Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[N:20][NH:21]4)=[CH:11][CH:10]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.Br[CH:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C.O>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][CH2:35][N:21]1[C:22]2[C:18](=[C:17]([CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([C:5]4[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=4[O:26][CH3:27])=[CH:14][CH:13]=3)[CH:25]=[CH:24][CH:23]=2)[CH:19]=[N:20]1)[CH3:34]
Reactant: CCOC(=O)C(C)Br
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc3[nH]ncc23)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ncc2c(COc3ccc(-c4cc(F)c(F)cc4OC)cc3)cccc21
Temperature: 90 °C
Yield: 85.7 %

Procedure:
4-(4′,5′-Difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indazole (0.09 g, 0.245 mmol), ethyl bromopropionate (0.045 g, 0.245 mmol), cesium carbonate (81 mg, 0.294 mmol) in 6 mL DMF was stirred at RT overnight and then heated to 90° C. for 35 min. The reaction was cooled and distributed between EtOAc and H2O. The organic layer was separated and concentrated in vacuo. The crude product was purified by flash chromatography with a gradient from 0-30% ethyl acetate in hexanes to yield 3-[4-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indazol-1-yl]-propionic acid ethyl ester as a white solid (98 mg, 85.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][N+]#[C-])[CH:7]=1.[NH3:11].[CH3:12]O>[Ni]>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:12][NH2:11])[CH:5]=[N:4][CH:3]=1
Reactant: CO
Reactant: [C-]#[N+]Cc1cncc(Cl)c1
Reactant: N
Agent: [Ni]
Product: NCCc1cncc(Cl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3-chloro-5-(isocyanomethyl)pyridine (810 mg, 5.36 mmol) in MeOH (15 mL) was added Raney-nickel and ammonia. The resulting reaction mixture was stirred at room temperature for 5 h under hydrogen. The reaction mixture was filtered and the filtrate was concentrated to afford the crude title compound (780 mg, crude). MS (ESI) m/z 157.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH2:18][CH3:19])[N:14]([CH3:20])[C:13]=2[CH:12]=[C:11](Br)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:41][NH:42][CH3:43].[C:44](=[O:46])=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:41][N:42]([CH3:43])[C:44]([C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17]2[N:16]=[C:15]([CH2:18][CH3:19])[N:14]([CH3:20])[C:13]=2[CH:12]=1)=[O:46]
Reactant: CNC
Reactant: O=C=O
Reactant: CCc1nc2c(OCc3ccccc3)cc(Br)cc2n1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCc1nc2c(OCc3ccccc3)cc(C(=O)N(C)C)cc2n1C
Yield: 91 %

Procedure:
10 g (29 mmol) 4-Benzyloxy-6-bromo-2-ethyl-1-methyl-1H-benzimidazole, 4.6 g (17.4 mmol) triphenylphosphine, 1.0 g (4.3 mmol) palladium(II) acetate in 145 ml (290 mmol) dimethylamine (2 M in THF) were transferred to an autoclave and carbonylated (6 bar CO2) at 120° C. for 24 h. The catalyst was filtered off and the filtrate was concentrated in vacuo. Purification of the residue by column chromatography on silica gel (dichloromethane/methanol=93:7) and crystallization from diethyl ether afforded 11.3 g (91%) of the title compound as white crystals. m.p. 104°-108° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11][N:10]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:9][CH2:8]1)=[O:5])[CH3:2].[CH2:31]([N:39]([CH2:44][CH:45]1[CH2:47][O:46]1)[S:40]([CH3:43])(=[O:42])=[O:41])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>C(O)C>[CH2:31]([N:39]([S:40]([CH3:43])(=[O:42])=[O:41])[CH2:44][CH:45]([OH:46])[CH2:47][N:16]1[CH2:15][CH2:14][N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11][N:10]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:9][CH2:8][N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:18][CH2:17]1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCOC(=O)CN1CCNCCN(CC(=O)OCC)CCN(CC(=O)OCC)CC1
Reactant: CCCCCCCCN(CC1CO1)S(C)(=O)=O
Solvent: CCO
Product: CCCCCCCCN(CC(O)CN1CCN(CC(=O)OCC)CCN(CC(=O)OCC)CCN(CC(=O)OCC)CC1)S(C)(=O)=O

Procedure:
200 ml of absolute ethanol is poured over 8.61 g (20 mmol) of N,N',N"-tris-(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (produced according to DE 36 25 417 A1) in a bomb tube. After 5.27 g (20 mmol) of N-octyl-N-[(2-oxiranyl)-methyl]-methanesulfonic acid amide is added (Example 2b), the bomb tube is closed, flushed with nitrogen, and the resulting reaction mixture is heated for 16 hours to 90° C. After the reaction (TLC control) is completed, the solvent is evaporated in a vacuum and the yellowish, oily residue is chromatographed on silica gel (eluent: chloroform/methanol; methanol: 0-80%).
Reaction SMILES: [CH:1]([S:4]([NH:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])(=[O:6])=[O:5])([CH3:3])[CH3:2].O1CCCC1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[Cl-].[Na+]>O>[CH:1]([S:4]([NH:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[NH2:22])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])(=[O:6])=[O:5])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)Nc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)S(=O)(=O)Nc1cc(C(=O)c2ccccc2)ccc1N

Procedure:
A solution of 3.91 g. (0.0112 m.) of 3-(isopropylsulfonyl)amino-4-nitrobenzophenone in 60 ml. of tetrahydrofuran (THF) was added dropwise over a period of 30 minutes to a stirred solution of 23.7 g. of sodium hydrosulfite in 200 ml. of water. After 60 minutes of additional stirring, solid sodium chloride was added and the layers were separated. The aqueous layer was extracted with THF, and the combined THF extracts were washed with a saturated solution of sodium chloride. Evaporation of the THF gave crude 3-(isopropylsulfonyl)amino-4-aminobenzophenone which was used without further purification in the subsequent cyclization. A small sample was crystallized from isopropanol several times to give the pure compound as colorless blocks, m.p. about 143°-145° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1)=[O:13].S([C:34]#[N:35])(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[N:14]1([C:12](=[O:13])[CH2:11][S:10][C:2]2[N:3]([C:34]#[N:35])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: O=C(CSc1nc2ccccc2[nH]1)N1CCCc2ccccc21
Solvent: C1CCOC1
Product: N#Cn1c(SCC(=O)N2CCCc3ccccc32)nc2ccccc21
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 59.2 %

Procedure:
To a solution of compound 16 (0.52 g, 1.6 mmol, 1.0 eq) in 6 mL of dry THF stirred at −78° C. under N2 LiHMDS (1.7 mL, 1.05 eq) was added. The mixture was stirred for 15 min. at −78° C. and then TosCN (306 mg, 1.05 eq. in 1 mL of THF) was added dropwise. The reaction mixture was quickly allowed to warmed up to RT. The reaction mixture was quenched with 10 mL of NH4Cl (sat.), extracted into ethyl acetate, washed with brine and concentrated to give creamy solid. The crude was purified by column chromatography (ethyl acetate/hexanes) to give 79 (330 mg, 59%). MP=153.3-154.2° C. Anal/Calcd. for C19H16H4OS: C, 65.50; H, 4.63; N, 16.08; S, 9.20. Found C, 65.59; H, 4.66; N, 16.06, S 9.16.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.C(O)(C(F)(F)F)=O>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)=[CH:17][CH:16]=1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: COc1ccc(C=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Yield: 79.2 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (15 g, 94.9 mmol), 4-methoxybenzaldehyde (12.9 g, 1.1 equiv.) and TFA (14.6 mL, 2 equiv.) to give the title compound (20.9 g, 80%) as a brownish powder. MP: 131° C.
Reaction SMILES: C([C@@H]1COC(=O)[N:9]1[C:14](=[O:30])[CH:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH3:28])=[CH:22][C:21]=1[Cl:29])[CH2:16][CH:17]=C)C1C=CC=CC=1.N[N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[ClH:26].[Cl:26][C:25]1[CH:24]=[C:23]([O:27][CH3:28])[CH:22]=[C:21]([Cl:29])[C:20]=1[CH2:19][C@@H:15]1[CH2:16][CH2:17][N:9]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[C:14]1=[O:30]
Reactant: NN1CCCCC1
Reactant: C=CCC(Cc1c(Cl)cc(OC)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc(Cl)c(C[C@@H]2CCN(N3CCCCC3)C2=O)c(Cl)c1
Product: Cl

Procedure:
Add to a solution of (R)-4-((R)-4-benzyl-3-[2-(4-methoxy-2,6-dichloro-benzyl)-pent-4-enoyl]-oxazolidin-2-one (0.90 g, 2 mmol) in THF (20 mL) at room temperature 1-amino piperidine (0.40 g, 4 mmol) and acetic acid (0.2 mL). Stir the reaction at room temperature for 20 minutes and add sodium triacetoxy borohydride (1.69 g, 8 mmol) and continue stirring at room temperature for 12 h. Partition the mixture between ethyl acetate (20 mL) and water (20 mL). Separate the organic layer, wash three times with water (15 mL each) and then with brine (15 mL). After drying the organic layer over sodium sulfate, filter and concentrate under vacuum. Purify the residue by silica gel chromatography with 2:3 ethyl acetate/hexane to afford the free base of the title compound and then treat with 1 M HCl in ether to afford 0.34 g (43%): MS (m/z): 357 (M+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:24](=[O:25])[C:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[CH:22][NH:21][CH:20]=3)=[O:18])=[C:11]([F:33])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:34][N:35]1[CH:39]=[C:38](B(O)O)[CH:37]=[N:36]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:33][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:38]3[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=3)[CH:7]=2)[C:14]([F:15])=[CH:13][C:12]=1[NH:16][C:17]([C:19]1[C:24](=[O:25])[C:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:22][NH:21][CH:20]=1)=[O:18]
Reactant: O=C(Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Reactant: Cn1cc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc(Oc3cc(F)c(NC(=O)c4c[nH]cc(-c5ccc(F)cc5)c4=O)cc3F)ccn2)cn1
Temperature: 80 °C
Yield: 82 %

Procedure:
N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (0.100 g, 0.212 mmol), 1-methyl-pyrazole-4-boronic acid (0.055 g, 0.265 mmol) and K2CO3 (0.088 g, 0.636 mmol) were combined in dioxane (2 mL) and H2O (0.500 mL), sparged with argon, treated with Pd(PPh3)4 (0.012 g, 10.60 μmol) and heated at 80° C. for 22 h. Additional 1-methyl-pyrazole-4-boronic acid (0.055 g, 0.265 mmol) was added, the mixture sparged with argon, treated with additional Pd(PPh3)4 (0.012 g, 10.60 μmol) and heated at 100° C. overnight. The mixture was cooled to RT, diluted with EtOAc, filtered through diatomaceous earth and the filtrate washed with brine (2×), dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(2,5-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (90 mg, 82%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 13.48 (s, 1H), 12.72 (s, 1H), 8.63 (s, 1H), 8.57 (dd, J=12.6, 6.9 Hz, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.27 (s, 1H), 8.09 (s, 1H), 7.97 (s, 1H), 7.69 (m, 2H), 7.58 (dd, J=11.1, 7.6 Hz, 1H), 7.26 (m, 3H), 6.74 (d, J=5.6 Hz, 1H), 3.84 (s, 3H); MS (ESI) m/z: 518.2 (M+H+).
Reaction SMILES: [CH3:1][SiH:2]([CH3:4])[Cl:3].[CH2:5]=[CH:6][CH2:7][CH2:8][CH:9]=[CH2:10]>[Pt]>[CH3:1][Si:2]([CH3:4])([CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10])[Cl:3]
Reactant: C[SiH](C)Cl
Reactant: C=CCCC=C
Agent: [Pt]
Product: C=CCCCC[Si](C)(C)Cl

Procedure:
Dimethyl chlorosilane was reacted with an excess 1,5-hexadiene in the presence of a platinum catalyst to form dimethyl-5-hexenylchloro silane. Then indene was reacted with butyl lithium in a mixture of diethyl ether and tetrahydrofuran to produce the indenyl lithium salt which was then reacted with the dimethyl-5-hexenylchlorosilane to yield the omega alkenyl dimethyl indene which can be called 5-hexenyl-dimethyl-silyl-1-indene.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Li+].[OH-]>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:16](=[O:17])[C:15]3[CH:19]=[CH:20][CH:21]=[N:22][C:14]=3[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: Cc1ncccc1C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ncccc1C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.7 %

Procedure:
5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), 2-methylnicotinic acid (250 mg, 1.83 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (465 mg, 1.83 mmol), and triethylamine (0.606 mL, 4.35 mmol) were placed in DCM (5 mL) and stirred at room temperature for 90 minutes. 3M LiOH (5 mL) was added. The reaction was stirred for 20 minutes and then was poured onto water. The mixture was then filtered and washed with water and DCM. The filtered solid was dried to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylnicotinamide (254 mg, 84% yield).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:15][C:16]([F:34])([F:33])[C:17]1[N:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]3)[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1.[CH3:35][C:36]1[CH:37]=[CH:38][C:39](=O)[NH:40][N:41]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:35][C:36]1[N:41]=[N:40][C:39]([O:32][CH:29]2[CH2:30][CH2:31][N:26]([C:23]3[CH:24]=[CH:25][C:20]4[N:21]([C:17]([C:16]([F:15])([F:33])[F:34])=[N:18][N:19]=4)[N:22]=3)[CH2:27][CH2:28]2)=[CH:38][CH:37]=1
Reactant: OC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Reactant: Cc1ccc(=O)[nH]n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(OC2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)nn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 12.3 %

Procedure:
DIAD (0.102 mL, 0.52 mmol) was added to 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (obtained as described in Example 310, preparation of starting materials) (135 mg, 0.47 mmol), 6-methylpyridazin-3(2H)-one (56.9 mg, 0.52 mmol) and triphenylphosphine (136 mg, 0.52 mmol) in THF (5 mL). The resulting solution was stirred at ambient temperature for 3 days. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 2M ammonia in methanol and evaporated to give crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-[4-[(6-methylpyridazin-3-yl)oxy]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (22.00 mg, 12%) as a solid.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[CH:17]([CH2:27][CH2:28][CH:29]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[OH:30])[C:16]3=[O:38])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH2:41]1[N:46]2[CH2:47][CH2:48][N:43]([CH2:44][CH2:45]2)[CH2:42]1>C1(C)C=CC=CC=1>[Br-:1].[F:37][C:34]1[CH:35]=[CH:36][C:31]([CH:29]([OH:30])[CH2:28][CH2:27][CH:17]2[C:16](=[O:38])[N:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]4[CH:39]=[CH:40][C:3]([CH2:2][N+:43]56[CH2:48][CH2:47][N:46]([CH2:45][CH2:44]5)[CH2:41][CH2:42]6)=[CH:4][CH:5]=4)=[CH:10][CH:11]=3)[CH:18]2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:32][CH:33]=1
Reactant: C1CN2CCN1CC2
Reactant: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(OCc3ccc(CBr)cc3)cc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(OCc3ccc(C[N+]45CCN(CC4)CC5)cc3)cc2)cc1
Product: [Br-]

Procedure:
Compound (25) and DABCO were dissolved in toluene and reacted analogously to Example IV, giving the product (26) as a colorless solid of molecular weight 716.70 (C39H43BrFN3O4); MS (ESI): 636.3 (MH+).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:13][C:14]1[CH:30]=[CH:29][C:17]2[NH:18][C:19]([S:21][C:22]3[O:26][C:25]([CH:27]=O)=[CH:24][CH:23]=3)=[N:20][C:16]=2[CH:15]=1.[CH3:31][C:32]1([CH3:40])[CH2:39][C:37](=O)[CH2:36][C:34](=[O:35])[CH2:33]1.C(N(CC)C(C)C)(C)C>C(O)C>[CH2:11]([O:10][C:8]([C:4]1[NH:5][CH:6]=[C:7]2[CH:27]([C:25]3[O:26][C:22]([S:21][C:19]4[NH:18][C:17]5[CH:29]=[CH:30][C:14]([CH3:13])=[CH:15][C:16]=5[N:20]=4)=[CH:23][CH:24]=3)[C:36]3[C:34](=[O:35])[CH2:33][C:32]([CH3:40])([CH3:31])[CH2:39][C:37]=3[NH:2][C:3]=12)=[O:9])[CH3:12]
Reactant: Cc1ccc2[nH]c(Sc3ccc(C=O)o3)nc2c1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: CCOC(=O)c1[nH]ccc1N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CC(C)(C)C1)C2c1ccc(Sc2nc3cc(C)ccc3[nH]2)o1
Temperature: 20 °C
Reaction time: 0.19 h

Procedure:
387 μmol of 3-amino-2-ethoxycarbonylpyrrole hydrochloride, 387 μmol of 5-(5-Methyl-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde (obtained from example 108, step 1), 387 μmol of dimedone and 202 μL of N,N-diisopropylethylamine in 1.5 mL of ethanol are poured into a flask suitable for microwave irradiation (Personal Chemistry model Emrys Optimizer instrument). The flask is locked then irradiation is performed at 100° C. during 700 seconds. After cooling down to 20° C., the reaction mixture is concentrated under reduced pressure. The residue is purified on silica gel (Analogix model Intelliflash 280 instrument, SiO2 40 g; Eluent EtOAc/cyclohexane; from 30/70 to 75/25. (v/v), rate: 25 mL/min, during 70 minutes). The fractions containing the expected compound are combined and concentrated under reduced pressure. The remaining oil is solubilized in 0.5 mL of dichloromethane (DCM) then crystallized by addition of small amounts of diisopropyloxide. 62 mg of expected compound are collected as a solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])([CH3:3])[CH3:2].CO.Cl>C1COCC1>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([CH2:9][OH:10])=[CH:7][C:6]=1[C:14]([F:15])([F:16])[F:17])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C(F)(F)F
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(CO)cc1C(F)(F)F
Temperature: 25 °C
Yield: 99.1 %

Procedure:
To a solution of 4-isopropoxy-3-(trifluoromethyl)benzoic acid (191 g, 770 mmol) in THF (2 L) at 0° C. in a 5-L round bottomed flask under N2 was added BH3 THF (1M solution in THF, 1.08 L, 1.08 mol) slowly over 15 min. The mixture was allowed to stir at 0° C. for 30 min at which time the ice bath was removed and the reaction warmed to room temperature. The reaction was quenched with MeOH (80.0 mL, 506 mmol) followed by aq. HCl (1 M, 1000 mL, 1000 mmol) (slight exotherm to 36° C. was observed). The volatile organics were removed in vacuo and the aqueous phase was extracted with EtOAc (2×1 L). The organic layers were combined and washed with sat. NaHCO3 (750 mL) and brine (750 mL). Dried organics over MgSO4, filtered, and concentrated to give (4-isopropoxy-3-(trifluoromethyl)phenyl)methanol (181 g, 763 mmol, 99% yield) as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.37 (d, J=6.1 Hz, 6 H), 1.66 (s, 1H) 4.59-4.69 (m, 3 H), 6.99 (d, J=8.5 Hz, 1 H), 7.46 (dd, J1=8.5, J2=2.2 Hz, 1 H), 7.56 (d, J=1.9 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@H:15]([O:16][C:17](=O)[CH3:18])[NH:14][C:13]1=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21]CCO.O>C1C=CC=CC=1.C1(C)C=CC=CC=1.O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:15]([O:16][CH2:17][CH2:18][Br:21])[NH:14][C:13]1=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(=O)OCc1ccccc1
Reactant: OCCBr
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(N[C@@H]1C(=O)N[C@@H]1OCCBr)OCc1ccccc1
Yield: 14.1 %

Procedure:
A mixture of (3S,4S)-3-benzyloxycarbonylamino-4-acetoxy-azetidin-2-one (11.76 g, 42.3 mmole) which prepared by the known method (Eur. J. Med. Chem. 1992, 27, 131-140), 2-bromoethanol (3 ml, 42.3 mmole), and zinc acetate dihydrate (9.28 g, 42.3 mmole) in a mixture of benzene (100 ml) and toluene (100 ml) was refluxed for 5 hrs using Dean-Stark water separator. After cooling, the reaction mixture was partitioned between ethyl acetate (800 ml), acetone (100 ml) and water (500 ml). The organic layer was washed with water, brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography using ethyl acetate-hexane (6:4) as eluent and 2.04 g of (3S,4R)-3-benzyloxycarbonylamino-4-bromoethoxy-azetidin-2-one was obtained as white solid (yield: 14%).
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([C:9]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[O:10])[O:8][C:4]=2[CH:3]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:41][C:42]([F:57])([F:56])[C:43]1[CH:48]=[CH:47][C:46]([N:49]2[CH2:54][CH2:53][CH:52](O)[CH2:51][CH2:50]2)=[CH:45][CH:44]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[F:57][C:42]([F:41])([F:56])[C:43]1[CH:44]=[CH:45][C:46]([N:49]2[CH2:54][CH2:53][CH:52]([O:1][C:2]3[CH:26]=[CH:25][C:5]4[N:6]=[C:7]([C:9]([NH:11][CH:12]5[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17]5)=[O:10])[O:8][C:4]=4[CH:3]=3)[CH2:51][CH2:50]2)=[CH:47][CH:48]=1
Reactant: OC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2nc3ccc(O)cc3o2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2nc3ccc(OC4CCN(c5ccc(C(F)(F)F)cc5)CC4)cc3o2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a stirred solution of tert-butyl 4-(6-hydroxybenzo[d]oxazole-2-carboxamido)piperidine-1-carboxylate (0.15 g, 0.41 mmol) in toluene (4 mL) at room temperature was added diisopropyl azodicarboxylate (0.1 g, 0.49 mmol), 1-(4-(trifluoromethyl)phenyl)piperidin-4-ol (0.1 g, 0.41 mmol), and triphenylphosphine (0.13 g, 0.49 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue obtained was purified by flash chromatography (silica gel, ethyl acetate/hexanes=2/3) to afford tert-butyl 4-(6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]oxazole-2-carboxamido)piperidine-1-carboxylate (compound 1) as a off-white solid (0.16 g, 66%). 1H-NMR (CDCl3, 300 MHz): δ 7.65 (m, 1H), 7.48 (m, 2H), 7.15 (m, 1H), 7.05 (m, 2H), 6.96 (m, 2H), 4.56 (m, 1H), 4.12 (m, 3H), 3.60 (m, 2H), 3.28 (m, 2H), 2.93 (m, 2H), 2.04 (m, 8H), 1.47 (s, 9H) ppm; MS (ESI): 589.6 (M+1).