroform/methanol=97/3 to 80/20) to obtain (1H-benzoimidazol-5-yl)methanol as a pale yellow solid (143 mg, 16%).
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([C@@H:7]2[CH2:12][CH2:11][N:10](C(OC)=O)[C@H:9]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[CH2:8]2)[O:4][NH:3]1.Br>>[F:27][C:24]([F:25])([F:26])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][C@@H:9]1[CH2:8][C@H:7]([C:5]2[O:4][NH:3][C:2](=[O:1])[CH:6]=2)[CH2:12][CH2:11][NH:10]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@H]1Cc1ccccc1C(F)(F)F
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@H](Cc3ccccc3C(F)(F)F)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
(2S,4R)-Methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(2-(trifluoromethyl)benzyl)piperidine-1-carboxylate (624 mg, 1.62 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 10 mL, 57.10 mmol) and the mixture stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx III, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2S,4R)-2-(2-(trifluoromethyl)benzyl)piperidin-4-yl)isoxazol-3(2H)-one (359 mg, 68%). 1H NMR (600 MHz, cd3od) δ 1.68 (q, 1H), 1.84 (dq, 1H), 2.11 (d, 1H), 2.22 (d, 1H), 3.04-3.19 (m, 3H), 3.23-3.30 (m, 4H), 3.49-3.54 (m, 1H), 3.59-3.66 (m, 1H), 5.74 (s, 1H), 7.48 (t, 1H), 7.52 (d, 1H), 7.64 (t, 1H), 7.74 (d, 1H). HRMS Calculated for [C16H17F3N2O2+H]+: 327.1320. Found: 327.1321
Reaction SMILES: [Br-].[CH3:2][O:3][CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].[Br:27][C:28]1[CH:33]=[CH:32][N:31]2[CH:34]=[N:35][C:36]([CH:37]=O)=[C:30]2[CH:29]=1.Cl>CN(C)C=O>[Br:27][C:28]1[CH:33]=[CH:32][N:31]2[CH:34]=[N:35][C:36]([CH:37]=[CH:5][CH2:4][O:3][CH3:2])=[C:30]2[CH:29]=1
Reactant: O=Cc1ncn2ccc(Br)cc12
Reactant: COCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Agent: [H-]
Solvent: CN(C)C=O
Product: COCC=Cc1ncn2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 12.04 g of (2-methoxyethyl)triphenylphosphonium bromide [55894-16-1] in 50 ml of anhydrous N,N-dimethylformamide is admixed with 2.60 g of sodium hydride (60% dispersion). The reaction mixture is stirred at room temperature for 30 minutes and a solution of 6.75 g of 7-bromoimidazo[1,5-a]pyridine-1-carbaldehyde in 20 ml of N,N-dimethylformamide is added. The reaction mixture is subsequently stirred at 50° C. for 1 hour. The reaction mixture is cooled to room temperature and poured onto ice-water. The quenched mixture is acidified with 1M HCl and extracted with tert-butyl methyl ether (3×100 ml). The combined organic phases are washed with water (100 ml) and brine (100 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60 F).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:31])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([Cl:29])[CH:27]=3)[NH:22][CH:21]=2)[OH:19])[C:12]=1[F:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>O1CCCC1>[CH2:1]([O:8][C:9](=[O:31])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([Cl:29])[CH:27]=3)[NH:22][CH:21]=2)=[O:19])[C:12]=1[F:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(F)c(C(O)c2c[nH]c3ncc(Cl)cc23)c1F)OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Cl)cc23)c1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.7 %

Procedure:
Into a round bottom flask was added {3-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluoro-phenyl}-carbamic acid benzyl ester (6, 1.01 g, 2.28 mmol) in 5.00 mL of tetrahydrofuran. Dess-Martin periodinane (1.20 g, 2.89 mmol) was added in portions. The reaction mixture was stirred at room temperature for 10 minutes, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum and purified by silica gel chromatography to give the desired compound (7, 914 mg, 91%). MS (ESI) [M+H+]+=442.
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[C:9]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[CH:8]=1.[CH:24]1([C:27]2[CH:28]=[C:29]([CH3:39])[C:30]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[N:31][CH:32]=2)[CH2:26][CH2:25]1>>[CH:24]1([C:27]2[CH:28]=[C:29]([CH3:39])[C:30]([N:33]3[CH2:34][CH2:35][N:36]([C:11]([C:10]4[CH:15]=[CH:16][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:23])=[CH:8][C:9]=4[N:17]4[CH2:21][CH2:20][CH2:19][C:18]4=[O:22])=[O:12])[CH2:37][CH2:38]3)=[N:31][CH:32]=2)[CH2:26][CH2:25]1
Reactant: COC(=O)c1ccc(N2CCCS2(=O)=O)cc1N1CCCC1=O
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2N2CCCC2=O)CC1
Yield: 4.1 %

Procedure:
Using methyl 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-(2-oxopyrrolidin-1-yl)benzoate (131 mg) described in Preparation Example 33 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (84 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 109, the title compound (8.3 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:15]([C:16](OCC)=[O:17])=[CH:14][C:13]3[CH:21]=[CH:22][S:23][C:12]=3[S:11]2(=[O:25])=[O:24])=[CH:5][CH:4]=1.CC(C[AlH]CC(C)C)C.C1C[O:38][CH2:37]C1>>[OH:38][CH2:37][C:15]1([CH2:16][OH:17])[CH2:14][C:13]2[CH:21]=[CH:22][S:23][C:12]=2[S:11](=[O:24])(=[O:25])[N:10]1[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)C1=Cc2ccsc2S(=O)(=O)N1Cc1ccc(OC)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: COc1ccc(CN2C(CO)(CO)Cc3ccsc3S2(=O)=O)cc1
Reaction time: 1 h

Procedure:
To a solution of the product from Step B (1.80 g, 4.75 mmol) in anhydrous THF (40 mL) at ambient temperature was added DIBAL (1.0M, 11.87 mL, 11.87 mmol) and the mixture was stirred for 1 h. Additional DIBAL (1M, 15 mL,15 mmol) was added (TLC showed starting material remained) and the reaction mixture was stirred for 20 h, cooled (ice bath) and the reaction was quenched by the slow addition of 1N HCl (100 mL). THF was evaporated and the aqueous mixture was extracted with ethyl acetate (2×100 mL). The combined extracts were dried (MgSO4), filtered and evaporated to give an oil (1.60 g) which was used in the next step without further purification.
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.[F:20][C:21]([F:32])([F:31])[O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>>[F:20][C:21]([F:31])([F:32])[O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:29][CH:30]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Product: FC(F)(F)Oc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-(trifluoromethoxy)benzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[[4-(trifluoromethoxy)phenyl]methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Mg].II.C(Cl)CCC.[CH3:9][CH:10]([CH2:13][CH2:14][CH3:15])[CH2:11][OH:12].CCCC.C([Mg:24][Cl:25])CCC.[Cl-]>CCCCCCCCC(C)C>[CH3:9][CH:10]([CH2:13][CH2:14][CH3:15])[CH2:11][O:12][Mg:24][Cl:25]
Reactant: CCCC(C)CO
Reactant: CCCC[Mg]Cl
Agent: CCCCCCCCC(C)C
Agent: II
Agent: [Cl-]
Solvent: CCCCCl
Solvent: CCCC
Product: CCCC(C)CO[Mg]Cl
Temperature: 145 °C
Reaction time: 2 h

Procedure:
Magnesium powder 6.65 gm, (0.273 moles) along with 225.0 ml Isopar "H" hydrocarbon solvent and 0.20 gm of iodine crystals were placed in a 3-necked reaction flask under an argon atmosphere. This mixture was heated under the argon atmosphere to 145° C. for about 60 minutes for metal activation. n-Butyl chloride (40 ml, 0.385 moles) was then gradually added to the reaction slurry in 30 minutes. The heating was cut off due to exothermic reaction and reflux. The reaction of the slurry was continued for about two hours at reflux temperature. The reflux temperature during this period dropped to about 110° C. The reflux solvent contained alkenes (i.e., butene/octene, etc.). After two hours of reaction, heating was cut off and then, the first 15 ml of 2-methyl-1-pentanol of a total of 60 ml was added drop by drop to the reaction slurry. On addition of this alcohol, butane was released with exothermic reaction and the slurry turned into a thick gum-like gel. When the temperature dropped to about 50° C., the remaining 45 ml of 2-methyl-1-pentanol, along with 50 ml of Isopar H solvent, was added quickly under good agitation to reduce the viscosity of the slurry. The 2-methyl-1-pentanol reacted with BuMgCl as was evidenced by the release of butane. The reaction fluid containing some grayish particles was heated slowly with reflux. The reflux butane with some alkene, such as butene/octene, was distilled off through the reflux condenser to increase the reaction temperature close to 145° C. It is important to keep the temperature two to three degrees lower than 2-methyl-1-pentanol's reflux temperature (148° C.-150° C.). The reaction was continued at 145° C. for about 30 minutes. The reaction slurry was filtered while hot (90° C.-120° C.). The filtration was fast and completed in about ten minutes. Final volume of the filtrate was about 340 ml. Fine gray suspended particles of solid were collected on the filter. The clear filtrate was analyzed and found to have a 0.79 molar magnesium concentration with about 98% magnesium recovery. The detailed analysis of the liquid product was found to be 0.79 moles magnesium, 0.50 moles 2MPO (as total base), 1.08 moles chloride per liter, along with solvent Isopar H and excess 2-methyl-1-pentanol. The product formula can be presented as