Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[NH2:28][C:29]1[S:30][CH:31]=[CH:32][N:33]=1>ClCCl.O>[CH:1]1([O:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:28][C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(OC1CCCC1)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1nccs1)C(OC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.3 %

Procedure:
A solution of rac-cyclopentyloxy-(3,4-dichloro-phenyl)-acetic acid (52 mg, 0.17 mmol) in dichloromethane (10 mL) was treated with O—(1H-benzotriazolo-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) (72 mg, 0.19 mmol), diisopropyl-ethylamine (0.09 mL, 0.52 mmol) and 2-aminothiazole (26 mg, 0.25 mmol). The resulting brownish-orange solution was then stirred 16 h at 25° C. The reaction was then diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (1×10 mL), 1N sodium hydroxide solution (1×10 mL), 1N hydrochloric acid (1×10 mL) and brine (1×10 mL), then were dried over sodium sulfate and concentrated in vacuo. The product was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) to furnish rac-2-cyclopentyloxy-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide (45 mg, 70% yield) as a white foam: EI-HRMS m/e calcd for C16H16Cl2O2N2S (M+) 370.0309, found 370.0309.
Reaction SMILES: [CH2:1]([OH:7])[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([O:7][CH2:1][CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1)(=[O:18])=[O:17]
Reactant: OCC1CCCO1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCCO1
Temperature: 0 °C
Reaction time: 14 h
Yield: 91.8 %

Procedure:
Tetrahydrofurfuryl alcohol (2.01 g, 19.7 mmol, 1.0 eq.) was dissolved in dichloromethane (100 mL) under an argon atmosphere, cooled to 0° C. and treated sequentially with triethylamine (3.02 mL, 21.7 mmol, 1.1 eq) and methanesulfonyl chloride (1.60 mL, 20.7 mmol, 1.05 eq.). The ice bath was removed and stirring continued for 14 h before the mixture was poured into a separatory funnel containing water. The phases were separated and the organic layer was washed with water (4×), dried on MgSO4, filtered and concentrated in vacuo to yield 3.26 g [92%] of tetrahydrofurfuryl methanesulfonate as a crude pale yellow oil, used in the subsequent displacement step without purification.
Reaction SMILES: [C:1](O)(=[O:31])[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][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH2:1]([OH:31])[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][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO
Temperature: 40 °C

Procedure:
Triacontanol is prepared from triacontanoic acid by suspending 0.1 mol of the acid in 40 ml of anhydrous chloroform followed by the addition of thionyl chloride while maintaining the temperature at 40° C. for 2 hours. Chloroform and excess thionyl chloride were removed in a rotary evaporator, and the resulting acid chloride was reacted with 10 ml of absolute ethanol to form the ester. Excess ethanol was removed in a similar manner, and the ester was dissolved in 100 ml of anhydrous ether.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:33][C:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[CH:36][N:35]=1>>[Cl:33][C:34]1[CH:39]=[C:38]([C:15]2[N:14]=[C:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:8]=3)[N:17]([CH3:18])[C:16]=2[C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[O:20])[CH:37]=[CH:36][N:35]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Product: CCCCCCc1cccc(-c2nc(-c3ccnc(Cl)c3)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 7, [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 2) was reacted with 2-chloro-pyridin-4-yl-boronic acid to give the title compound as light yellow gum. MS: 534.3 (MH+, 1Cl).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[N:9]2)=[CH:4][C:3]=1[O:20][CH3:21].[C:22]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([N:13]([CH3:22])[C:14](=[O:19])[C:15]([F:18])([F:16])[F:17])=[N:9]2)=[CH:4][C:3]=1[O:20][CH3:21]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(-n2ccc(NC(=O)C(F)(F)F)n2)ccc1Br
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(-n2ccc(N(C)C(=O)C(F)(F)F)n2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a mixture of N-(1-(4-bromo-3-methoxyphenyl)-1H-pyrazol-3-yl)-2,2,2-trifluoroacetamide (320 mg, 0.879 mmol) and K2CO3 (146 mg, 1.055 mmol) in DMF (2 mL) was added MeI (202 mg, 1.055 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with Et2O. The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure to give N-(1-(4-bromo-3-methoxyphenyl)-1H-pyrazol-3-yl)-2,2,2-trifluoro-N-methylacetamide (300 mg, MS: 380.0 [M+H+]).
Reaction SMILES: C([O:4][CH2:5][C@:6]1([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[C@H:8]([O:20]C(=O)C)[C@@H:7]1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=O)C.C[O-].[Na+].Cl>CO>[CH2:25]([O:24][C@@H:7]1[C@@:6]([CH2:5][OH:4])([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[C@@H:8]1[OH:20])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(=O)OC[C@]1(COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cn([C@@H]2O[C@](CO)(COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of nucleoside 34 (533 mg, 1.05 mmol) in methanol (5.5 cm3) was added sodium methoxide (287 mg, 5.25 mmol). The reaction mixture was stirred at room temperature for 10 min, then neutralised with dilute hydrochloric acid. The solvent was partly evaporated and extraction was performed with dichloromethane (2×20 cm3). The combined organic phase was washed with saturated aqueous sodium hydrogencarbonate (3×20 cm3) and was dried (Na2SO4). The solvent was removed under reduced pressure to give 35 as a white solid material (476 mg, 97%). δH (CDCl3) 7.47 (1 H, d, J 1.0 6-H), 7.36-7.22 (10 H, m, Bn), 6.07 (1 H, d, J 3.8, 1′-H), 4.87 (1 H, d, J 11.7, Bn), 4.55 (1 H, d, J 11.7, Bn), 4.50-4.32 (4 H, m, Bn, 2′-H, 3′-H), 3.84-3.53 (4 H, m, 5′-Ha, 5′-Hb, 1″-Ha, 1″-Hb), 1.50 (3 H, d, J 1.1, CH3). δC (CDCl3) 164.3 (C-4), 151.3 (C-2), 137.6 (C-6), 136.4, 136.3, 128.8, 128.6, 128.4, 128.3, 127.9 (Bn), 111.1 (C-5), 91.1, 91.0, 88.1 (C-1′, C-3′, C-4′), 77.4 (C-2′), 74.8, 73.8, 71.4, 63.2 (Bn, C-5′, C-1″), 12.0 (CH3). FAB-MS m/z 491 [M+Na]+. Found: C, 63.4; H, 6.0; N, 5.5; C25H28N2O7, ¼ H2O requires C, 63.5; H, 6.1; N, 5.9%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]([Cl:30])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1>C(O)C.Cl.O1CCOCC1.CCOCC>[Cl:30][C:22]1[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=[C:20]([CH:21]=1)[NH:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: Nc1cc(Cl)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Solvent: C1COCCO1
Product: FC(F)(F)c1cc(Cl)cc(Nc2nnc(Cc3ccncc3)c3ccccc23)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A suspension of 27.9 g (109 mMol) of 1-chloro-4-(4-pyridyl-methyl)-phthalazine (Example 67A.1 in WO 98/35958) and 21.4 g (109 mMol) of 5-amino-3chloro-benzotrifluoride (Example 5b) in 500 ml of ethanol and 27.4 ml of 4 N HCl/dioxane is stirred during 3 h a 80° C. After cooling down, the reaction mixture is diluted with 0.3 l of ether, filtrated, and washed with ether. The remaining solid is then taken up in water and EtOAc, brought to alkaline pH by means of NH3 solution, stirred for 15 min at room temperature and then filtered and washed with ether (→raw product). The water layer is removed from the filtrate and extracted twice with ethyl acetate. The organic layers are washed with water and brine, dried over Na2SO4 and evaporated. The residue is combined with the raw product mentioned above, and the solid is dissolved in ethyl acetate and methanol. About 100 g SiO2 are added, followed by evaporation, and the powder is applied onto a silica gel column and eluted with ethyl acetate and subsequently with a mixture of ethyl acetate and methanol (98:2→95:5, v/v). Solving the obtained fractions in ethyl acetate/methanol, partial evaporation and crystallization by addition of ether/hexane leads to the title compound: m.p. 231-232° C.; An. calc. (C21H14N4ClF3) C, 60.81%; H, 3.40%; N, 13.51; %; Cl, 8.55%; F, 13.74%; An meas. C, 60.8%; H, 3.4%; N, 13.5%; Cl, 8.5%; F, 13.8%; 1H-NMR (DMSO-d6) 9.63 (s, HN), 8.60 (d, 1H), 8.56 (s, 1H), 8.44 (d, 2H), 8.39 (s, 1H), 8.16 (d, 1H), 8.03 (t, 1H), 7.97 (t, 1H), 7.43 (s, 1H), 7.32 (d, 2H), 4.63 (s, 2H); FAB-MS (M+H)+=415.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH3:6])=[O:4].[F:7][C:8]([F:15])([F:14])[C:9](=[CH2:13])[C:10](Cl)=[O:11].C(N(CC)CC)C.O>CN(C=O)C>[CH3:1][N:2]1[CH2:13][CH:9]([C:8]([F:15])([F:14])[F:7])[C:10](=[O:11])[N:5]([CH3:6])[C:3]1=[O:4]
Reactant: C=C(C(=O)Cl)C(F)(F)F
Reactant: CNC(=O)NC
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CC(C(F)(F)F)C(=O)N(C)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 49.3 %

Procedure:
A solution of 1,3-dimethylurea (168 mg; 1.9 mmoles) in DMF (2 ml) was cooled to 0° C., and α-trifluoromethylacryloyl chloride (317 mg; 2.0 mmoles) and triethylamine (0.31 ml; 2.2 mmoles) were added dropwise. The mixture was stirred at 0° C. for 2 hours, and then water (20 ml) was added. The mixture was extracted with methylene chloride (20 ml×1, 10 ml×2). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a column chromatography on silica gel (chloroform) to give 197 mg (yield: 49%) of 1,3-dimethyl-5-trifluoromethyl-5,6-dihydrouracil.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[C:17]([Cl:19])[C:16]([F:20])=[CH:15][C:3]=1C(C1C=CC=C([N+]([O-])=O)C=1)=O.OO.BrC1C=C(Cl)C(F)=CC=1C(O)=[O:27].[N+](C1C=C(O)C=CC=1)([O-])=O.[N+](C1C=C(C=CC=1)C(O)=O)([O-])=O>OS(O)(=O)=O.O=S(=O)=O.O>[Br:1][C:2]1[CH:18]=[C:17]([Cl:19])[C:16]([F:20])=[CH:15][C:3]=1[OH:27]
Reactant: O=C(O)c1cc(F)c(Cl)cc1Br
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1cc(F)c(Cl)cc1Br
Agent: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: O
Product: Oc1cc(F)c(Cl)cc1Br

Procedure:
The reaction of 35.8 g (0.1 mol) of 2-bromo-4-chloro-5-fluoro-3'-nitrobenzophenone in 150 g of 5% oleum with 9.7 g (0.2 mol) of 70% hydrogen peroxide solution gives a mixture (29.0 g) of 2-bromo-4-chloro-5-fluorophenol, 2-bromo-4-chloro-5-fluorobenzoic acid, 3-nitrophenol and 3-nitrobenzoic acid (proportions in GC area-%: 14, 35, 36, 15) after dilution (300 g of water), refluxing for 4 h and extraction with methyl tert-butyl ether after removal of the solvent.
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[CH3:13][CH2:14]O>>[O:1]=[C:2]([CH2:6][CH3:7])[C:3]([O:5][CH2:13][CH3:14])=[O:4]
Reactant: CCO
Reactant: CCC(=O)C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(=O)CC
Reaction time: 4 h
Yield: 98 %

Procedure:
To a solution of 2-oxobutanoic acid (6.0 g, 58.8 mmol) in EtOH (100 mL) was added sulfuric acid (1 mL) at room temperature. The resulting mixture was stirred for 4 h under reflux. The solvent was removed, and the residue was diluted with water (50 mL) and the pH was adjusted to ˜7 with a solution of NaOH (1 N). The mixture was extracted with EtOAc (100 mL×3). The combined organic layer was dried over sodium sulfate and concentrated to give ethyl 2-oxobutanoate (7.5 g, 98% yield). ESI MS: m/z 131 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:5]([CH3:8])=[CH:6][CH:7]=1.Cl.CN(C)[CH:16]=[O:17]>[Cu](I)I>[CH3:16][O:17][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(Br)ccc1C
Reactant: CN(C)C=O
Agent: I[Cu]I
Agent: Cl
Product: COC(=O)c1cc(OC)ccc1C

Procedure:
12.6 g of a 28% sodium methylate methanol solution and 4.2 g of copper iodide were added to 5 g of methyl 4-bromo-toluate dissolved in 20 ml of dimethylformamide and the mixture was refluxed under heating for 2 hours. The reaction mixture was adjusted to about pH 2 by adding 1N-hydrochloric acid thereto and extracted with ethyl acetate. and the organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The residue obtained by removing the solvent was applied to silica gel column chromatography to obtain 2.47 g of the title compound.
Reaction SMILES: [CH:1]([C:4]1[C:9]2[N:10]=[C:11]([NH2:13])[S:12][C:8]=2[C:7]([CH3:14])=[C:6]([S:15][C:16]#[N:17])[CH:5]=1)([CH3:3])[CH3:2].Cl[C:19]([O:21][CH3:22])=[O:20].O.CCOC(C)=O>C(Cl)Cl.N1C=CC=CC=1>[CH3:22][O:21][C:19]([NH:13][C:11]1[S:12][C:8]2[C:7]([CH3:14])=[C:6]([S:15][C:16]#[N:17])[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:9]=2[N:10]=1)=[O:20]
Reactant: COC(=O)Cl
Reactant: Cc1c(SC#N)cc(C(C)C)c2nc(N)sc12
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)Nc1nc2c(C(C)C)cc(SC#N)c(C)c2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4-isopropyl-7-methyl-6-thiocyanato-benzothiazol-2-yl-amine (Example L-4; 4.0 g, 17 mmol) dissolved in CH2Cl2 (25 mL) and pyridine (5 mL), was added methyl chloroformate at 0° C. The reaction mixture was stirred at room temperature for 2 hours. H2O was added to the reaction mixture followed by EtOAc (100 mL). The organic layer was washed with 2N HCl, H2O, saturated sodium bicarbonate solution and brine, and was dried (MgSO4). The solvents were evaporated, and the residue was purified by flash chromatography (100% hexanes to 25% EtOAc in hexanes) to give 2-(methyloxycarbonyl)amino-4-isopropyl-7-methyl-6-thiocyanato-benzothiazole. MS (APCI): 322 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]([C:8]2[S:19][C:11]3[N:12]=[C:13]([CH3:18])[N:14]=[C:15]([CH2:16][OH:17])[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:21][S:22]([O:17][CH2:16][C:15]1[C:10]2[CH:9]=[C:8]([CH:5]3[CH2:6][CH2:7][C:2]([CH3:20])([CH3:1])[CH2:3][CH2:4]3)[S:19][C:11]=2[N:12]=[C:13]([CH3:18])[N:14]=1)(=[O:24])=[O:23]
Reactant: Cc1nc(CO)c2cc(C3CCC(C)(C)CC3)sc2n1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(COS(C)(=O)=O)c2cc(C3CCC(C)(C)CC3)sc2n1
Reaction time: 1 h

Procedure:
To a mixture of [6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanol (16.0 g), TEA (10 mL) and DCM (200 mL) was added dropwise MsCl (5.0 mL) at 0° C. for 15 minutes, followed by stirring at the same temperature for 1 hour. To the reaction mixture was added saturated aqueous sodium bicarbonate, followed by extraction with chloroform. The organic layer was washed sequentially with saturated aqueous sodium bicarbonate and brine. To the organic layer were added MgSO4, activated carbon (5 g), and basic silica gel (20 mL), followed by stirring. The mixture was filtered through Celite and then concentrated under reduced pressure to obtain [6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl methanesulfonate (18.9 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:21]=[C:9]2[N:10]=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1.[Cl:22][C:23]1[C:32]([CH:33]=O)=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH3:35])[CH:29]=2)[N:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:22][C:23]1[C:32]([CH2:33][N:18]2[CH2:17][CH2:16][N:15]([C:11]3[N:12]=[C:13]([NH2:14])[N:8]4[N:7]=[C:6]([C:2]5[O:1][CH:5]=[CH:4][CH:3]=5)[CH:21]=[C:9]4[N:10]=3)[CH2:20][CH2:19]2)=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH3:35])[CH:29]=2)[N:24]=1
Reactant: Nc1nc(N2CCNCC2)nc2cc(-c3ccco3)nn12
Reactant: Cc1ccc2nc(Cl)c(C=O)cc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccc2nc(Cl)c(CN3CCN(c4nc(N)n5nc(-c6ccco6)cc5n4)CC3)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
7-Furan-2-yl-2-piperazin-1-yl-pyrazolo[1,5-a][1,3,5]triazin-4-ylamine (0.15 mmol) was dissolved in 4 mL of CH2Cl2 along with 2 eq. of 2-chloro-6-methyl-quinoline-3-carbaldehyde and 25 mL of glacial acetic acid. The reaction mixture was stirred at room temperature for 30 minutes and sodium triacetoxyborohydride (4 eq.) was added in a single portion. The resulting reaction mixture was then stirred at room temperature for 18 hours. It was then concentrated under a stream of N2 and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H NMR (DMSO-d6) δ 7.60 (d, J=1.0 Hz, 1H), 7.28 (br s, 2H), 7.22 (d, J=3.6 Hz, 1H), 7.4-8.0 (m, 4H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H), 6.2 (s, 1H) 3.8 (br s, 2H), 2.2-3.2 (m, 8H), 2.35 (br s, 3 H). MS: m/z: 476 [M+H]+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.Br[C:30]1[CH:31]=[CH:32][C:33]([CH:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[N:34][CH:35]=1.[F-].C([N+:47](CCCC)(CCCC)CCCC)CCC.C(=O)(O)[O-].[Na+]>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCCC1.C1(C)C=CC=CC=1>[O:39]1[CH2:40][CH2:41][CH:36]([C:33]2[N:34]=[CH:35][C:30]([NH2:47])=[CH:31][CH:32]=2)[CH2:37][CH2:38]1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: Brc1ccc(C2CCOCC2)nc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Nc1ccc(C2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After 1.0M toluene-solution (9.8 ml) of lithium bis(trimethylsilyl)amide was added to bis(dibenzylideneacetone)palladium (0) (67 mg) and tri-tert-butylphosphine tetrafluoroborate (118 mg) at 70° C. under an atmosphere of nitrogen, a toluene solution (8.2 ml) of 5-bromo-2-(tetrahydro-2H-pyran-4-yl)pyridine (1.97 g) was added dropwise and stirred at the same temperature for 0.5 hour. Next, the reaction solution was cooled to room temperature, 1.0M tetrahydrofuran-solution (7.0 ml) of tetrabutylammonium fluoride was added and stirred at the same temperature for 1.5 hours. After completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give the titled compound (1.1 g) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]#[N:9].Cl[CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15].[OH-].[Na+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.O>[CH:14]([N:13]([CH:17]([CH3:19])[CH3:18])[CH2:12][CH2:11][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:8]#[N:9])([CH3:16])[CH3:15]
Reactant: N#CCc1ccccn1
Reactant: CC(C)N(CCCl)C(C)C
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C)N(CCC(C#N)c1ccccn1)C(C)C
Temperature: 35 °C

Procedure:
8 g of 2-pyridyl acetonitrile, 8.8 g of 1-chloro 2-diisopropylamino ethane and 0.27 g of benzyltrimethylammonium chloride are mixed, then, maintaining the temperature below 35° C., 35 ml of 50% sodium hydroxide solution are added. The mixture is heated to 35° C. for 5 hours. After cooling, it is diluted with water and extracted with ether. The organic phase is separated and dried over sodium sulfate, then the solvent is evaporated to dryness.
Reaction SMILES: CCCC=S.[CH3:6][CH:7]1[CH2:12][CH:11]([O:13][CH2:14][C:15](Cl)=[O:16])[CH:10]([CH:18]([CH3:20])[CH3:19])[CH2:9][CH2:8]1.C[OH:22]>N1C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:6][CH:7]1[CH2:12][CH:11]([O:13][CH2:14][C:15]([OH:22])=[O:16])[CH:10]([CH:18]([CH3:20])[CH3:19])[CH2:9][CH2:8]1
Reactant: CC1CCC(C(C)C)C(OCC(=O)Cl)C1
Reactant: CO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC=S
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC1CCC(C(C)C)C(OCC(=O)O)C1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
1-L-methoxyacetyloxy-3-methylthiopropene is prepared from 3-methylthiopropionaldehyde, L-menthoxyacetyl chloride, and pyridine catalyst. A 70 mL stainless steel high pressure reactor fitted with a Pyrex glass liner and magnetic stir bar is charged with THF (5 mL), (PPh3)2PdCl2 (0.05 mmol), CH3OH (0.5 mmol), and 1-L-menthoxyacetyloxy-3-methylthiopropene (0.5 mmol). The reactor is sealed, pressurized to 1000 psig with CO, and stirred for 24 hours at 100° C. The product mixture, isolated after removal of gas from the reactor vessel, contains a diastereomeric mixture of methyl 2-L-menthoxyacetyl-4-methylthio-L-2-hydroxybutyrate and methyl 2-L-menthoxyacetyl-4-methylthio-D-2-hydroxybutyrate. The diastereomers are separated by preparative gas chromatography using an SE-30 liquid phase column. Each diastereomer is hydrolyzed separately by treatment with 2N HCI (aq) for 2 hours at 100° C. to give pure L- and D-4-methylthio-2-hydroxybutyric acid (methionine hydroxy analog), methanol, and L-menthoxyacetic acid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][CH:19]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>ClCCl>[CH3:34][S:35]([O:26][CH2:25][CH2:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:7]3[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]3)=[CH:15][N:14]=2)=[CH:23][CH:22]=1)(=[O:37])=[O:36]
Reactant: CC(=O)N1CCN(c2ccc(CCc3ccc(CCO)cc3)nc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCN(c2ccc(CCc3ccc(CCOS(C)(=O)=O)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96 %

Procedure:
To a solution of 2-(4-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}phenyl)ethanol (354.1 mg, 1.002 mmol) in dichloromethane (14 ml) were added triethylamine (0.25 ml, 1.5 mmol) and methanesulfonyl chloride (0.116 ml, 1.67 mmol), and the mixture was stirred at room temperature for 45 mins. Water was added to the reaction mixture, and the mixture was extracted twice with dichloromethane. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness to give 2-(4-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}phenyl)ethyl methanesulfonate (415.0 mg, yield 96.0%) as a slightly brown solid.