Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4]([OH:6])=[O:5].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1.N1CCCCC1.CCCCC>C(OCC)(=O)C>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:2]([CH3:7])([CH3:1])[CH2:3][C:4]([OH:6])=[O:5])=[CH:12][CH:11]=1
Reactant: CC(C)=CC(=O)O
Reactant: COc1ccc(S)cc1
Solvent: CCCCC
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: COc1ccc(SC(C)(C)CC(=O)O)cc1
Temperature: 107.5 °C

Procedure:
A heavy-walled screw-cap tube was charged with 3-methyl-2-butenoic acid (13.86 gm) 3,3-dimethylacrylic acid, (138.4 mmol), 4-methoxythiophenol (143.2 mmol), and piperidine (41.6 mmol) [Aldrich]. The mixture was heated to 105-110° C. for 32 hours, then cooled to room temperature. The reaction mixture was dissolved in ethyl acetate (EtOAc) (700 ml) with stirring, and the resulting solution was washed with 1M aqueous HCl (50 ml×2), water (50 ml), and saturated aqueous NaCl (50 ml). The organic solution was thereafter dried over NaSO4. Concentration of this organic solution under reduced pressure afforded an oil and 2 days incubation at −20° C. yielded a crystalline solid. Forty ml of pentane were added to the solid, which was then crushed and filtered. The solid was washed on filter paper with pentane (20 ml, 2 times) to yield the product 3-(4-methoxyphenylthio)-3-methyl-butyric acid, as pale yellow crystals (31.4 grams, 94.4% yield, m.p. 62-64° C.), [1H-NMR(CDCl3): d7.5 (t, 2H, J=8 Hz), d6.9 (t, 2H, J=6.7 Hz), d3.9 (s, 3H, J=16.1 Hz), d2.6 (s, 2H), d1.3 (s, 6H)].
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]([NH2:28])=[N:15][CH:16]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:18]=1)[CH3:11].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([N:42]2[CH:46]=[C:45](Br)[CH:44]=[N:43]2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[C:29]([O:33][C:34]([N:36]1[CH2:37][CH2:38][CH:39]([N:42]2[CH:46]=[C:45]([C:17]3[CH:16]=[N:15][C:14]([NH2:28])=[C:13]([O:12][C@@H:10]([C:3]4[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=4[Cl:1])[CH3:11])[CH:18]=3)[CH:44]=[N:43]2)[CH2:40][CH2:41]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Br)cn2)CC1
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: C[C@@H](Oc1cc(-c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 87 °C
Reaction time: 16 h
Yield: 62.1 %

Procedure:
To a stirred solution of 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (4.2711 g, 10.0 mmol) and 4-(4-bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (see procedure 11) (3.9628 g, 12.0 mmol) in DME (40 mL) was added a solution of Na2CO3 (3.1787 g, 30.0 mmol) in water (10 mL). The solution was degassed and charged with nitrogen three times. To the solution was added Pd(PPh3)2Cl2 (351 mg, 0.50 mmol). The reaction solution was degassed and charged with nitrogen again three times. The reaction solution was stirred at 87° C. oil bath for about 16 hours (or until consumption of the borane pinacol ester), cooled to ambient temperature and diluted with EtOAc (200 mL). The reaction mixture was filtered through a pad of celite and washed with EtOAc. The EtOAc solution was washed with brine, dried over Na2SO4, and concentrated. The crude product was purified on a silica gel column eluting with EtOAc/hexane system (0% EtOAc to 100% EtOAc) to afford 4-(4-{6-amino-5-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (3.4167 g, 65% yield, ˜95% purity) with a Rf of 0.15 (50% EtOAc/Hexanes). MS m/e 550 (M+1)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])SCCCS1.O.BrN1C(=[O:25])CCC1=O>CC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][C:5](=[O:25])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: COCCC1(C(=O)OC(C)(C)C)SCCCS1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(C)=O
Solvent: O
Product: COCCC(=O)C(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
tert-Butyl 2-(2-methoxyethyl)-1,3-dithiane-2-carboxylate (1.68 g, 6.03 mmol) was dissolved in acetone (57 mL), and water (3.0 mL) was added. The flask was cooled in a cold bath at −30° C. Small aliquots of N-bromosuccinimide (10.68 g, 60 mmol) were added over 20 minutes. The reaction mixture was stirred at the same temperature for 10 minutes, and then quenched by adding an aqueous solution of sodium bicarbonate (5.05 g in 50 mL of water). Insoluble material was removed by filtration, and the solid was washed with n-hexane. To the filtrate was then added an aqueous solution of 5% sodium sulfite until the filtrate became colorless from yellow. The filtrate was diluted in water to a total volume of 250 mL, and extracted twice with n-hexane. The organic layer was washed with a saturated brine, then dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the target compound as oil at a yield of 67%.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[CH:16][C:15]=1[CH3:20]
Reactant: Cc1ccccc1F
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C(=O)CCC(=O)O)ccc1F
Temperature: 80 °C

Procedure:
200 gm of succinic anhydride and 800 gm of aluminum chloride were added to 250 ml of 2-fluorotoluene, and the mixture was heated at 80° C. for 1 hour. Upon the addition of 5 l of 1% cold hydrochloric acid aqueous solution, the reaction mixture was extracted with ethyl acetate, washed with 1 N hydrochloric acid and water, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 345 gm of the title compound. NMR(CDCl3) δ: 1.89-1.97(2H, m), 2.24(3H, s), 2.36(2H, t, J=7.3 Hz), 2.60(2H, t, J=7.3 Hz), 6.84-6.99(3H, m).
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1>CS(C)=O>[C:1]([CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)#[N:2]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55 %

Procedure:
A solution of sodium cyanide (20 g, 0.41 mol) in dimethylsulfoxide at 40° C. was treated dropwise with a solution of methyl 4-(bromomethyl)benzoate (52 g, 0.227 mol) in dimethylsulfoxide, stirred for 90 min., cooled to room temperature, quenched with saturated aqueous sodium chloride and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. Purification of the concentrate via column chromatography (silica, hexane:ethyl acetate 0→5%) provided methyl 4-(cyanomethyl)benzoate (55%). 1H NMR (400 MHz, CDCl3): 8.05 (d, J=8 Hz, 2H); 7.42 (d, J=8 Hz, 2H); 3.93 (s, 3H); 3.81 (s, 2H). [M+H] 176
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[N:25]1([CH:30]2[CH:39]3[CH:34]([CH2:35][CH2:36][CH2:37][NH:38]3)[CH2:33][CH2:32][CH2:31]2)[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:38]2[CH:39]3[CH:34]([CH2:33][CH2:32][CH2:31][CH:30]3[N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:35][CH2:36][CH2:37]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: C1CNC2C(C1)CCCC2N1CCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCCC2CCCC(N3CCCC3)C21
Temperature: 25 °C
Reaction time: 4 h
Yield: 113.6 %

Procedure:
A solution of 873 mg of 3,4-dichlorophenyl-acetic acid and 690 mg of carbonyldiimidazole in tetrahydrofuran was stirred for 1 hour at 20° to 25° C. and then 645 mg of the product of Step C in solution in 3 ml of tetrahydrofuran was added. After stirring for 4 hours at ambient temperature, the tetrahydrofuran was eliminated under reduced pressure at less than 40° C. and the residue was taken up in 20 ml of ether. The solution was washed with a saturated solution of sodium bicarbonate, then with water saturated with sodium chloride and the ethereal phase was dried and distilled to dryness under reduced pressure to obtain 1.39 g of the crude product.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[Cl:18].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[C:1]([CH:3]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[Cl:18])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: Clc1cccc(CBr)c1Cl
Reactant: CCOC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Yield: 18.4 %

Procedure:
A mixture of ethyl 2-cyanoacetate (4.52 g, 40 mmol), 1-(bromomethyl)-2,3-dichlorobenzene (4.8 g, 20 mmol) and potassium carbonate (11.04 g, 80 mmol) in THF (80 mL) was under reflux for 30 h. After cooled to room temperature, the solvent was removed in vacuo and the resulting mixture was acidified with 2 N hydrochloric acid. The resulting solution was extracted with ethyl acetate (80 mL×3). The combined organic layers were washed with water and brine, dried over sodium sulphate, concentrated under reduced pressure. The residue was crystallized with MeOH to give the titled product (1.0 g, 18%) as a white solid. The mother liquor was concentrated in vacuo and the residue was purified by a silica gel chromatography eluted with PE/EA=20/1 to give the titled product (1.53 g, 33%) as a colorless oil; LC/MS: MS (ES+) m/e 272 (MH+); 1H NMR (300 MHz, CDCl3) δ ppm 1.31 (t, J=7.2 Hz, 3H), 3.24 (dd, J=9.6, 13.8 Hz, 1H), 3.56 (dd, J=6.3, 13.8 Hz, 1H), 3.90-3.96 (dd, J=6.3, 9.6 Hz, 1H), 4.28 (dq, J=0.9, 7.2 Hz, 2H), 7.18-7.29 (m, 2H), 7.44 (dd, J=1.8, 7.8 Hz, 1H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]([CH3:15])=[CH:12][CH2:13]Br.[CH3:16][N:17]1[C:25]2[N:24]=[C:23]([Br:26])[NH:22][C:21]=2[C:20](=[O:27])[NH:19][C:18]1=[O:28]>CN(C)C=O.O>[CH3:16][N:17]1[C:25]2[N:24]=[C:23]([Br:26])[N:22]([CH2:13][CH:12]=[C:11]([CH3:15])[CH3:10])[C:21]=2[C:20](=[O:27])[NH:19][C:18]1=[O:28]
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Reactant: CC(C)=CCBr
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)=CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C

Procedure:
15.37 ml of Hünig base and 9.98 ml of 3,3-dimethylallylbromide are added to 20.00 g of 3-methyl-8-bromo-xanthine in 200 ml of N,N-dimethylformamide. The reaction mixture is stirred for about half an hour at ambient temperature and then diluted with 500 ml of water. The precipitate formed is suction filtered, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17](=[O:20])[CH2:18]Br.CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:18][C:17]([O:16][CH3:15])=[O:20])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CNc1cccc(Cl)c1
Temperature: 60 °C

Procedure:
To a solution of 3-chloroaniline and potassium carbonate (3 equiv.) in DMF is added methylbromoacetate (1.1 equiv.), and the reaction is stirred at 60° C. After complete reaction, the solution is poured into EtOAc and washed with water, sat. aq. NaHCO3 soln., and brine. The solution is dried (Na2SO4), filtered, and concentrated in vacuo. The resulting material is purified by silica gel chromatography to provide the titled compound.
Reaction SMILES: [ClH:1].N[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:13])[CH:4]=1.Cl.N([O-])=O.[Na+].[S:19](=[O:21])=[O:20]>O.CC(O)=O.[Cu]Cl.CCCCCC>[Cl:1][S:19]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:13])[CH:4]=1)(=[O:21])=[O:20]
Reactant: O=S=O
Reactant: COC(=O)c1ccc(N)cc1F
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCCCCC
Product: COC(=O)c1ccc(S(=O)(=O)Cl)cc1F
Reaction time: 0.17 h
Yield: 50649.4 %

Procedure:
To a suspension of methyl 4-amino-2-fluorobenzoate hydrochloride (Preparation 12, 33.2 g, 0.154 mmol, 1 eq) in a 1:1 mixture of concentrated HCl and water (70 ml:70 ml) cooling in an ice bath was added a solution of sodium nitrite (11.71 g, 0.169 mol, 1.1 eq) in warm water (20 ml) dropwise maintaining the temperature below 50° C. The reaction mixture was allowed to stir for 10 minutes then filtered through a pad of Celite and the solid washed with water. The filtrate was added portionwise to a solution of sulphur dioxide (49.4 g, 0.771 mmol, 5 eq) and copper (1) chloride (100 mg) in AcOH (120 ml) at 0° C. and the reaction mixture stirred for 30 minutes. The mixture was extracted with DCM (3×150 ml), washed with saturated sodium hydrogen carbonate, water and brine, dried over magnesium sulphate, filtered and evaporated in vacuo. The crude material was purified by column chromatography eluting with 10% ethyl acetate:hexane to yield the title compound as a red oil (19.68 g, 0.078 mol, 50%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[N:13]=2)=[N:6][CH:7]=1.C(N(C(C)C)C(C)C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(CC)(CC)C=3C=CC=2)C=CC=CC=1.[SH:88][CH2:89][CH2:90][C:91]([O:93][CH3:94])=[O:92]>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].C(OCC)(=O)C.O1CCOCC1>[CH3:94][O:93][C:91](=[O:92])[CH2:90][CH2:89][S:88][C:2]1[CH:3]=[C:4]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[N:13]=2)=[N:6][CH:7]=1
Reactant: COC(=O)CCS
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)CC1
Agent: [Pd]
Agent: CCC1(CC)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)CCSc1cnc(Nc2nc(CC3CCN(C(=O)OC(C)(C)C)CC3)cs2)c(Oc2ccccc2)c1
Temperature: 95 °C
Yield: 94.4 %

Procedure:
The atmosphere above a mixture of tert-butyl 4-((2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)methyl)piperidine-1-carboxylate (1.52 g, 2.79 mmol), N-ethyl-N-isopropylpropan-2-amine (0.971 mL, 5.57 mmol), 4,5-bis(diphenylphosphino)-9,9-diethyl-9H-xanthene (0.161 g, 0.279 mmol), and dioxane (25 mL) was purged with nitrogen. Methyl 3-mercaptopropanoate (0.332 mL, 3.07 mmol) and Pd2dba3 (0.128 g, 0.139 mmol) were added, and the reaction was heated at 95° C. overnight. The reaction was cooled to ambient temperature and filtered through celite. The filtrate was concentrated and purified by MPLC (Biotage) eluting with 3:2 hexane:ethyl acetate to afford the title compound (1.54 g, 94.5% yield) as a tacky white solid: 1H NMR (CDCl3) δ 8.70 (s, 1H), 8.16 (s, 1H), 7.40 (t, 2H), 7.24 (t, 1H), 7.14 (s, 1H), 7.06 (d, 2H), 6.46 (s, 1H), 4.08 (m, 2H), 3.65 (s, 3H), 2.99 (t, 2H), 2.67 (m, 2H), 2.56 (d, 2H), 2.55 (t, 2H), 1.85 (m, 1H), 1.66 (m, 2H), 1.45 (s, 9H), 1.16 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:54]1([CH2:57][NH:58][CH2:59][C:60]2[NH:61][C:62](=[O:70])[C:63]3[CH2:69][O:68][CH2:67][CH2:66][C:64]=3[N:65]=2)[CH2:56][CH2:55]1>CN(C=O)C.O>[CH:54]1([CH2:57][N:58]([CH2:59][C:60]2[NH:61][C:62](=[O:70])[C:63]3[CH2:69][O:68][CH2:67][CH2:66][C:64]=3[N:65]=2)[C:16](=[O:18])[CH2:15][N:12]2[CH2:11][CH2:10][CH:9]([C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[CH2:56][CH2:55]1
Reactant: O=c1[nH]c(CNCC2CC2)nc2c1COCC2
Reactant: COc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)C2CCN(CC(=O)N(Cc3nc4c(c(=O)[nH]3)COCC4)CC3CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.3 %

Procedure:
To a solution of [4-(4-methoxy-benzoyl)-piperidin-1-yl]-acetic acid (0.071 g, 0.26 mmol, 1 eq.) and DIEA (0.089 mL, 0.51 mmol, 2 eq.) in 2 mL of DMF was added HATU (0.107 g, 0.281 mmol, 1.1 eq.). The resulting mixture was stirred at room temperature for 30 min. 2-[(Cyclopropylmethyl-amino)-methyl]-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (0.06 g, 0.26 mmol, 1 eq.) in 1 mL of DMF was added and the mixture was stirred at room temperature overnight. After 18 h, the reaction mixture was diluted with H2O (10 mL) and extracted with dichloromethane (3×50 mL). The combined organics were concentrated and purified by preparative HPLC (20-100% CH3CN/H2O over 10 min with 0.1% TFA, sun fire C18 OBD 50×50 mm column with flow rate of 60 mL/min) to give the title compound as a white solid (0.03 g, 24%). 1H NMR (400 MHz, MeOD) δ ppm 7.94-8.07 (m, 2H), 6.98-7.10 (m, 2H), 4.64-4.70 (m, 1H), 4.54-4.60 (m, 1H), 4.44-4.52 (m, 2H), 4.28-4.37 (m, 1H), 3.94-3.99 (m, 1H), 3.91-3.95 (m, 2H), 3.88 (s, 3H), 3.67-3.80 (m, 2H), 3.40-3.61 (m, 1H), 3.33-3.40 (m, 2H), 3.09-3.27 (m, 2H), 2.50-2.72 (m, 2H), 1.92-2.26 (m, 4H), 0.83-1.15 (m, 1H), 0.12-0.67 (m, 4H). HRMS calculated for C27H35N4O5 495.2607. found (ESI, [M+H]+) 495.2606. MS (ESI) m/z 495.3 (M+H)+. Retention time: 2.89 min (5-95% CH3CN/H2O over 7.75 min with 0.1% formic acid, Inertsil ODS3 100×3 mm C18 column with flow rate of 1.0 mL/min).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:5](=[O:6])[C:4]([CH3:8])([CH3:7])[C:3]1=[O:9]>[Ru].C(O)(C)C>[CH3:7][C:4]1([CH3:8])[CH:5]([OH:6])[C:2]([CH3:10])([CH3:1])[CH:3]1[OH:9]
Reactant: CC1(C)C(=O)C(C)(C)C1=O
Agent: [Ru]
Solvent: CC(C)O
Product: CC1(C)C(O)C(C)(C)C1O
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A 2 liter Parr autoclave was charged with 100 grams of 2,2,4,4-tetramethylcyclobutane-1,3-dione, 300 grams of isopropyl alcohol, and 50 grams of 2% ruthenium on alumina (surface area=10 m2/g, purchased from BASF Catalysts). The autoclave was pressure purged three times with nitrogen and three times with hydrogen, and the pressure was increased to 3.5 MPa (500 psig) with hydrogen. The autoclave was heated to 80° C. with stirring at approximately 1400 rpm and held for 6 hours at 3.5 MPa (500 psig). Analysis of the product by gas chromatography indicated that 99.8% conversion of the 2,2,4,4-tetramethylcyclobutane-1,3-dione was obtained with 100% selectivity to 2,2,4,4-tetramethycyclobutane-1,3-diol with a cis:trans ratio of 1.50:1.
Reaction SMILES: CC(N(C)C)=O.Cl[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=2)[N:13]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.C(N(CC)CC)C>O>[F:18][C:17]([F:20])([F:19])[C:14]1[N:12]2[N:13]=[C:8]([N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=4)[CH2:23][CH2:22]3)[CH:9]=[CH:10][C:11]2=[N:16][N:15]=1
Reactant: Oc1ccc(C2CCNCC2)cc1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: Oc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 40 °C
Yield: 92 %

Procedure:
Dimethylacetamide (250.0 mL) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine [CAS: 40971-95-7] (50.0 g, 225 m mol) at 22-25° C. in a suitable round bottom flask followed by 4-(piperidin-4-yl)phenol [CAS: 62614-84-0] (60.9 g, 236 m mol) at 22-25° C. The reaction mass was stirred to obtain a clear solution. Triethylamine (79.1 mL, 561 m mol) was slowly added to the reaction mass by drop wise addition over a period of 60 min at 25-30° C. Temperature was raised to 40° C. and the reaction mass stirred for 1.0 h. After completion of reaction, water (500.0 mL) was added to the reaction mass by drop wise addition over a period of 30 min at 40-43° C. The slurry mass was stirred for 30 min at 40° C. and then filtered under reduced pressure. The wet material was slurry washed using water (500.0 mL) for 30 min at 40° C. The solid was collected by filtration and the material washed with water (125.0 mL). The material was dried under reduced pressure with nitrogen gas bleed at 50° C. to afford the desired product 4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenol (75.1 g, 89.9%) as a free flowing solid.
Reaction SMILES: [CH2-:1][C:2]([CH3:4])=[O:3].[CH2-]C(C)=O.[C:9]([OH:18])(=[O:17])[CH:10]([CH:12]([C:14]([OH:16])=[O:15])O)O.CC(C)([O-])C.[K+].Cl.O1CCOCC1>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:4])[O:16][C:14](=[O:15])/[C:12](=[CH:10]/[C:9]([OH:18])=[O:17])/[O:3]1
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: [CH2-]C(C)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)OC(=O)/C(=C/C(=O)O)O1
Temperature: -40 °C

Procedure:
A solution of tartaric acid bis(acetonide) prepared as in Example 1 (1.84 g, 8.0 mmol) in anhydrous tetrahydrofuran (15 mL) was cooled to −40° C. A 1 M solution of potassium tert-butoxide in tetrahydrofuran (8.0 mL, 8 mmol) was added by syringe over the course of 5 min. The mixture was stirred an additional 20 min. at −40° C. after which 4 M HCl in dioxane (3.0 mL, 12 mmol) was added and the reaction was allowed to warm. Ethyl acetate (75 mL) and 1 N HCl (25 mL) were added. The organic layer was separated and washed with water (25 mL). Removal of volatiles on the rotary evaporator afforded the crude product (1.37 g, 99%). This material contained ca. 5% of a side-product presumed to be the E-stereoisomer and characterized by an NMR singlet at δ 5.48 as well as ca. 10% of recovered bis(acetonide) starting material. A 0.63 g sample of this material was crystallized from hot ethyl acetate to afford Z-2,2-dimethyl-5-carboxymethylene-1,3-dioxolan-4-one as fine white needles (0.37 g).
Reaction SMILES: [Na].[C:2]([O:6][CH3:7])(=[O:5])[CH2:3][SH:4].C[O:9][C:10](=O)[C:11](Cl)=[CH2:12].Cl>CO>[OH:9][C:10]1[CH:11]=[CH:12][S:4][C:3]=1[C:2]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CS
Reactant: C=C(Cl)C(=O)OC
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COC(=O)c1sccc1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To dry methanol (81 mL), under nitrogen, was added sodium metal (3.68 g, 304 mmol). After H2 evolution ceased, the solution was cooled to 0° C. and methyl thioglycolate (10 g, 179 mmol) was added dropwise. A solution of methyl-2-chloroacrylate (10.88 g, 179 mmol) in methanol (21 mL) was then added slowly, resulting in the formation of yellow precipitate. The solution was allowed to warm to ambient temperature and stirred for 2 h. The solvent was removed in vacuo to give a dark yellow solid that was acidified to pH 2 with 4 N HCl. The resulting aqueous solution was extracted with dichloromethane (3×150 mL) and the combined organic solutions were washed with water (3×150 mL), dried over MgSO4, filtered, and concentrated to give a dark oil. The oil was subjected to column chromatography on silica gel (20:1 hexanes/ethyl acetate) to give (12) (18.4 g) as a crystalline solid in 64% yield. TLC (20:1 hexanes/ethyl acetate) Rf 0.47; 1H NMR (CDCl3) δ 9.58 (s, 1H), 7.59 (d, J=5.7 Hz, 1H), 6.75 (d, J=4.8 Hz, 1H), 3.90 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.8, 164.7, 131.7, 119.4, 52.2; EI-MS m/e 158.0039 (M+ calculated 158.0038 for C6H6O3S).