Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:4]([NH:9][NH2:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[I:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16](F)[C:15]=1[CH:21]=O>CN1C(=O)CCC1>[I:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[N:9]([C:4]3[C:3]([C:2]([F:1])([F:11])[F:12])=[CH:8][CH:7]=[CH:6][N:5]=3)[N:10]=[CH:21][C:15]=12
Reactant: O=Cc1c(I)ccnc1F
Reactant: NNc1ncccc1C(F)(F)F
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1cccnc1-n1ncc2c(I)ccnc21
Temperature: 185 °C
Yield: 89.3 %

Procedure:
To a dry 15 mL ChemGlass pressure bottle under nitrogen was added 3-(trifluoromethyl)pyrid-2-ylhydrazine (499 mg, 2.82 mmol), 4-iodo-2-fluoro-3-formylpyridine (706.8 mg, 2.82 mmol) and anhydrous NMP (4.5 mL). The reaction mixture was flushed with argon, securely capped and heated to 185° C. for 1.5 h. The reaction mixture was worked up according to the procedure described in Intermediate 69A to give 982 mg (89%) of the title compound as an oil. LC/MS (Condition B): ret. T=3.4 min, (M+H)+ 390.94.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12]>C1CCN2C(=NCCC2)CC1.O1CCCC1>[N:1]1([CH2:12][CH2:11][C:10]([O:14][CH3:15])=[O:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C=CC(=O)OC
Reactant: c1ccc2[nH]cnc2c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)CCn1cnc2ccccc21
Yield: 91.5 %

Procedure:
A solution of 10.0 g (84 mmol) of benzimidazole, 22.7 ml (250 mmol) of methyl acrylate and 3 drops of DBU in 50 ml of tetrahydrofuran was heated at reflux for 2 days. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel chromatography using 3% methanol in chloroform to provide 15.7 g (92%) of the desired compound (Rf 0.58, 10% methanol in chloroform).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](I)[C:3]=1[OH:10].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1.O>CN(C=O)C.C(NCC)C.[Cu]I>[F:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]2[O:10][C:19]([C:16]3[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=3)=[CH:20][C:4]=2[CH:5]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: Oc1c(F)cc(F)cc1I
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: O
Solvent: CCNCC
Product: COc1ccc(-c2cc3cc(F)cc(F)c3o2)cc1
Reaction time: 1 h

Procedure:
A solution of 2,4-Difluoro-6-iodo-phenol (1.0 g, 3.9 mmol), 4-Methoxyphenylacetylene(0.53 g, 4.0 mmol), PdCl2P(PH3)2 (70 mg), and CuI (50 mg) in DMF/Diethylamine (10 ml) was heated to 60° C. After 1 hr, the reaction was cooled and poured into water which was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to give a solid which was triturated with MeOH and filtered to give 86 as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([O:13]CC)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[OH-].[Na+].Cl>CO>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([OH:13])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)c1cnc2cc(Br)ccn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnc2cc(Br)ccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate (67 g, 250 mmol) in methanol (500 mL), sodium hydroxide (2N, 249 ml, 500 mmol) was added. The resulting solution was stirred overnight at room temperature. The pH of the solution was adjusted to pH=6 with HCl (2N). The solids were collected by filtration to afford 7-bromo-imidazo[1,2-a]pyridine-3-carboxylic acid as white solid. MS [M+H]+ 241/243. 1H-NMR: (DMSO-d6, 300 MHz): 13.3 (br, 1H), 9.19 (dd, J=7.5, 0.9 Hz, 1H), 8.25 (s, 1H), 8.15 (d, J=1.5 Hz, 1H), 7.39 (dd, J=7.5, 1.8 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([NH:24][C:25](=[O:34])[C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=1[Cl:33])[CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23])[CH:10]=[CH:9]2.[OH-].[Na+]>C1COCC1>[Cl:33][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([Cl:32])[C:26]=1[C:25]([NH:24][C@@H:4]([CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([C:16]1[C:17]([Cl:23])=[CH:18][CH:19]=[CH:20][C:21]=1[Cl:22])[CH:10]=[CH:9]2)[C:3]([OH:35])=[O:2])=[O:34]
Reactant: COC(=O)[C@H](Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)c1c(Cl)cncc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)C(=O)O)c1c(Cl)cncc1Cl
Yield: 68.3 %

Procedure:
Methyl-(2S)-2-[(3,5-dichloroisonicotinoyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate (410 mg, 0.75 mmol) was dissolved in THF (2 ml) and added drop wise over 3 hrs to a stirred aqueous solution of NaOH (2 M, 2.5 ml). After addition was complete the reaction was stirred at RT for 1 hour, before the THF was removed in vacuo. The resulting slurry was diluted with water (6 ml) and acidified to pH-4 using HCl (12 M). The resultant precipitate was collected by filtration, washed with water (15 ml) and dried overnight in vacuo (40° C.) to yield the desired product as a white powder (274 mg, 68%). LCMS M+1 (535, 537), M−1 (534, 536) Retention Time 3.39 min, 1H NMR, 300 Mz, d6-DMSO-13.00 (1H, brs), 9.40 (1H, d), 8.65 (2H, s), 8.42 (1H, d), 7.98 (1H, d), 7.94 (1H, d), 7.78 (1H, dd), 7.65 (2H, d), 7.54 (2H, m), 4.90 (1H, m), 3.45 (1H, brs), 3.20 (1H, dd). Chiral HPLC 97% ee Retention time 6.29 min (Column-CHIRALPAK AD 250*4.6 mm, 10 m; Solvent A 1-Propanol+0.1% TFA, Solvent B Isohexane; Isocratic 20% A: 80% B; Temperature 40° C.; Run Time 15 min; Detection 280 nM).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][C:19]1=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]#[CH:33]>CC#N>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:33][C:32]#[CH:31])[CH2:20][C:19]1=[O:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1c(CN2CCNCC2=O)cc2cnccc21
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCN1CCN(Cc2cc3cnccc3n2C(=O)OC(C)(C)C)C(=O)C1
Temperature: 25 °C
Yield: 70.6 %

Procedure:
A solution containing 2-(2-oxo-piperazin-1-ylmethyl)-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (4.3 g, 13.0 mmol), EXAMPLE 69, in CH3CN (250 mL) is cooled to 0° C. Potassium carbonate (1.98 g, 14.3 mmol) is added to the reaction mixture followed by propargyl bromide (1.55 g, 13.0 mmol). The mixture is slowly warmed to ambient temperature and maintained until complete consumption of starting material is observed by TLC (approx. 8 h). The mixture is concentrated to dryness and then partitioned between aqueous NaHCO3 (200 mL) and CH2Cl2 (200 mL) and the layers are separated. The aqueous phase is extracted twice with CH2Cl2 (100 mL) and the combined organic phase is washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue is purified by flash silica gel chromatography (CH2Cl2 to 5% MeOH/CH2Cl2) to provide 3.38 g (70%) of the title compound as a pale yellow solid. 1H NMR (300 MHz, CDCl3) δ1.69 (s, 9H), 2.34 (t, J=2.4 Hz, 1H), 2.89 (m, 2H), 3.42 (s, 2H), 3.45 (d, J=2.4 Hz, 2H), 3.52 (m, 2H), 4.95 (d, J=1.4 Hz, 2H), 6.42 (br s, 1H), 7.88 (dd, J=5.8, 0.8 Hz, 1H), 8.41 (d, J=5.8 Hz, 1H), 8.78 (d, J=0.8 Hz, 1H) ppm; MS (EI): m/z 368 (M+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]>CO.C(OCC)(=O)C.[Pd]>[CH3:1][S:2]([C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CS(=O)(=O)c1ccc(Oc2ccc(N)cc2)cc1
Reaction time: 3 h
Yield: 99.9 %

Procedure:
4-(4-Methanesulfonyl-phenoxy)nitrobenzene (28 g, 95 mmol) prepared in Step B was dissolved in methanol (500 mL) and ethyl acetate (500 mL). 10% Pd/C (1.0 g) was added thereto, and the mixture was stirred under hydrogen gas of atmospheric pressure for 3 h. After completion of the reaction, the reaction mixture was filtered through a cellite, washed with methanol, concentrated under reduced pressure, and dried over anhydrous magnesium sulfate to give the title compound (25 g, Yield 100%).
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)Cl>[C:4]1([CH2:3][CH2:2][C:1]([O:11][CH3:12])=[O:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)/C=C/c1ccccc1
Solvent: ClCCl
Product: COC(=O)CCc1ccccc1
Reaction time: 48 h
Yield: 97.4 %

Procedure:
According to the general procedure, a solution of methyl trans cinnamate (49 mg, 0.30 mmol) and rac-32 (9.8 mg, 0.0062 mmol, 2.0 mol %) in CH2Cl2 (3 mL) was pressurized with H2 to 62 bar and stirred for 48 h. Filtration of the reaction mixture and evaporation of the solvent gave 40 as a clear oil (48 mg, 95%). 1H NMR26 (300 MHz, CDCl3): δ 7.33-7.19 (m, 5H), 3.68 (s, 3H), 2.97 (t, 2H, J=8.1 Hz), 2.65 (t, 2H, J=7.8 Hz); 13C NMR (75.5 MHz, CDCl3): δ 173.4, 140.6, 128.6, 128.4, 126.4, 51.7, 35.8, 31.0.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]([CH3:17])([CH3:16])[CH2:9]2)=[CH:4][CH:3]=1.O.[H][H]>C(O)C.[Ru]>[OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH:8]2[CH2:9][C:10]([CH3:17])([CH3:16])[NH:11][C:12]([CH3:15])([CH3:14])[CH2:13]2)[CH2:4][CH2:3]1
Reactant: CC1(C)CC(c2ccc(O)cc2)CC(C)(C)N1
Reactant: [H][H]
Agent: [Ru]
Solvent: O
Solvent: CCO
Product: CC1(C)CC(C2CCC(O)CC2)CC(C)(C)N1

Procedure:
10 parts of 4-(4'-hydroxyphenyl)-2,2,6,6-tetramethylpiperidine were dissolved in 150 parts of ethanol and treated with 30 parts of water, the mixture being warmed to maintain solution. The solution was then hydrogenated using 3 parts of ruthenium on carbon (5%) catalyst at 125° C and 100 atmospheres of hydrogen. The catalyst was separated and the solvent evaporated under reduced pressure. The residue was dissolved in chloroform, dried with magnesium sulphate and evaporated under reduced pressure. The residue was crystallised from petroleum (b.p. 80°-100° C) to yield the desired product melting at 145°-150° C and having the following elemental analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:19][CH2:18][C@H:17]([F:20])[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:27])[CH3:13])[C:9]([N:15]2[CH2:19][CH2:18][C@H:17]([F:20])[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CC[C@H](F)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CC[C@H](F)C1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[(3S)-3-fluoropyrrolidin-l-yl]quinolin-7-yl}ethanone (0.10 g, 0.34 mmol) and ammonium acetate (0.263 g, 3.42 mmol) in methanol (1.5 mL) and acetonitrile (1.5 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, sodium cyanoborohydride (0.064 g, 1.0 mmol). The reaction was heated at 65° C. overnight, cooled to room temperature and quenched with sat. NaHCO3 solution and extracted with Ethyl acetate. The combined organic layers were dried over MgSO4, concentrated and purified on a preparative LCMS (pH=10) to give the desired product. LCMS calculated for C15H18ClFN3 (M+H)+: m/z=294.1; Found: 294.0.
Reaction SMILES: O1CCOCC1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH:18]3[CH:16]([O:17]3)[CH2:15]2)=[CH:10][CH:9]=1.[N-:20]=[N+]=[N-].[Na+].[Cl-].[Na+]>C(OCC)(=O)C>[NH2:20][C@@H:18]1[CH2:19][N:14]([C:11]2[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=2)[CH2:15][C@H:16]1[OH:17]
Reactant: Fc1ccc(N2CC3OC3C2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N[C@@H]1CN(c2ccc(F)cc2)C[C@H]1O
Temperature: 100 °C
Reaction time: 7 h
Yield: 74.3 %

Procedure:
To a 1,4-dioxane (3 mL) solution of 3-(4-fluorophenyl)-6-oxa-3-azabicyclo[3.1.0]hexane (75 mg), an aqueous (1 mL) solution of sodium azide (82 mg) was added, and the reaction solution was agitated at 100° C. for 7 hours. After the reaction solution was allowed to be cooled to room temperature, ethyl acetate and a saturated sodium chloride solution were added to the reaction solution, and the organic layer was partitioned. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 10% Palladium carbon (48% water content, 10 mg) was added to an ethanol (5 mL) solution of the residue, and the reaction solution was agitated at room temperature under a hydrogen current for 3 hours. 61 mg of the title compound was obtained by carrying out celite filtration of the reaction solution, and condensing the filtrate under reduced pressure. The physical properties of the compound are as follows.
Reaction SMILES: Br[CH:2]([C:4]1[N:13]([CH3:14])[C:12](=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:5]=1)[CH3:3].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(#N)C>[CH3:19][S:16]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([CH:2]([N:34]1[CH2:33][CH2:32][N:31]([S:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=3)(=[O:30])=[O:29])[CH2:36][CH2:35]1)[CH3:3])[N:13]([CH3:14])[C:12]2=[O:15])(=[O:18])=[O:17]
Reactant: CC(Br)c1nc2ccc(S(C)(=O)=O)cc2c(=O)n1C
Reactant: COc1ccc(S(=O)(=O)N2CCNCC2)cc1
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)N2CCN(C(C)c3nc4ccc(S(C)(=O)=O)cc4c(=O)n3C)CC2)cc1
Temperature: 80 °C
Yield: 51.9 %

Procedure:
In a test tube containing of 2-(1-Bromo-ethyl)-6-methanesulfonyl-3-methyl-3H-quinazolin-4-one (40.0 mg, 0.12 mmol) in acetonitrile (2 ml) was added KI (28.0 mg, 0.18 mmol), and (1-(4-Methoxy-benzenesulfonyl)-piperazine (39.6 mg, 0.18 mmol). The reaction was heated at 80° C. for 18 hours. The solution was concentrated under reduced pressure. The residue was partitioned between water (2 ml) and dichloromethane (5 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The solvent was removed under vacuum. The resulting residue was dissolvent in DMSO (2 ml) and purified by HPLC (Gilson-215, 0.035% TFA in acetonitrile and 0.05% water as mobile phase). The product was collected and dried under reduced pressure to give 6-Methanesulfonyl-2-{1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-3-methyl-3H-quinazolin-4-one (Yield 32.4 mg, 55.2%). 1H NMR (400 MHz, CDCl3): δ 1.82 (d, 3H, J=7.07 Hz), 3.12 (s, 3H), 3.64-3.40 (m, 4H), 3.70 (s, 3H), 4.00-3.86 (m, 7H), 4.89 (q, 1H, J=14.40, 6.03 Hz), 7.05 (d, 2H, J=9.09 Hz), 7.68 (d, 2H, J=9.09, Hz), 7.84 (d, 1H, J=8.84 Hz), 8.25 (dd, 1H J=8.84, 2.02 Hz), 8.82 (d, 1H, J=2.02 Hz). MS m/z calc. 490.1, found (ESI); 491.2 (M+1)+. Retention time 2.17 minutes.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[NH2:20]C1C=CC2OC(=O)N(CC(N)=O)C=2C=1>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH2:20])[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: NC(=O)Cn1c(=O)oc2ccc(N)cc21
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: Nc1ncc(F)c(Nc2ccc3c(c2)OCCO3)n1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 2-chloro-5-fluoro-N4-(3,4-ethylenedioxyphenyl)-4-pyrimidineamine with 2-[5-amino-2-oxo-1,3-benzoxazol-3(2H)-yl)acetamide gave N2-15-(N-aminocarbonylmethylene-2-oxo-1,3-oxazol-3(2H)-yl)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrmidinediamine. 1H NMR (CD3OD): δ 7.95 (d, 1H, J=8.4 Hz), 7.32 (dd, 1H, J=2.4 and 8.1 Hz), 7.24 (d, 1H, J=2.4 Hz), 7.19 (m, 2H), 6.95 (dd, 1H, J=2.7 and 9 Hz), 6.80 (d, 1H, J=9 Hz), 4.51 (s, 2H), 4.21 (m, 4H).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[N:16]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:51]=[CH:50][C:33]([O:34][CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]3)=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>CN(C=O)C>[F:21][C:20]([F:23])([F:22])[C:17]1[N:15]2[N:16]=[C:11]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]4[CH:51]=[CH:50][C:33]([O:34][CH2:35][CH2:36][N:37]5[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])[CH2:39][CH2:38]5)=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)[CH:12]=[CH:13][C:14]2=[N:19][N:18]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: CC(C)(C)OC(=O)N1CCN(CCOc2ccc(C3CCNCC3)cc2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(CCOc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
DIPEA (2.348 mL, 13.48 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Monatsh. Chem. 1972, 103, 1591) (2 g, 8.99 mmol) and tert-butyl 4-[2-[4-(piperidin-4-yl)phenoxy]ethyl]piperazine-1-carboxylate (3.68 g, 9.44 mmol) in DMF (30 mL). The resulting solution was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature and the solvents evaporated to dryness. The resulting solid was triturated with water then collected by is filtration, washed with ether and dried to afford tert-butyl 4-[2-[4-[1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]ethyl]piperazine-1-carboxylate (5.02 g, 97%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])[CH:3]=1.[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC(Cl)(Cl)Cl>[Br:20][CH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][S:13]([C:16]([F:19])([F:17])[F:18])(=[O:14])=[O:15])[CH:3]=1
Reactant: COC(=O)c1ccc(C)cc1OS(=O)(=O)C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1OS(=O)(=O)C(F)(F)F
Yield: 55 %

Procedure:
A solution of methyl 4-methyl-2-trifluoromethylsulfonyloxybenzoate (23.79 g; 7.9 mmol), N-bromosuccinimide (14.19 g; 7.9 mmol), 2,2-azobis (2′-methylproprionitrile) (0.5 g; 3 mmol) and benzoylperoxide (0.5 g; 2 mmol) in tetrachloromethane (250 ml) was heated at reflux for 6 hours. The solid was filtered and the filtrate evaporated to dryness to give methyl 4-bromomethyl-2-trifluoromethylsulfonyloxybenzoate. Yield=55%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O>C(COC)OC>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:18][CH:19]=1)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: COCCOC
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccc(-c2ccccc2)cc1
Reaction time: 0.08 h

Procedure:
Similarly to a method reported in Tetrahedron Lett., 1991, 923, to a stirred solution of (S)-2-t-butoxycarbonylamino-3-(biphenyl-4-yl)-propionic acid (3 g, 8.8 mmol) in dimethoxyethane (DME; 8 mL) at -15° is added N-methylmorpholine (0.975 mL, 8.8 mmol), followed by isobutyl chloroformate (1.2 mL, 9.25 mmol). After 5 minutes, the precipitate is removed by filtration and washed with DME (5 mL). The filtrate is cooled to 0° and treated at once with a freshly prepared clear solution of sodium borohydride (500 mg) in water (5 mL). After the strong evolution of gas has ceased, water (100 mL) is added and the product is extracted in ethyl acetate. The organic layer is separated, dried over magnesium sulfate, decolorized with activated charcoal, filtered and concentrated in vacuo to yield (S)-2-(t-butoxycarbonylamino)-3-(biphenyl-4-yl)-propan-1-ol as a white solid, m.p.: 116°, [α]D =-22.90 (c 0.74, MeOH).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH:7]([CH3:20])[CH:8]([O:14][CH:15]([O:17][CH2:18][CH3:19])[CH3:16])[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])(=O)C.C(=O)([O-])[O-].O>CO>[CH3:20][CH:7]([CH:8]([O:14][CH:15]([O:17][CH2:18][CH3:19])[CH3:16])[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[CH2:6][CH2:5][OH:4]
Reactant: CCOC(C)OC(CC=C(C)C)C(C)CCOC(C)=O
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O
Product: CCOC(C)OC(CC=C(C)C)C(C)CCO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 8-acetoxy-2,6-dimethyl-5-[(1-ethoxyethoxy)]-2-octene (0.5 mmole), saturated potassim carbonate solution (9 ml), water (6 ml) and methanol (100 ml) is stirred for 3 hours at room temperature. Most of the methanol is removed in vacuo and the residue is treated with ethyl acetate (500 ml) and water (200 ml). The organic phase is dried (Na2SO4) and evaporated in vacuo to give the crude product. This material is further purified by column chromatography on silica gel (25 g, 15% ethyl acetate in hexane) to give 3,7-dimethyl-4-[(1-ethoxyethoxy)]-6-octen-1-ol as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([N+:14]([O-])=O)=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([NH2:8])=[O:7]>[Pd].C(O)C>[NH2:14][C:9]1[CH:10]=[C:11]([O:12][CH3:13])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OC
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)c(C(N)=O)cc1OC
Reaction time: 1 h

Procedure:
1.5 g of 10% palladium on charcoal was added to a suspension of 7.5 g (33 mmol) of 3,4-dimethoxy-6-nitrobenzamide in 200 ml of ethanol, and the mixture was hydrogenated for 1 hour under a pressure of 45 psi. After removal of the catalyst, the filtrate was concentrated in vacuo and the residue triturated with 80 ml of ether/petroleum ether 1:1. The crystals were filtered, washed with petroleum ether and dried in vacuo; yield: 6.15 g, melting point 142.7° C.
Reaction SMILES: [CH2:1]([N:5]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:7]([CH3:17])=[N:6]1)[CH2:2][C:3]#[CH:4].Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[C:7]([CH3:17])=[N:6][N:5]([CH2:1][CH2:2][C:3]#[C:4][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:9]=2)=[CH:15][CH:14]=1
Reactant: C#CCCn1nc(C)c(-c2ccc(F)cc2)n1
Reactant: Brc1ccccn1
Product: Cc1nn(CCC#Cc2ccccn2)nc1-c1ccc(F)cc1
Yield: 86.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-(but-3-ynyl)-4-(4-fluorophenyl)-5-methyl-2H-1,2,3-triazole (265 mg, 1.16 mmol) and 2-bromopyridine (201 mg, 1.27 mmol). Reaction time: 2 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 306 mg (1.00 mmol, 86%) of 2-(4-(4-(4-fluorophenyl)-5-methyl-2H-1,2,3-triazol-2-yl)but-1-ynyl)pyridine as a brown oil.