Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[Li]CCCC.[O:14]=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]2([OH:14])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
Into a 1-L 3-necked round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1-chloro-4-iodobenzene (10.0 g, 41.9 mmol) in tetrahydrofuran (150 mL). The solution was cooled to −78° C., then n-BuLi (2.4 M) (16.6 mL, 39.8 mmol) was added dropwise and the resulting mixture was stirred for 0.5 h at −78° C. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (7.60 g, 38.1 mmol) in tetrahydrofuran (50 mL) was added dropwise and the resulting mixture was stirred for 1 h at -78° C. The reaction was then warmed to 0° C., and carefully quenched by the slow addition of water (150 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (150 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:50 to 1:3) to yield the title compound as a light yellow solid (9.3 g, 78%).
Reaction SMILES: [C:1]1([CH:7]([CH2:22][CH3:23])[C:8]([O:10]C(=O)C(C2C=CC=CC=2)CC)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1>C(OCC)C>[C:1]1([CH:7]([CH2:22][CH3:23])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(C(=O)OC(=O)C(CC)c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCC(C(=O)O)c1ccccc1
Yield: 91.5 %

Procedure:
A solution of 2,3-isopropylidene-D(+)-ribono-1,4-lactone (188 mg) and 2-phenylbutyric anhydride (310 mg) in d5 -pyridine (0.35 ml) was monitored by 1H n.m.r. until reaction was complete (1.5 hours). The mixture was dissolved in diethyl ether (20 ml), partitioned with aqueous hydrochloric acid (2×20 ml, 1M) and aqueous sodium hydroxide (2×10 ml, 1M). The combined alkaline extracts were acidified with 10M hydrochloric acid to pH 2, extracted with diethyl ether (2×10 ml) and the dried (MgSO4) ether extracts concentrated in vacuo to give (+)2-phenylbutyric acid (150 mg), [α]D25 +31° (c=1.0, benzene).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][C:21]1([CH3:32])[C@H:26]2[CH2:27][C@@H:22]1[CH2:23][CH2:24][C@H:25]2[CH2:28][C:29](O)=[O:30]>>[CH3:20][C:21]1([CH3:32])[C@H:26]2[CH2:27][C@@H:22]1[CH2:23][CH2:24][C@H:25]2[CH2:28][C:29]([NH:1][N:2]1[N:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19])=[O:30]
Reactant: CC1(C)[C@H]2CC[C@@H](CC(=O)O)[C@@H]1C2
Reactant: Cc1ccc(-c2nn(N)c(=O)c3ccccc23)cc1
Product: Cc1ccc(-c2nn(NC(=O)C[C@@H]3CC[C@H]4C[C@@H]3C4(C)C)c(=O)c3ccccc23)cc1

Procedure:
The product of Example 135A and 2-[(1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.34 (s, 1H), 8.37-8.41 (m, 1H), 7.86-8.04 (m, 2H), 7.72-7.77 (m, 1H), 7.46-7.50 (m, 2H), 7.36-7.40 (m, 2H), 2.51-2.60 (m, 2H), 2.42 (s, 3H), 2.29-2.45 (m, 2H), 1.79-2.06 (m, 5H), 1.47-1.63 (m, 1H), 1.20 (s, 3H), 1.07 (d, J=0.6 Hz, 3H), 0.91 (d, J=9.5 Hz, 1H); MS (APCI+) M/Z 416 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([NH2:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:20])=CC=1>C(Cl)CCl.CCOC(C)=O>[OH:1][C:2]1[C:3]([C:8](=[S:20])[NH2:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1ncccc1O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: NC(=S)c1ncccc1O
Yield: 69.1 %

Procedure:
A stirred solution of 3-hydroxypicolinamide (1.35 g, 9.75 mmol) and Lawesson's reagent (2.37 g, 5.85 mmol) in dry ClCH2CH2Cl (12 mL) was heated to reflux under nitrogen for 5 hr. At ambient temperature, the mixture was diluted with EtOAc (50 mL), washed with half-saturated aq. NaCl (30 o5 mL) containing NaHCO3 (840 mg) and with brine (20 mL). After drying over MgSO4 and filtration, the filtrate was concentrated in vacuo to give a brown solid, which was subject to flash chromatography on silica gel CH2Cl2 as eluent) to provide 3c (623 mg, 42%) as a greenish yellow solid after crystallization from EtOAc/hexane. mp 152.0°-153.0° C.; IR (KBr) 3372, 3259, 2464, 1626, 1458, 1317 cm-1 ; 1H NMR (DMSO-d6) δ 7.33 (1H, dd, J=8.6 and 1.0 Hz, Ar), 7.46 (1H, dd, J=8.6 and 4.3 Hz, Ar), 8.07-8.10 (1H, m, Ar), 8.15(1H, s, NH), 8.49 (1H, s, NH), 12.76 (1H, s, OH); FABMS m/z 154 (M+); Anal. Calcd for C6H6N2OS: C, 46.74; H, 3.92; N, 18.17. Found: C, 46.83; H, 3.89; N, 17.90.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[C:11]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH:30]=O)[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>>[C:11]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: c1cscn1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2C=O)CC1
Agent: [Li]CCCC
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2Cc2nccs2)CC1

Procedure:
Thiazole was lithiated with n-butyllithium and reacted with N-Boc-4-(2-formylphenyl)-piperazine in a manner similar to preparation 113A. The resulting alcohol was deoxygenated in a manner similar to preparation 115A to afford the final compound. LRMS (ESI+): 360.1 (M+1)
Reaction SMILES: S(S([O-])(=O)=O)([O-])(=O)=[O:2].[Na+].[Na+].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](=NO)[CH3:23])=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12].Cl>O.CO>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](=[O:2])[CH3:23])=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(CC(C)=NO)cc1
Reactant: O=S(=O)([O-])S(=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(CC(C)=O)cc1

Procedure:
Sodium metabisulphate (131 g) in water (300 ml) was added to 1-(4-carbomethoxyphenyl)propan-2-one oxime (37.5 g) in methanol (200 ml) and the mixture refluxed for 6 hours. The reaction mixture was cooled, concentrated hydrochloric acid (100 ml) added, the mixture extracted with chloroform and the combined chloroform extracts washed with water followed by sodium bicarbonate solution. The chloroform layer was dried (MgSO4) and evaporated to give the title compound as an oil (bp 126°-129°/0.7 mm) which crystallised on standing, (mp 40°-47°). τ (CDCl3) 7.88 (3H, s), 6.28 (2H, s), 6.14 (3H, s), 2.77 (2H, d, J=8 Hz), 2,04 (2H, d, J=8 Hz).
Reaction SMILES: [Si]([O:8][CH:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[NH:18][C:19]([CH:23]([C:31]3[CH:36]=[CH:35][C:34]([S:37]([CH:40]4[CH2:42][CH2:41]4)(=[O:39])=[O:38])=[CH:33][CH:32]=3)[CH2:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:20][C:21]=2[CH3:22])=[N:15][CH:16]=1)[CH3:10])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH:40]1([S:37]([C:34]2[CH:33]=[CH:32][C:31]([CH:23]([C:19]3[NH:18][C:17]([C:14]4[N:15]=[CH:16][C:11]([CH:9]([OH:8])[CH3:10])=[CH:12][CH:13]=4)=[C:21]([CH3:22])[CH:20]=3)[CH2:24][CH:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[CH:36][CH:35]=2)(=[O:39])=[O:38])[CH2:42][CH2:41]1
Reactant: Cc1cc(C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)[nH]c1-c1ccc(C(C)O[Si](C)(C)C(C)(C)C)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)[nH]c1-c1ccc(C(C)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To a solution (5 mL) of 5-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-3-methyl-1H-pyrrol-2-yl)pyridine (130 mg) in tetrahydrofuran (5 mL) was added tetrabutylammonium fluoride (1M tetrahydrofuran solution, 256 μL), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (83.0 mg, yield 79%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (3:1, volume ratio). MS: 495 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][O-:11].[Na+]>CO.O1CCOCC1.CO>[CH3:10][O:11][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: N#Cc1ccnc(Cl)c1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc(C#N)ccn1
Yield: 110.8 %

Procedure:
2-Chloro-4-cyanopyridine (115.53 g) in methanol/dioxan (1:1, 850 ml) was added to a solution of sodium methoxide (prepared from 20.8 g sodium) in methanol (285 ml) and the mixture was boiled under reflux for 2.5 hours and was allowed to cool. The mixture was filtered and the volume of the filtrate was reduced by evaporation to 200 ml and water (400 ml) was added. The solid which precipitated out was filtered off to give 2-methoxy-4-cyanopyridine (57.2 g, 51%) m.p. 93°-95.5°.
Reaction SMILES: [CH2:1]1[CH:9]([CH2:10][C:11]([OH:13])=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.C(N(CC)CC)C.Cl.Cl.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1.C(OP(C#N)(=O)OCC)C>C(Cl)Cl>[CH:9]1([CH2:10][C:11]([N:34]2[CH2:33][CH2:32][N:31]([C:28]3[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=3)[CH2:36][CH2:35]2)=[O:13])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1]1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: O=C(O)CC1CCc2ccccc21
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N2CCN(C(=O)CC3CCc4ccccc43)CC2)cc1
Reaction time: 3 h

Procedure:
A mixture of 1-indanylacetic acid (CIX, EXAMPLE 66, 7.4 g, 42 mmol) and triethylamine (29.3 ml, 210 mmol), and 1-(4-methoxyphenyl)piperazine dihydrochloride (LXV, 13.3 g, 50.4 mmol) in methylene chloride (420 ml) is stirred at 20°-25° under a nitrogen atmosphere. Diethylcyanophosphonate (12.7 ml, 84 mmol) is added over a period of 10 min at 20°-25°. After the stirring for 3 hr, the reaction is quenched with sodium hydroxide (20%) and extracted with methylene chloride (2×500 ml). The organic phase is washed with saline, dried (magnesium sulfate), filtered and concentrated under reduced pressure. The crude product is purified by crystallization from ethyl acetate/methanol. The mother liquor is purified by liquid chromatography on silica gel 60 (230-400 mesh, 400 g), eluting with hexane/ethyl acetate (1/2). The appropriate fractions homogeneous by TLC are combined and concentrated under reduced pressure to give a solid. Both solids are combined to give the title compound, mp=111°-112°; NMR (CDCl3, TMS) 7.26-6.83, 3.77 and 3.85-1.54 δ.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>ClCCl.C1CCN2C(=NCCC2)CC1>[OH:13][N:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8](=[O:9])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=Nc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])cc1)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 96.8 %

Procedure:
Scale up: DBU (3.8 mg, 0.025 mmol) was added under argon to a solution of 4-nitrobenzaldehyde (3 g, 20 mmol), nitrosobenzene (2.14 g, 20 mmol) and catalyst (9 mg, 0.025 mmol) in dichloromethane (100 mL). The reaction mixture was stirred at room temperature for 2 min. The product precipitated as a yellow solid. The solvent was removed under vacuum, and the solid was washed with hexane and ether to yield a pure product (5 g).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:20])[C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19].CCN(C(C)C)C(C)C.F[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]=1>CN1C(=O)CCC1>[CH3:17][O:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([O:18][CH3:19])[C:10]=1[C:9]([NH:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[NH:2][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]=1)=[O:20]
Reactant: COc1cccc(OC)c1C(=O)N[C@H]1CCC[C@@H]1N
Reactant: Fc1cccc(C(F)(F)F)n1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(OC)c1C(=O)N[C@H]1CCC[C@@H]1Nc1cccc(C(F)(F)F)n1
Reaction time: 0.33 h

Procedure:
To a microwave vial were charged N-[(1S,2S)-2-Aminocyclopentyl]-2,6-dimethoxybenzamide hydrochloride (Intermediate 5; 80 mg, 0.266 mmol) in dry NMP (1 ml). To this was then added DIPEA (138 μl, 0.798 mmol) and 2-fluoro-6-(trifluoromethyl)pyridine (CAS number 94239-04-0; 53 mg, 0.319 mmol). The reaction was subjected to microwave irradiation at 200° C. for 30 minutes and then at 250° C. for 20 minutes. The reaction mixture was directly purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[O:32][CH3:33])=[CH:20][CH:19]=1)[NH:5][C:6](=[O:16])[C:7]1[C:12]([Cl:13])=[CH:11][C:10](Br)=[CH:9][C:8]=1[Cl:15].[CH3:35][Si:36]([CH3:50])([CH3:49])[CH2:37][CH2:38][O:39][CH2:40][N:41]1[C:45](B(O)O)=[CH:44][CH:43]=[N:42]1>C1COCC1>[CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[O:32][CH3:33])=[CH:20][CH:19]=1)[NH:5][C:6](=[O:16])[C:7]1[C:12]([Cl:13])=[CH:11][C:10]([C:45]2[N:41]([CH2:40][O:39][CH2:38][CH2:37][Si:36]([CH3:50])([CH3:49])[CH3:35])[N:42]=[CH:43][CH:44]=2)=[CH:9][C:8]=1[Cl:15]
Reactant: C[Si](C)(C)CCOCn1nccc1B(O)O
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=O)c1c(Cl)cc(Br)cc1Cl
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=O)c1c(Cl)cc(-c2ccnn2COCC[Si](C)(C)C)cc1Cl
Yield: 95.6 %

Procedure:
N-(4-Bromo-2,6-dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester (0.240 g) was coupled with 1-[[2-(trimethylsilyl)ethoxy]methyl]-5-pyrazoleboronic acid (0.343 g) in THF (10 mL) as described in Example 7-2) to give N-[4-[1-[[2-(trimethylsilyl)ethoxy]methyl ]-5-pyrazolyl]-2,6-dichlorobenzoyl]-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester (0.277 g). ESMS: m/z 684 (MH+) and 682 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH:35][NH:36][C:37](=O)[CH2:38][CH3:39])=[N:10][N:11]([CH2:23][C:24]3[C:25]([CH3:34])=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=3)[C:12](=[O:22])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([C:37]([CH2:38][CH3:39])=[N:36][N:35]=3)[N:11]([CH2:23][C:24]3[C:25]([CH3:34])=[N:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)[C:12](=[O:22])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CCC(=O)NNc1nn(Cc2ccc(C(F)(F)F)nc2C)c(=O)c(-c2ccc(C#N)cc2)c1-c1ccc(Cl)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1nnc2c(-c3ccc(Cl)cc3)c(-c3ccc(C#N)cc3)c(=O)n(Cc3ccc(C(F)(F)F)nc3C)n12
Temperature: 130 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a round bottom flask was added N′-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)propionohydrazide (45 mg, 0.0794 mmol) and toluene (3 ml). The reaction was heated to 130° C. and stirred at this temperature for 1 hr. After this time, POCl3 (1 ml) was added and the reaction mixture was stirred at 130° C. for additional 4 hrs. The reaction was then cooled to rt and concentrated under reduced pressure. The residue was dissolved in EtOAc (30 ml) and the resulting solution was washed with 0.5N NaOH (10 ml), water (15 ml), saturated aqueous NaCl (10 mL). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give the crude product. The crude product was purified using an automated column chromatography system (ISCO, 4 gm silica gel) eluting with a gradient of 65%-100% EtOAc/Hex to give product 4-(8-(4-chlorophenyl)-3-ethyl-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile (30 mg) as off-white solid. 69% yield. HPLC retention time (method A) 3.110 min; LCMS (M+H)=549.4. 1HNMR (CDCl3, 500 Hz): 7.49-7.53 (3H, m), 7.35-7.37 (1H, m), 7.22-7.24 (6H, m), 5.57 (2H, s), 2.73 (2H, q), 2.65 (3H, s), 1.38 (3H, t); 13CNMR (CDCl3, 500 Hz) 159.8, 155.7, 148.6, 147.5(q), 143.9, 138.0, 137.1, 136.6, 133.5, 131.9, 131.8, 128.9, 120.8(q), 118.6, 118.2, 112.6, 49.2, 22.2, 20.5, 12.4.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1([CH3:26])[CH:10]([CH3:11])[C:9](=[N:12][OH:13])[CH2:8][C:7]([CH2:15][CH3:16])([CH3:14])[N:6]1[O:17][CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[CH3:4].[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31]Cl>CN(C=O)C>[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31][O:13][N:12]=[C:9]1[CH2:8][C:7]([CH2:15][CH3:16])([CH3:14])[N:6]([O:17][CH:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH3:19])[C:5]([CH2:3][CH3:4])([CH3:26])[CH:10]1[CH3:11]
Reactant: CN(C)CCCCl
Reactant: CCC1(C)CC(=NO)C(C)C(C)(CC)N1OC(C)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1(C)CC(=NOCCCN(C)C)C(C)C(C)(CC)N1OC(C)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 60.1 %

Procedure:
To a slurry of sodium hydride (4.36 g, 0.1 mol, 55% in mineral oil) in DMF (30 ml) is added dropwise the solution of 2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-piperidine-4-one oxime (16.6 g, 0.05 mol, prepared as described in WO 02/100831 A1). The mixture is stirred 150 min at 25° C. and then 3-dimethylaminopropylchloride (9.48 g, 0.06 mol) is added during 1 h. The mixture is stirred at room temperature for 18 h, the DMF is then evaporated in vacuo. The residue is dissolved in ethyl acetate (100 ml), washed with water (2×25 ml), dried over MgSO4 and evaporated. Chromatography on silica gel column (hexane-ethylacetate 1:1) affords 12.55 g of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:31]=[CH:30][C:21]([C:22]([O:24][CH:25]([C:27](Cl)=[O:28])[CH3:26])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl.[CH3:33][NH:34][CH3:35]>N1C=CC=CC=1>[CH2:1]([NH:17][C:18]1[CH:31]=[CH:30][C:21]([C:22]([O:24][CH:25]([C:27](=[O:28])[N:34]([CH3:35])[CH3:33])[CH3:26])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC(C)C(=O)Cl)cc1
Reactant: CNC
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC(C)C(=O)N(C)C)cc1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a solution of 3 g. (6.32 m moles) 1-(chlorocarbonyl)ethyl 4-(hexadecylamino)benzoate in 25 ml. pyridine is added 0.6 g. (7.5 m moles) dimethylamine hydrochloride. The solution is stirred at 50° C. for 15 hours, then evaporated to dryness. The residue is partitioned between 50 ml. water and 50 ml. methylene chloride. The layers are separated, and the aqueous solution is washed once more with 50 ml. methylene chloride. The combined organic solutions are dried, condensed, and the residue is crystallized from acetonitrile to yield the title compound as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:12][CH:13]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15]>COCCO>[CH2:14]([CH:13]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:15]
Reactant: CCCCC(CC)CBr
Reactant: Oc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: CCCCC(CC)COc1ccc(Br)cc1
Reaction time: 0.25 h
Yield: 83.7 %

Procedure:
86.5 g (0.5 mol) of 4-bromophenol in 500 ml of Methylcellosolve are placed in a 1 l sulfonating flask fitted with stirrer, condenser, dropping funnel and internal thermometer. This mixture is heated to 60 C., and then 70.0 g of 30% NaOH (0.53 mol) are run in slowly. The mixture is stirred for 15 minutes and then 116.8 g (0.575 mol) of 3-bromomethylheptane are added dropwise over the course of 45 minutes. The reaction is continued at 100 C. overnight. The thin-layer chromatogram indicates virtually quantitative conversion. Solvent and excess bromide are removed in vacuo and the residue (an oil) is taken up in 600 ml of toluene. The mixture is subjected three times to extraction by shaking with water and the extracts are dried over sodium sulfate and evaporated to dryness, to give 119.3 g (84% of theory) of 4-(2-ethylhexyloxy)bromobenzene as a light yellow oil.
Reaction SMILES: Cl[CH:2](Cl)[C:3]1[N:15]=[C:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[N:11][C:12]=3[CH:13]=[CH:14][N:5]2[N:4]=1.[OH2:17]>CNC>[N:15]1[C:3]([CH:2]=[O:17])=[N:4][N:5]2[CH:14]=[CH:13][C:12]3[N:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:6]=12
Reactant: ClC(Cl)c1nc2c3cccnc3ccn2n1
Reactant: O
Agent: CNC
Product: O=Cc1nc2c3cccnc3ccn2n1
Temperature: 70 °C
Yield: 60 %

Procedure:
A microwave tube was charged with a mixture of 2-(dichloromethyl)-[1,2,4]triazolo[5,1-f][1,6]naphthyridine (180 mg, 0.71 mmol) in dimethylamine in water (5 mL, 33% wt in water) and heated at 70° C. in oil bath for 5 h, and then cooled to room temperature. The mixture was extracted with EtOAc (3×20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with DCM/MeOH v/v 100/1 and 50/1) to yield [1,2,4]triazolo[5,1-f][1,6]naphthyridine-2-carbaldehyde as a white solid (85 mg, yield 60%). ESI MS: m/z 199 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H), 9.06 (m, 1H), 8.97 (m, 1H), 8.56 (d, J=7.2 Hz, 1H), 7.65 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([C:38]2[N:42]([CH:43]3[CH2:46][N:45]([CH:47]([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[CH2:44]3)[N:41]=[CH:40][CH:39]=2)[CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:13]2[C:14]([F:16])=[CH:15][C:10]([S:7]([N:6]([CH2:5][C:4]3[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:3]=3[O:2][CH3:1])[C:19]3[S:23][N:22]=[CH:21][N:20]=3)(=[O:9])=[O:8])=[C:11]([F:18])[CH:12]=2)=[C:33]([C:38]2[N:42]([CH:43]3[CH2:46][N:45]([CH:47]([C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=4)[C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[CH2:44]3)[N:41]=[CH:40][CH:39]=2)[CH:32]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Reactant: Oc1ccc(Cl)cc1-c1ccnn1C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccnn3C3CN(C(c4ccccc4)c4ccccc4)C3)cc2F)c(OC)c1

Procedure:
N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 647, 157 mg, 0.353 mmol), 4-chloro-2-{1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}phenol (Preparation 689, 147 mg, 0.353 mmol) and potassium carbonate (147 mg, 1.06 mmol) were stirred in dimethyl sulphoxide (1.0 ml) for 18 hours. The mixture was partitioned between methyl-t-butyl ether (40 ml) and water (20 ml), the organic layer was dried over anhydrous sodium sulphate, filtered and evaporated to give the title compound as a glass, 270 mg.