Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][N:28]5[CH2:33][CH2:32][S:31][CH2:30][CH2:29]5)=[CH:23][CH:22]=4)=[O:19])=[CH:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[I:35].[C:36](OCC)(=O)C>CN(C=O)C>[I-:35].[CH3:36][N+:28]1([CH2:27][C:24]2[CH:25]=[CH:26][C:21]([NH:20][C:18]([C:14]3[CH2:13][CH2:12][C:11]4[C:16](=[CH:17][C:8]([C:5]5[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=5)=[CH:9][CH:10]=4)[CH:15]=3)=[O:19])=[CH:22][CH:23]=2)[CH2:33][CH2:32][S:31][CH2:30][CH2:29]1
Reactant: CI
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCSCC4)cc2)CC3)cc1
Reactant: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C[N+]4(C)CCSCC4)cc2)CC3)cc1
Product: [I-]
Temperature: 25 °C
Reaction time: 17 h

Procedure:
In DMF (3 ml) was dissolved 7-(4-methylphenyl)-N-[4-(thiomorpholinomethyl)phenyl]-3,4-dihydronaphthalene-2-carboxamide (160 mg), and to the mixture was added methyl iodide (66 μl). The mixture was stirred at room temperature for 17 hours, and to the mixture was added ethyl acetate (100 ml). The resulting precipitate was filtered and recrystallized from ethyl acetate-methanol to give 4-methyl-4-[4-[7-(4-methyl-phenyl)-3,4-dihydronaphthalene-2-carboxamido]benzyl]-thiomorpholinium iodide (Compound 55) (165 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][C:5]1[N:6]=[C:7](Cl)[C:8]2[CH2:14][O:13][CH2:12][CH:11]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)[C:9]=2[N:10]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:4][C:5]1[N:6]=[C:7]([NH:3][CH2:1][CH3:2])[C:8]2[CH2:14][O:13][CH2:12][CH:11]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)[C:9]=2[N:10]=1
Reactant: CCN
Reactant: Fc1cc(F)cc(C2COCc3c(Cl)nc(Cl)nc32)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCNc1nc(Cl)nc2c1COCC2c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
The mixture of ethanamine (406 μL, 0.812 mmol), 2,4-dichloro-8-(3,5-difluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (Preparation X)(117 mg, 0.369 mmol) and DIEA (161 μL, 0.922 mmol) in THF (1845 μL) was stirred at RT for 2 h. The mixture was concentrated and purified by column chromatography on silica gel to give 2-chloro-8-(3,5-difluorophenyl)-N-ethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (104 mg, 0.319 mmol, 87% yield). LC-MS (M+H)+=326.1.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([CH:9]=[O:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.N1CCCCC1.[NH2:17][C:18]1[C:27](O)=[CH:26][CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]>[Ag-]=O.CO>[N:1]12[CH2:8][CH2:7][C:4]([C:9]3[O:10][C:27]4[C:18](=[C:19]([C:20]([O:22][CH3:23])=[O:21])[CH:24]=[CH:25][CH:26]=4)[N:17]=3)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: O=CC12CCN(CC1)CC2
Reactant: COC(=O)c1cccc(O)c1N
Agent: O=[Ag-]
Solvent: CO
Solvent: C1CCNCC1
Product: COC(=O)c1cccc2oc(C34CCN(CC3)CC4)nc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 21.3 %

Procedure:
A mixture of quinuclidine-4-carbaldehyde (0.57 g, 4.10 mmol), piperidine (0.86 g, 1 mL, 10.10 mmol), methyl 2-amino-3-hydroxybenzoate (0.68 g, 4.10 mmol) and methanol (10 mL) was heated to reflux for 40 h. Analysis by LCMS indicated the presence of the requisite intermediate Schiff base. The solvent was removed under reduced pressure, the residue was dissolved in methylene chloride (20 ml) and silver (I) oxide (1.23 g, 5.34 mmol) was added. The reaction mixture was stirred at room temperature for 5 h. Analysis by LCMS indicated consumption of the Schiff base intermediate. The reaction mixture was filtered though diatomaceous earth (10 g) eluting with methylene chloride (50 mL) and concentrated. The crude product was purified by column chromatography (silica gel, 5 to 20% methanol in chloroform) to afford methyl 2-(quinuclidin-4-yl)benzoxazole-4-carboxylate (250 mg, 17%) as an brown solid: 1H NMR (300 MHz, CDCl3) δ 7.96 (dd, J=8.0, 1.0 Hz, 1H), 7.67 (dd, J=8.0, 1.0 Hz, 1H), 7.37 (d, d, J=8.0 Hz, 1H), 4.01 (s, 3H), 3.06-3.02 (m, 6H), 2.06-2.01 (m, 6H); MS (ESI+) m/z 287 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:14])=[CH:3][CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[N+:11]([O-:13])=[O:12].[ClH:15].[N:16]([O:18]CCC(C)C)=O>>[Cl:15][C:2]([CH3:14])([CH3:1])[CH:3]([N:16]=[O:18])[CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[N+:11]([O-:13])=[O:12]
Reactant: CC(C)=CCCn1ccnc1[N+](=O)[O-]
Reactant: CC(C)CCON=O
Reactant: Cl
Product: CC(C)(Cl)C(CCn1ccnc1[N+](=O)[O-])N=O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 81 %

Procedure:
4-Methyl-1-(2-nitro-1H-imidazol-1-yl)-3-pentene (8 g, 41 mmol) was dissolved in isoamyl nitrite (50 mL) at room temperature. The solution was cooled to 0° C. in an ice-salt bath and concentrated HCl (12 mL) was added dropwise. The reaction temperature was maintained between 3°-5° C. during the HCl addition; the reaction was stirred in an ice-salt bath for 45 minutes after the addition of HCl. The product was filtered, washed with ethanol-ether (1:2) and dried in vacuum to give 8.6 g (81%) of the title product as a white solid; mp: 96°-97° C. MS: (M+H)+ =261, M+ =260. 1H NMR (DMSO-d6) δ 1.70 (s, 6H, gem-di-CH3), 2.94 (t, 2H, CH2C=NOH), 4.65 [t, 2H, CH2 -(2-nitroimidazole)], 7.16 and 7.52 (s, 2H, 2-nitroimidazolyl-H), 11.43 (s, 1H, CH2C=NOH).
Reaction SMILES: [C:1]1([C:11]2([CH:16]=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].C(OCC)(=O)C>CO.CCCCCC>[C:1]1([C:11]2([CH2:16][OH:17])[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=CC1(c2cccc3ccccc23)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: OCC1(c2cccc3ccccc23)CCCC1
Yield: 86.7 %

Procedure:
A solution of 1-naphthalen-1-yl-cyclopentanecarbaldehyde (339) (10 g, 44.6 mmol) in methanol (150 mL) was cooled to 0° C. and NaBH4 (3.373 g, 89.2 mmol) was added in portions (8 portions). After the addition was completed the reaction mixture was allowed to stir at room temperature for 1 h (silica TLC, 10% ethyl acetate in hexane; Rf=0.3). The reaction mixture was quenched with aqueous NH4Cl solution and concentrated in vacuo as much as possible; diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic part was washed with brine (50 mL), dried and concentrated in vacuo to get a crude mass which was purified by CombiFlash using gradient eluent mixture of ethyl acetate and hexane to get pure (1-naphthalen-1-yl-cyclopentyl)-methanol (340) (8.75 g, 87%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)[C:3]#N.[OH-:18].[K+].N.C([OH:23])C>>[CH3:1][CH:2]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)[C:3]([OH:23])=[O:18]
Reactant: [OH-]
Reactant: CCO
Reactant: CC(C#N)c1ccc2c(c1)Cc1ccccc1-2
Agent: N
Agent: [K+]
Product: CC(C(=O)O)c1ccc2c(c1)Cc1ccccc1-2

Procedure:
2.1g. of α-methylfluorene-2-acetonitrile is refluxed in 60% aqueous ethanol (50ml.) containing potassium hydroxide (5g.) until the evolution of ammonia ceases. The ethanol is evaporated and the aqueous solution acidified to pH 2.0 with HCl and extracted with ether. The ether extracts are washed with water, dried (MgSO4) and evaporated to give the title compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:22])=[N:12][CH:13]=[C:14]([C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=2)[N:15]=1.C(N(CC)CC)C.Cl[C:31]1[S:32][CH:33]=[CH:34][N:35]=1>CS(C)=O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:22])=[N:12][CH:13]=[C:14]([C:16]2[CH2:17][CH2:18][N:19]([C:31]3[S:32][CH:33]=[CH:34][N:35]=3)[CH2:20][CH:21]=2)[N:15]=1
Reactant: Nc1ncc(C2=CCNCC2)nc1-c1nc2ccccc2[nH]1
Reactant: Clc1nccs1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1ncc(C2=CCN(c3nccs3)CC2)nc1-c1nc2ccccc2[nH]1
Temperature: 160 °C
Yield: 28.5 %

Procedure:
A solution of 3-(1H-benzo[d]imidazol-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-amine (100 mg, 0.1922 mmol) in DMSO (2.000 mL) was treated with triethylamine (58.35 mg, 80.37 μL, 0.5766 mmol) and 2-chlorothiazole (27.57 mg, 0.2306 mmol) and heated in the microwave for 40 minutes at 160° C. The reaction mixture was filtered and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound (20.6 mg, 15% Yield). 1H NMR (400.0 MHz, DMSO) d 2.89 (s, 2H), 3.80 (t, J=5.7 Hz, 2H), 4.21 (d, J=2.5 Hz, 2H), 6.86 (s, 1H), 6.94-6.96 (m, 1H), 7.28-7.31 (m, 3H), 7.69 (s, 2H) and 8.41 (s, 1H) ppm; MS (ES+) 376.0
Reaction SMILES: [NH:1]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C@H:2]([C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])[CH:3]([CH3:5])[CH3:4].C=O.O.[C:33]1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:4][CH:3]([CH3:5])[CH:2]([NH:1][C:20](=[O:21])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:6]([N:8]1[CH:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17](=[O:19])[O:18][CH2:33]1)=[O:7]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C=O
Solvent: O
Solvent: c1ccccc1
Product: CC(C)C(NC(=O)OCc1ccccc1)C(=O)N1COC(=O)C1Cc1ccccc1
Temperature: 25 °C
Yield: 187.4 %

Procedure:
Cbz-Val-Phe-OH (4.67 g, 11.7 mmol, obtained from Sigma Chemical Company, St. Louis, Mo. 63178) is combined with paraformaldehyde (5 g) and p-toluenesulfonic acid monohydrate (500 mg, 2.6 mmol) in benzene (120 mL). The reaction is heated at reflux for 23 hours with continuous removal of water with a Dean-Stark trap. The reaction then cooled to room temperature and concentrated under vacuum. The residue is dissolved in ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (60 ) is added with mixing. The layers are then separated and the aqueous layer is extracted with ethyl acetate (2×50 mL). The organic layer and organic extracts are combined and dried over anhydrous magnesium sulfate, passed through a short pad of silica gel and the filtrate is concentrated under vacuum. The residue is then purified by flash chromatography (hexane/ethyl acetate, 95:5 to 90:10 to 80:20, silica gel) to provide [S-(R*,R*)]-[2-methyl-1-[[5-oxo-4-(phenylmethyl)-3-oxazolidinyl]carbonyl]propyl]-carbamic acid, phenylmethyl ester (2.00 g, 42%) as a foam; [α]20D +113.95 (c 0.55, CHCl3); IR (CHCl3) 3314, 3032, 2934, 1804, 1714, 1659, 1437, 1233 cm-1 ; MS m/z 411 (M+H+), 367, 268, 234, 206, 178, 162, 91.
Reaction SMILES: [CH:1]12[N:8]([C:9]3[N:14]=[C:13](Cl)[N:12]=[C:11]([CH2:16][N:17]([CH3:19])[CH3:18])[CH:10]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2.C(=O)([O-])[O-].[Na+].[Na+].[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)=[O:34])[CH:27]=1>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.COCCOC>[CH:1]12[N:8]([C:9]3[CH:10]=[C:11]([CH2:16][N:17]([CH3:19])[CH3:18])[N:12]=[C:13]([C:39]4[CH:38]=[CH:37][C:36]([NH:35][C:33]([NH:32][C:28]5[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=5)=[O:34])=[CH:41][CH:40]=4)[N:14]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3cccnc3)cc2)OC1(C)C
Reactant: CN(C)Cc1cc(N2C3CCC2COC3)nc(Cl)n1
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: [Na+]
Solvent: COCCOC
Product: CN(C)Cc1cc(N2C3CCC2COC3)nc(-c2ccc(NC(=O)Nc3cccnc3)cc2)n1
Temperature: 120 °C
Yield: 74.6 %

Procedure:
A microwave vial was charged with 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-chloropyrimidin-4-yl)-N,N-dimethylmethanamine (0.080 g, 0.283 mmol) and sodium carbonate (2M in water, 0.425 mL, 0.849 mmol). DME (1.5 mL) was then added to give a yellow biphasic solution. The solution was sparged with nitrogen for 10 minutes, and tetrakis(triphenylphosphine)palladium(0) (0.020 g, 0.017 mmol) and 1-(pyridin-3-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (0.106 g, 0.311 mmol) were added. The vial was sealed and heated to 120° C. for 2 hours via microwave. The vessel was then cooled to room temperature and the reaction mixture was filtered through Celite™. The filter cake was washed with ethyl acetate and the filtrate was washed with saturated sodium chloride and concentrated under reduced pressure to provide a brown oil. The crude product was added to a HPLC column and was eluted with 5-90% acetonitrile in water (0.05% TFA buffer) to provide the mono-TFA salt of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-(pyridin-3-yl)urea (0.097 g, 75%) as a light yellow solid. HRMS; [M+H]+ Obs'd=460.2454, [M+H]+ Calc'd=460.2455.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([N+:36]([O-])=O)=[C:7]([OH:35])[C:8]([NH:12][C:13](=[O:34])[CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:27][CH3:28])([CH3:26])[CH3:25])=[CH:20][C:19]=2[C:29]([CH2:32][CH3:33])([CH3:31])[CH3:30])[CH2:15][CH3:16])=[CH:9][C:10]=1[Cl:11])(=[O:3])[CH3:2].[OH-].[Na+].O.[C:42](O)(=[O:44])C>CO>[Cl:11][C:10]1[C:5]2=[N:4][C:1](=[O:3])[CH2:2][C:42](=[O:44])[N:36]=[C:6]2[C:7]([OH:35])=[C:8]([NH:12][C:13](=[O:34])[CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:27][CH3:28])([CH3:25])[CH3:26])=[CH:20][C:19]=2[C:29]([CH2:32][CH3:33])([CH3:30])[CH3:31])[CH2:15][CH3:16])[CH:9]=1
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(Cl)c(NC(C)=O)c([N+](=O)[O-])c1O
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(Cl)c2c(c1O)=NC(=O)CC(=O)N=2
Temperature: 25 °C

Procedure:
In 200 ml of methanol was dispersed 40 g of the 3-acetylamino-4-chloro-2-nitro-6-[2-(2,4-di-t-amylphenoxy)butanoylamino]phenol, and the dispersion was stirred while refluxing for 5 hours together with 9 g of sodium hydroxide and 40 ml of water. The reaction mixture was cooled to room temperature and then poured into 300 ml of water. Upon dropwise addition of 15 ml of acetic acid, red crystals were precipitated. The crystals were collected by filtration, recrystallized from acetonitrile, and dried to provide 21 g of the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]([NH2:26])=[O:25])=[CH:18][CH:17]=1)=[O:14].I[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1.C(NCC)C.C(O)=O>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19](/[C:22](/[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[CH:23]\[C:24]([NH2:26])=[O:25])=[CH:18][CH:17]=1)=[O:14]
Reactant: NC(=O)C#Cc1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Reactant: COc1ccc(I)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O=CO
Solvent: CCNCC
Solvent: CCOC(C)=O
Product: COc1ccc(/C(=C/C(N)=O)c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)cc1
Temperature: 75 °C
Yield: 31.1 %

Procedure:
A mixture of 3-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}prop-2-ynamide (31.0 mg, 0.085 mmol), 4-iodoanisole (0.010 mL, 0.089 mmol), diethylamine (0.029 mL, 0.281 mmol), formic acid (0.0083 mL, 0.221 mmol), and bis(dibenzylideneacetone)palladium(0) (3.4 mg, 0.006 mmol) in 1.4 mL EtOAc (degassed) was heated at 75° C. for 20 hours. The reaction was partitioned between EtOAc and H2O/brine mixture. The EtOAc layer was washed with dilute aqueous HCl, then aqueous NaHCO3, brine, and dried with anhydrous Na2SO4 to give 20 mL of EtOAc solution of crude material. The EtOAc solution was filtered past a plug of silica gel eluting with EtOAc, evaporated, and the resulting solid chromatographed eluting with EtOAc/CHCl3 to give the title compound as a grey-purple solid (12.5 mg, 31%). 1H NMR (Acetone-d6) δ: 8.80 (d, J=7.6 Hz, 1H), 8.42 (s, 2H), 7.32-7.45 (m, 4H), 7.21-7.26 (m, 2H), 7.10-7.16 (m, 2H), 6.98 (br. s., 1H), 6.88-6.94 (m, 2H), 6.63 (br. s., 1H), 6.43 (s, 1H), 3.81 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].[CH:24]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH:21][C:29]([CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:30])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2]
Reactant: O=C(Cl)C1CCCC1
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)C3CCCC3)cc2)n1

Procedure:
Following the procedure described in Example 1 with 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline and cyclopentancarbonyl chloride provided the title compound. ESMS [M+H]+: 400.4
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)=[CH:20][CH:19]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Product: O=c1[nH]c2ncccc2c2cc(NCc3ccc(Cl)cc3)ccc12
Yield: 13.9 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 448 using 6 (100 mg, 0.43 mmol) and (4-chloro-phenyl)methanamine (245 mg, 1.73 mmol) to provide 452 (20 mg, 14% yield) as a white powder. LC-MS (M+H=337, obsd.=337). 1H NMR (400 MHz, DMSO-D6) δ 11.49 (s, 1H), 8.56 (d, J=8.3, 1H), 8.41 (s, 1H), 7.99 (d, J=8.8, 1H), 7.44 (dd, J=8.5, 22.3, 2H), 7.37 (s, 2H), 7.25 (d, J=12.5, 2H), 6.95 (s, 1H), 4.51 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:14]=[CH:15][CH2:16][CH:17]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19](OC)=[N:18]2)=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])([O-:3])=[O:2].[Cl-:26].[NH4+:27]>>[ClH:26].[NH:27]=[C:19]1[NH:18][CH:17]([CH2:16][CH:15]=[CH:14][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1C=CCC1CCCCC(OC)=N1
Product: COC(=O)c1cc([N+](=O)[O-])ccc1C=CCC1CCCCC(=N)N1
Product: Cl

Procedure:
The product of Example 160 is reacted with ammonium chloride by the method of Example 5 to generate the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1.[C:12]1([CH:18]([NH2:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CN1C(=O)CCC1>CO.O>[CH3:11][C:8]1[N:6]2[N:7]=[C:2]([NH:20][CH:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:19])[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: CC(N)c1ccccc1
Reactant: Cc1nnc2ccc(Cl)nn12
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CO
Product: Cc1nnc2ccc(NC(C)c3ccccc3)nn12
Temperature: 150 °C
Reaction time: 0.75 h

Procedure:
6-Chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine (200 mg, 1.186 mmol; commercially available or prepared according to patent WO2006/039325A2), rac-1-phenylethanamine (575 mg, 4.75 mmol; commercially available from Aldrich) and anhydrous NMP (1 mL) were charged into a microwave tube equipped with a magnetic stirbar (light brown solution). After the vessel was sealed, the mixture was heated at 150° C. for 15 min, followed by an extra 45 min using microwave irradiation. The reaction was then diluted with MeOH/H2O (19:1), filtered, purified by reverse phase chromatography and lyophilized to give the rac-3-methyl-N-(1-phenylethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-amine (Compound 1) as a white solid (42 mg; 14% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.84 (d, J=9.8 Hz, 1H), 7.81 (d, J=7.1 Hz, 1H), 7.42 (d, J=7.8 Hz, 2H), 7.32 (t, J=7.5 Hz, 2H), 7.21 (t, J=7.3 Hz, 1H), 6.80 (d, J=9.8 Hz, 1H), 4.92 (dd, J=7.0, 7.0 Hz, 1H), 2.42 (s, 3H), 1.49 (d, J=6.9 Hz, 3H). LRMS [M+H]+: 254 m/z.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH:7]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]1.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].Cl>O>[CH2:20]([O:19][C:17]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium carbonate (1.59 g, 0.0150 mol) was added to a solution of piperidine-4-carboxylic acid (0.970 g, 0.00751 mol) in water (15 mL). After the solid was dissolved, benzyl chloroformate (1.54 g, 0.00901 mol) was added dropwise. The mixture was stirred at rt for 3 h. The mixture was carefully acidified (pH=4) with 2N HCl, and then was extracted with DCM (4×10 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired product.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[CH:17][C:16]=1[SH:23].N1C=CC=CC=1.C(OCC)(=O)C>C(#N)C>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([S:23][C:16]2[CH:17]=[C:18]([Cl:22])[C:19]([Cl:21])=[CH:20][C:15]=2[Cl:14])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: Sc1cc(Cl)c(Cl)cc1Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)Oc1ccc(C(=O)Sc2cc(Cl)c(Cl)cc2Cl)cc1
Yield: 97 %

Procedure:
A solution of 4-acetoxybenzoyl chloride (8.37 g) in dry acetonitrile (20 ml) was added to a solution of 2,4,5-trichlorothiophenol (9.00 g) in dry acetonitrile (120 ml) and the mixture stirred at room temperature whilst pyridine (3.41 ml) was added dropwise over 10 minutes. Stirring was continued until the reaction was complete, when ethyl acetate was added and the solution washed with water. Evaporation of the solution, which had been dried over magnesium sulphate, afforded the desired thioester (15.36 g).