Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].O.[CH:13](O)([CH3:15])[CH3:14]>>[Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH:13]([CH3:15])[CH3:14])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: CC(C)O
Solvent: O
Product: CC(C)OC(=O)c1cnc(Cl)c(Cl)c1

Procedure:
5,6-Dichloronicotinic acid (2.00 g, 10.4 mmol) was dissolved in 50 mL isopropanol to which was added BF3 -diethyl etherate (3.84 mL, 3 eq). The solution was refluxed overnight. When cooled, the solution was poured into 100 mL water and extracted with Et2O (2×100 mL) The organics were collected, washed with water, brine, 1.0 N NaOH, dried over MgSO4, and concentrated to give isopropyl 5,6-dichloronicotinate (0.62 g) as a cream solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11]O)=[N:4][CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].S(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[ClH:1].[Cl:1][C:2]1[C:3]([CH2:11][Cl:15])=[N:4][CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9]
Reactant: O=S(Cl)Cl
Reactant: COc1c(C)cnc(CO)c1Cl
Solvent: ClC(Cl)Cl
Product: COc1c(C)cnc(CCl)c1Cl
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The above (3-chloro-4-methoxy-5-methylpyridin-2-yl)methanol (530 mg) was dissolved in 20 ml of chloroform, and thionyl chloride (1.03 ml) was then added dropwise to the solution under cooling on ice. The resulting mixture was stirred at room temperature for 3 hours. Thereafter, the reaction solution was concentrated, and it was then washed with a mixed solvent of ether-hexane, so as to obtain the title compound (410 mg) as a solid.
Reaction SMILES: [CH:1]([C@@:3]1([CH2:9][OH:10])[O:7][C:6](=[O:8])[CH2:5][CH2:4]1)=[CH2:2].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C.[Ag-]=O>[CH2:11]([O:10][CH2:9][C:3]1([CH:1]=[CH2:2])[O:7][C:6](=[O:8])[CH2:5][CH2:4]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: C=C[C@]1(CO)CCC(=O)O1
Agent: O=[Ag-]
Solvent: CN(C)C=O
Product: C=CC1(COCc2ccccc2)CCC(=O)O1
Yield: 80.1 %

Procedure:
A solution of 2.13 (0.140 g, 1.0 mmol) in DMF (5 mL) was stirred with silver(I) oxide (0.232 g, 1.0 mmol) and benzyl bromide (0.3 mL, 2.5 mmol) for 5 days at room temperature. The reaction mixture was filtered, diluted with water, and extracted thrice with EtOAc. The organic layer was washed with water, dried (Na2SO4), and concentrated. The residue was purified by flash column chromatography over silica gel with hexanes:EtOAc (2:1) as eluant to give the intermediate 5-[(benzyloxy)methyl]-5-vinyl-tetrahydro-2-furanone (0.186 g, 80%) as an oil; [α]22D -29.68° (c 3.08, CHCl3); IR (neat) 1772 (C=O) and 1653 cm-1 (C=C); 1H NMR (CDCl3) δ 2.05 (m, 1 H, H-4a), 2.35-2.74 (m, 3 H, H-4b, H-3), 3.55 (AB q, J=10.4 Hz, 2 H, CH2OH), 4.60 (AB q, J=12.0 Hz, 2 H, CH2OCH2Ph), 5.22 (dd, J=10.9, 0.5 Hz, 1 H, CH=CHH), 5.37 (dd, J=17.3, 0.6 Hz, 1 H, CH=CHH), 5.88 (dd, J=17.3, 10.9 Hz, 1 H, CH=CH2); 13C NMR (CDCl3) δ 28.88, 29.37, 73.66, 74.50, 86.81, 115.73, 127.58, 127.80, 128.46, 136.72, 137.65, 176.82. Anal. Calcd for C14H16O3 : C, 72.39; H, 6.94. Found: C, 72.62; H, 6.92.
Reaction SMILES: O=[CH:2][CH2:3][C:4]1([C:18]([O:20][CH3:21])=[O:19])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[CH:10]=2)[CH2:5]1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1.CC(O)=O.C([BH3-])#N.[Na+]>CO>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][CH2:2][CH2:3][C:4]2([C:18]([O:20][CH3:21])=[O:19])[CH2:13][CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[CH:10]=3)[CH2:5]2)=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc2c(c1)CCC(CC=O)(C(=O)OC)C2
Reactant: COc1ccc(CN)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)CCC(CCNCc1ccc(OC)cc1)(C(=O)OC)C2
Reaction time: 18 h

Procedure:
A solution of (1)-dimethyl 2-(2-oxoethyl)-1,2,3,4-tetrahydronaphthalene-2,6-dicarboxylate from Step C (436 mg, 1.50 mmol), 4-methoxybenzylamine (247 mg, 1.80 mmol), and AcOH (0.206 mL, 3.60 mmol) was stirred in MeOH (10 mL) at ambient temperature for 5 min, then sodium cyanoborohydride (113 mg, 1.80 mmol) was added. After 18 h, the mixture was concentrated in vacuo, and the residue was partitioned between saturated aqueous NaHCO3 (10 mL) and CH2Cl2 (20 mL). The aqueous phase was extracted further with CH2Cl2 (10 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z=412 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([NH:8][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)CBr
Reactant: Nc1ccccc1
Product: CCOC(=O)CNc1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
To a 250 mL round-bottom flask equipped with addition funnel and argon inlet was added 50 mL of aniline III which was stirred mechanically at 0° C. under argon atmosphere. Ethyl bromoacetate, 25 mL (224 mmol) was added in dropwise fashion over 60 min. The mixture slowly solidified and was allowed to stand unstirred at -25° C. for 18 hours. The solid was chipped from the flask and partitioned between dichloromethane (CH2Cl2) and water. The aqueous layer was made basic with 20 mL 50 NaOH solution and extracted with CH2Cl2. The combined organic layers were washed well with H2O, dried over MgSO4 and concentrated. The residue was crystallized from hexane containing a trace of CH2Cl2. Total yield was 28 g (156 mmol, 70% yield) based on ethyl bromoacetate used. mp. 54°-55° C., 1H-NMR (CDCl3) ppm δ7.19 (t, 2H, J= 7 Hz), 6.76 (t, 1H, J=7 Hz), 6.60 (d, 1H, J=7 Hz), 4.24 (q, 2H, J=7 Hz), 3.89 (S, 2H), 1.29 (t, 3H, J=7 Hz; IR (KBr) 3420, 1742, 1610, 1520, 1220 cm-1.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.Cl.CC1C=CC(S(O)(=O)=O)=CC=1>CCOCC.C1C=CC=CC=1>[C:11]1([C:7]2[S:6][CH:10]=[CH:9][CH:8]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: c1ccsc1
Reactant: O=C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: c1ccccc1
Solvent: CCOCC
Product: C1=C(c2cccs2)CCCC1
Reaction time: 16 h

Procedure:
n-Butyllithium (40.7 ml, 1.5 M) was added dropwise to a stirred solution of thiophene (5 g) in dry ether (50 ml) and the mixture heated under reflux for 30 min. After cooling to -78°, cyclohexanone (6.21 ml) in dry ether (30 ml) was added dropwise and the temperature allowed to rise to ambient. After 1h 2N hydrochloric acid (80 ml) was added and stirring continued for 16h. The organic layer was separated and the aqueous layer extracted with ether (2×40 ml). The combined extracts were washed with water, dried (MgSO4), filtered and evaporated to give an oil, which was dissolved in benzene (50 ml) and heated under reflux in the presence of PTSA for 0.75h. the cooled solution was washed twice with 8% NaHCO3 solution and the aqueous solution extracted with ether (2×40 ml), dried (MgSO4) filteed and evaporated to give the title compound as an oil (9.83 g). TLC(F) Rf 0.73
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[NH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:31]1[CH:36]=[C:35]([NH2:37])[N:34]=[C:33]([NH2:38])[N:32]=1.CO>O1CCOCC1>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[NH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:31]4[N:32]=[C:33]([NH2:38])[N:34]=[C:35]([NH2:37])[CH:36]=4)=[CH:17][CH:16]=3)=[N:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(C(F)(F)F)c3)[nH]2)cc1
Reactant: Nc1cc(Cl)nc(N)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cc(Oc2ccc(-c3nnc(Nc4cccc(C(F)(F)F)c4)[nH]3)cc2)nc(N)n1

Procedure:
4-(5-{[3-(trifluromethyl)phenyl]amino}-4H-1,2,4-triazol-3-yl)phenol (160 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous dioxane in 2-5 mL microwave vial (Personal Chemistry). Solid Cs2CO3 (163.0 mg, 0.5 mmol) was added, followed by 4-chloro-2,6,-diaminopyrimidine (79.5 mg, 0.55 mmol). The vial was capped and microwaved at 200° C. for 20 min. Then ca. 3 mL of MeOH was added to dissolve the formed suspension, the solution was transferred into a round-bottom flask and solvent was removed in vacuo. The residue was re-dissolved in 3 mL of DMF, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetontrile/water system with 0.01% of TFA.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([C:18]1[N:23]=[CH:22][C:21](Br)=[CH:20][N:19]=1)[C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(=[O:36])C.[K+].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.O>CS(C)=O.C(OCC)(=O)C>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([C:18]1[N:23]=[CH:22][C:21]([OH:36])=[CH:20][N:19]=1)[C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)[O-]
Reactant: O=C(OCc1ccccc1)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: O=C(OCc1ccccc1)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(O)cn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
Benzyl (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-carbamate (11.5 g), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium dichloromethane complex (3.51 g), potassium acetate (6.33 g) and bis(pinacolato)diboron (10.9 g) are dissolved in dimethylsulfoxide (75 ml), and the mixture is heated to 80° C. under nitrogen atmosphere and stirred for 30 minutes. The reaction solution is cooled to room temperature and thereto are added water and ethyl acetate, and the insoluble materials are removed by filtration through Celite™, and the mixture is separated and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (100 ml) and thereto is added dropwise a 30% aqueous hydrogen peroxide solution (50 ml) under ice-cooling and the mixture is stirred for 1 hour. Thereto is added a saturated aqueous sodium thiosulfate solution under ice-cooling to consume the excess hydrogen peroxide, followed by an addition of water and ethyl acetate, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give benzyl (3,5-bis-trifluoromethyl-benzyl)-(5-hydroxy-pyrimidin-2-yl)-carbamate (9.70 g). MS (m/z): 472 [M+H]+
Reaction SMILES: [O:1]([CH:8]([CH3:16])[CH2:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C>O1CCCC1>[O:1]([CH:8]([CH3:16])[CH2:9][N:10]1[CH2:11][CH2:12][N:13]([CH2:18][CH2:19][C:20]2[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=2)[CH2:14][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CN1CCNCC1)Oc1ccccc1
Reactant: CCOC(=O)c1ccc(CCBr)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(CCN2CCN(CC(C)Oc3ccccc3)CC2)cc1

Procedure:
A mixture of 8.2 g. (37 mmole) 1-(2-phenoxypropyl)-piperazine, 9.57 g. (37 mmole) ethyl 4-(2-bromoethyl)-benzoate, 3.77 g. (37 mmole) triethylamine and 100 ml. anhydrous tetrahydrofuran is heated for 36 hours at reflux temperature and then evaporated. The residue is taken up in diethyl ether and the hydrochloride precipitated from this solution with hydrogen chloride-containing diethyl ether to give 14.7 g. (84% of theory) of the desired compound as a hydrochloride; m.p. 232° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH2:14][N:13](C(=O)C(F)(F)F)[CH2:12][CH2:11]2.[Br:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34]=1[CH2:33][N:32](C(=O)C(F)(F)F)[CH2:31][CH2:30]2>CO.O.CCOC(C)=O>[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH2:14][NH:13][CH2:12][CH2:11]2.[Br:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34]=1[CH2:33][NH:32][CH2:31][CH2:30]2
Reactant: O=C(N1CCc2cc(Br)ccc2C1)C(F)(F)F
Reactant: O=C(N1CCc2cccc(Br)c2C1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: Brc1ccc2c(c1)CCNC2
Product: Brc1cccc2c1CNCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Potassium carbonate (66.2 mmol) was added in one portion to a solution of 6-bromo-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline and 8-bromo-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline (17.6 mmol) in MeOH (130 mL) and water (45 mL). The reaction mixture was allowed to stir at rt overnight and then diluted with EtOAc (150 mL). The mixture was washed with brined, dried over Na2SO4, filtered, and concentrated to give 6-bromo-1,2,3,4-tetrahydroisoquinoline and 8-bromo-1,2,3,4-tetrahydroisoquinoline (5.0 g, 100%) as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[N:15]=[C:14]3[C:10]([N:11]=[C:12]([O:23]C)[N:13]3[CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:9]([NH2:25])[N:8]=2)[CH2:3][CH2:2]1.Cl.[OH-].[Na+]>CO.O1CCOCC1.O>[NH2:25][C:9]1[N:8]=[C:7]([O:6][CH2:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:23])[N:13]2[CH2:16][CH:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: COc1nc2c(N)nc(OCCC3CC3)nc2n1CC1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: Nc1nc(OCCC2CC2)nc2c1[nH]c(=O)n2CC1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.8 %

Procedure:
2-[(2-Cyclopropylethyl)oxy]-8-(methoxy)-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (0.1259 g) was dissolved in methanol (5 mL) and added 4N hydrogen chloride in 1,4-dioxane (2 mL). The reaction was stirred at room temperature for 4 hours. The reaction mixture was evaporated under reduced pressure to give a solid which was then suspended in water (1 mL) and small quantity of methanol (2-3 mL). This was then neutralised (to pH 7) by the addition of 2N sodium hydroxide. The suspension was evaporated to near dryness under reduced pressure and then suspended the solid in water (3 mL). The solid was filtered off under suction and washed with a few drops of methanol before being air-dried under suction. This material was then dried to constant weight under vacuo at 50° C. to give the title compound (94 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C@H:4]([CH3:7])[CH2:5][OH:6].C(Cl)(Cl)(Cl)Cl.ClC(Cl)(Cl)C(=N)O[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.FC(F)(F)S(O)(=O)=O>C1CCCCC1>[CH2:18]([O:6][CH2:5][C@H:4]([CH3:7])[C:3]([O:2][CH3:1])=[O:8])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: COC(=O)[C@H](C)CO
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)[C@@H](C)COCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
An oven dried 1 L single-necked round bottom flask was equipped with a magnetic stir bar and then charged sequentially with 15.948 g (0.135 mol) of (R)-(−)-methyl-3-hydroxy-2-methylpropanoate, carbon tetrachloride (150 mL), cyclohexane (300 mL), and 35.796 g (0.142 mol) of benzyl 2,2,2-trichloroacetimidate. Trifluoromethanesulfonic acid (0.8 mL; 9.0 mmol) was added to the solution and the resulting mixture was stirred for 16 h at room temperature under an N2 atmosphere. The reaction mixture was then filtered and the filtrate concentrated in vacuo. The residue was redissolved in 150 mL EtOAc and extracted with saturated aqueous NaHCO3 (1×100 mL). The organic layer was washed with saturated NaCl, dried (MgSO4), filtered and evaporated. The residual oil was purified on a silica gel flash chromatography column eluted with 10% EtOAc-hexane. The purified fractions were combined and evaporated in vacuo to afford 20.787 (74%) of the title compound as an oil. MS (CI): m/e=209 (M+1).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH2:15]([CH:18]1[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]1)[C:16]#[CH:17]>>[CH2:15]([CH:18]1[CH2:23][CH2:22][N:21]([C:2]([O:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=2)=[O:3])[CH2:20][CH2:19]1)[C:16]#[CH:17]
Reactant: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Product: C#CCC1CCN(C(=O)Oc2ccc(C(=O)OC)cc2)CC1

Procedure:
4-(methoxycarbonyl)phenyl chloroformate (5.00 g, 23.3 mmol) was added to a solution of tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (4.00 g, 17.9 mmol) according to general procedure 1. Yield=5.54 g, 99%. m/z MH+=302.02. HPLC rt=10.8 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:18][CH3:19])[CH:13]=[CH:14][C:15]=2[OH:17])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].Br[CH2:37][CH2:38][CH2:39][F:40]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:18][CH3:19])[CH:13]=[CH:14][C:15]=2[O:17][CH2:37][CH2:38][CH2:39][F:40])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: FCCCBr
Reactant: COc1ccc(CC2c3c(O)ccc(OC)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Product: COc1ccc(CC2c3c(OCCCF)ccc(OC)c3CCN2CC(=O)NCc2ccccn2)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with 1-bromo-3-fluoro-propane
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([F:15])([F:14])[F:13])[C:5]([F:11])=[CH:6][C:7]=1[N+:8]([O-])=O>C(O)C.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]([C:12]([F:15])([F:13])[F:14])[C:5]([F:11])=[CH:6][C:7]=1[NH2:8]
Reactant: Nc1cc(C(F)(F)F)c(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(F)c(C(F)(F)F)cc1N
Reaction time: 2 h
Yield: 95.9 %

Procedure:
A mixture of 3-amino-6-fluoro-4-nitrobenzotrifluoride (328 mg, 1.45 mmol) and 10% Pd/C (50 mg) in ethanol (15 mL) was hydrogenated for 2 h at 25° C. under 25 psi H2. The catalyst was removed by filtration with celite and the solvent was removed by rota-evaporation to give 270 mg of 3,4-diamino-6-fluorobenzotrifluoride (95%) as a brown solid. 1H NMR (CDCl3): δ 3.432 (br, 4H), 6.469 (d, 1H, J=8.4 Hz); 6.860 (d, 1H, J=6.6 Hz).
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH2:17][C:18]([NH:20][O:21]C(OCC)(C)C)=[O:19])(=[O:15])=[O:14])=[CH:9][CH:8]=1.Cl>CCOC(C)=O>[F:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH2:17][C:18]([NH:20][OH:21])=[O:19])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: CCOC(C)(C)ONC(=O)CN(Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(OCCCCF)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(CN(CC(=O)NO)S(=O)(=O)c2ccc(OCCCCF)cc2)cc1

Procedure:
A solution of 0.22 g of 2-{[4-(4-fluorobutoxy)-benzenesulfonyl](4-methoxy-benzyl)-amino}-N-(1-ethoxy-1-methyl-ethoxy) acetamide in 30 ml of AcOEt is treated with 7 ml of 5N aqueous HCl for 10 min. at r.t. and the mixture is extracted with AcOEt. The combined extracts are washed with sat. NaHCO3 and brine, dried over MgSO4 and concentrated under reduced pressure to give solids which are washed with ether to afford 2-{[4-(4-fluorobutoxy)-benzenesulfonyl]-(4-methoxy-benzyl)-amino]-N-hydroxy-acetamide; NMR (CDCl3): 1.83–2.05 (m, 4H), 3.69 (s, 2H), 3.78 (s, 3H), 4.09 (t, 2H, J=5.56 Hz), 4.25 (s, 2H), 4.48 (t, 1H, J=5.52 Hz), 4.55–4.65 (m, 1H), 6.84 (d, 2H, J=8.56 Hz), 7.00 (d, 2H, J=9.04 Hz), 7.02 (br s, 1H), 7.15 (d, 2H, J=8.56 Hz), 7.77 (d, 2H, J=8.56 Hz), 8.85 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[N:18]=[N:17][C:16]([NH:19]CC4C=CC(OC)=CC=4OC)=[CH:15][CH:14]=3)[CH3:12])=[N:9][N:10]=2)[CH:7]=1.C1(OC)C=CC=CC=1.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[N:18]=[N:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[CH3:12])=[N:9][N:10]=2)[CH:7]=1.[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[N:18]=[N:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[CH3:12])=[N:9][N:10]=2)[CH:7]=1
Reactant: COc1ccc(CNc2ccc(C(C)c3nnc4ccc(Br)cn34)nn2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CC(c1ccc(N)nn1)c1nnc2ccc(Br)cn12
Temperature: 75 °C

Procedure:
A mixture of 6-(1-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-N-(2,4-dimethoxybenzyl)pyridazin-3-amine (750 mg, 1.598 mmol), anisole (0.349 mL, 3.20 mmol), and TFA (1.0 mL, 12.98 mmol) in DCM (5.0 mL) was heated in a microwave on high absorbance for 2 hrs at 75° C. The reaction was stripped to dryness via rotary evaporation, and the resulting oil was treated with Et2O to produce a solid. The solid was filtered and dried under vacuum to provide the title compound, 6-(1-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)pyridazin-3-amine 2,2,2-trifluoroacetate (400 mg, 0.923 mmol, 57.8% yield) as a yellow solid. 1H NMR 48F (400 MHz, DMSO-d6) δ ppm 1.77 (d, J=7.07 Hz, 3 H) 5.05 (d, J=7.07 Hz, 1 H) 7.44 (d, J=9.60 Hz, 1 H) 7.50 (dd, J=9.73, 1.64 Hz, 1 H) 7.73-7.84 (m, 1 H) 7.92 (d, J=9.60 Hz, 1 H) 8.56 (br. s., 2 H) 8.81 (s, 1 H). ESI-MS:m/z 319.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([N:26]4[CH2:30][CH2:29][NH:28][C:27]4=[O:31])[CH:23]=[CH:24][CH:25]=3)[CH2:14][CH2:13]2)[N:3]=1.[CH3:32]I.[H-].[Na+]>C1COCC1>[CH3:32][N:28]1[CH2:29][CH2:30][N:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][CH2:18][N:15]3[CH2:16][CH2:17][N:12]([C:8]4[CH:7]=[CH:6][CH:5]=[C:4]5[C:9]=4[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]5)[CH2:13][CH2:14]3)[CH:21]=2)[C:27]1=[O:31]
Reactant: CI
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N5CCNC5=O)c4)CC3)cccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5CCN(C)C5=O)c4)CC3)cccc2n1
Reaction time: 1 h
Yield: 45 %

Procedure:
To a stirred solution of 1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone (E85) in THF was added methyl iodide (1 eq.), followed by sodium hydride (1.2 eq), and the reaction was stirred for 60 minutes. The mixture was loaded onto an ion-exchange cartridge (SCX-2) and eluted with methanol followed by ammonia in methanol (1M). The basic fractions were concentrated under vacuum and purified by column chromatography (SPE cartridge, Silica) using as eluent a gradient from DCM-methanol (99:1) to DCM-methanol (98:2) affording the final compound (45% yield).