Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH3:15][CH:16]([CH3:34])[CH2:17][CH2:18][NH:19][C:20]([C:22]1[N:23]=[N:24][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:26][CH:27]=1)=[O:21]>>[CH3:15][CH:16]([CH3:34])[CH2:17][CH2:18][NH:19][C:20]([C:22]1[N:23]=[N:24][C:25]([N:28]2[CH2:33][CH2:32][N:31]([C:7](=[O:8])[C:6]3[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[C:11]([F:14])([F:13])[F:12])[CH2:30][CH2:29]2)=[CH:26][CH:27]=1)=[O:21]
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Reactant: O=C(Cl)c1cc(Cl)ccc1C(F)(F)F
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3cc(Cl)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 5-chloro-2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white solid (80%). m.p. 148-151° C. 1H NMR (400 MHz, CDCl3) δ 8.06, 7.85, 7.67, 7.54-7.50, 7.35, 7.01, 4.05-3.34, 1.73-1.46, 0.98. MS (ES+) m/z 484.3 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N:21]2[C:25]([CH3:26])=[N:24][N:23]=[N:22]2)[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[C:13]([N:21]3[C:25]([CH3:26])=[N:24][N:23]=[N:22]3)[CH:12]=2)[C:3]([OH:27])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(-n2nnnc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nnnn1-c1cc(C(CC2CCCC2)C(=O)O)ccc1S(C)(=O)=O
Yield: 89.4 %

Procedure:
A solution of 3-cyclopentyl-2-[4-methanesulfonyl-3-(5-methyl-tetrazol-1-yl)-phenyl]-propionic acid methyl ester (102 mg, 0.26 mmol) in ethanol (3 mL) was treated with a 1N aqueous sodium hydroxide solution (0.6 mL). The solution was 3heated at 45-50° C. for 5 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was concentrated in vacuo to remove ethanol. The residue was diluted with water (20 mL) and extracted with diethyl ether (1×30 mL) to remove any neutral impurities. The aqueous layer was then acidified with a 1N aqueous hydrochloric acid solution, and the resulting acid was extracted into ethyl acetate (2×25 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-[4-methanesulfonyl-3-(5-methyl-tetrazol-1-yl)-phenyl]-propionic acid (88 mg, 89%) as an amorphous white solid: EI-HRMS m/e calcd for C17H22N4O4S (M+) 378.1362, found 378.1364.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:9](=O)[C:10]1[C:11]([O:16][CH3:17])=[CH:12][CH:13]=[CH:14][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[Cl:8][C:3]1[C:2]([NH:1][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ccccc1C=O
Reactant: Nc1cccnc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccccc1CNc1cccnc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 112.8 %

Procedure:
To a 5 L 3-necked round bottom flask fitted with mechanical stirrer, thermometer, addition funnel, and nitrogen inlet, were added 1.6 L of acetic acid and 80.0 grams (0.62 moles) of 3-amino-2-chloropyridine. The mixture was agitated for approx. 10 minutes at 25° C. for dissolution. To the resulting solution was charged 105.9 grams (119.3 mL/0.78 moles/1.25 equivalents) of o-anisaldehyde (2-methoxybenzaldehyde), upon which was obtained a yellow solution after stirring 10 minutes at 25° C. Over a 30 minute period in portions were added 263.7 grams (1.24 moles, 2.0 equivalents) sodium triacetoxyborohydride, while maintaining a temperature of 20° C. The mixture was stirred for 12-18 hours and concentrated to a semi-solid, which was partitioned between methylene chloride and water (800 mL each). The pH was adjusted to 9.5 with 700 mL 25% sodium hydroxide solution while maintaining a temperature of 25°-30° C. by cooling. The layers were separated, the aqueous layer was washed with methylene chloride (3×300 mL each), and the methylene chloride layers were combined. The organic layer was washed with 300 mL of saturated sodium chloride solution, and then dried with magnesium sulfate for 30 minutes. The magnesium sulfate was removed by filtration, and the methylene chloride filtrate was evaporated and displaced with ethyl acetate, leaving an off white tacky material (174 grams). The product was reslurried in 120 mL of fresh ethyl acetate at 0°-5° C. for 1.5 hours, filtered, washed with cold ethyl acetate and dried, giving 133.2 grams (86.1%) of the title compound. M.P. 121°-125° C. 1H NMR (CDCl3) δ 7.70 (dd, 1H, J=1 Hz, 2 Hz), 7.25 (m, 2H), 7.05 (m, 1H), 6.90 (m, 3H), 4.95 (t, 1H), 4.40 (d, 2H, J=6), 3.85 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[N:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:36])[F:35])[N:22]=[CH:23][C:24]=3[CH:25]([CH3:27])[CH3:26])=[CH:14][C:13]=2[CH3:38])[CH:5]=1.[Li+].[OH-].O>O1CCOCC1>[CH:25]([C:24]1[CH:23]=[N:22][N:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:35])([F:36])[F:37])[C:20]=1[CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:11]=[CH:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:39])=[O:2])=[C:13]([CH3:38])[CH:14]=1)([CH3:27])[CH3:26]
Reactant: COC(=O)c1cccc(C=Cc2ccc(OCc3c(C(C)C)cnn3-c3ccccc3C(F)(F)F)cc2C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(OCc2c(C(C)C)cnn2-c2ccccc2C(F)(F)F)ccc1C=Cc1cccc(C(=O)O)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a solution of 3-(2-{4-[4-isopropyl-2-(2-trifluoromethyl-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-vinyl)-benzoic acid methyl ester (136 mg, 0.25 mmol) in 1,4-dioxane (7 mL) is added 2N LiOH/H2O (3 mL). The reaction mixture is stirred at 50° C. overnight. The solvent is evaporated and the residue is partitioned between EtOAc and 1N HCl. The layers are separated and the organic phase is washed with water and concentrated to give the title compound (129 mg, 97%). LC-ES-MS m/e 521 (M+1), 100%.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.[C:22]([Zn]C#N)#[N:23].[NH4+].[Cl-].CCOC(C)=O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:18]1[C:19]2[C:14](=[CH:13][C:12]([CH2:11][N:8]3[C:6]4=[N:7][C:2]([C:22]#[N:23])=[CH:3][N:4]=[C:5]4[N:10]=[N:9]3)=[CH:21][CH:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: N#C[Zn]C#N
Reactant: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 127 °C

Procedure:
To a degassed solution of 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (1.6 g, 4.69 mmol) in DMF (8 mL), was added Pd(PPh3)4 (0.434 g, 0.375 mmol) and dicyanozinc (0.441 g, 3.75 mmol). The reaction mixture was heated to 127° C. for 4 h. NH4Cl(aq) was added to quench the reaction, followed by EtOAc. The reaction mixture was filtered through celite, washed with saturated NaHCO3 and NH4Cl. The organic layer was separated, dried over Na2SO4, filtered and concentrated to give a crude product, which was purified with Analogix gel silica (Hexanes:EtOAc) to afford the title compound as a light yellow solid. LCMS (method B): [MH]+=288, tR=1.81 min.
Reaction SMILES: [H-].[OH-].[Li+].C[O:5][C:6](=[O:39])[CH:7]([NH:12][C:13]([C:15]1[N:16]=[N:17][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])[CH2:23][CH2:22]2)=[CH:19][CH:20]=1)=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10]>O1CCCC1.O>[CH3:10][CH:9]([CH3:11])[CH2:8][CH:7]([NH:12][C:13]([C:15]1[N:16]=[N:17][C:18]([N:21]2[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])[CH2:25][CH2:26]2)=[CH:19][CH:20]=1)=[O:14])[C:6]([OH:39])=[O:5]
Reactant: COC(=O)C(CC(C)C)NC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Agent: [H-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(NC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
Lithium hydroxide monohydride (25 mg, 0.595 mmol) was added to a solution of 4-methyl-2-({6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carbonyl}-amino)pentanoic acid methyl ester (130 mg, 0.256 mmol) in tetrahydrofuran (3 mL) and water (1.5 mL), the reaction mixture was stirred at ambient temperature for 3 hours, THF was removed by evaporation, the residue was adjusted with 5% citric acid to pH about 6, and diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and concentrated to afford 4-methyl-2-({6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carbonyl}amino)pentanoic acid (94 mg, 74%). 1H NMR (400 MHz, CDCl3) δ 8.17, 8.02, 7.78, 7.66-7.53, 7.38, 6.99, 6.72, 4.88-4.73, 4.25-3.60, 3.44-3.21, 1.79-1.06, 1.33-1.19, 1.03, 0.99.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH3:15][CH:16]([CH2:20][C:21]1[S:22][C:23]([CH3:26])=[CH:24][CH:25]=1)[C:17]([OH:19])=O.O>ClCCCl>[CH3:26][C:23]1[S:22][C:21]2[CH2:20][CH:16]([CH3:15])[C:17](=[O:19])[C:25]=2[CH:24]=1
Reactant: Cc1ccc(CC(C)C(=O)O)s1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: ClCCCl
Product: Cc1cc2c(s1)CC(C)C2=O
Temperature: 140 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
Under nitrogen atmosphere, a reactor was loaded with polyphosphoric acid (72.1 g) and phosphorus pentoxide (72.1 g, 0.51 mol) was added thereto and stirred at 140° C. for 1 hour. Then, a solution of 2-methyl-3-[5-methylthiophen-2-yl]propanoic acid (43.0 g, 0.23 mol) in 1,2-dichloroethane (75 mL) was added dropwise and stirred at 100° C. for 2 hours. The reaction mixture was added to iced water (1,000 mL) with stirring and after 30 minutes, extracted with chloroform to obtain an organic layer. The organic layer was washed with an aqueous saturated sodium carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a black oil. The oil was purified by silica gel chromatography (hexane/ethyl acetate=5/1) to obtain 2,5-dimethyl-5,6-dihydrocyclopenta[1,2-b]thiophen-4-one (32.6 g, 84.1%) as a reddish brown oil.
Reaction SMILES: O.[CH:2](=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10](O)[CH2:11][OH:12]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[C:3]1([CH:2]2[O:12][CH2:11][CH2:10][O:9]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: c1ccc(C2OCCO2)cc1
Yield: 89 %

Procedure:
A 500-mL three-necked flask equipped with a reflux condenser having a Dean-Stark water trap was charged with 5.0 g of benzaldehyde, 29.3 g of ethylene glycol, 0.09 g of p-toluenesulfonic acid monohydrate and 250 mL of benzene, and the contents were refluxed for 21 h. The resultant reaction solution was allowed to stand for cooling and then washed with 50 mL of a saturated aqueous solution of sodium hydrogen carbonate and 50 mL of water. After vacuum-concentrating the organic phase, 6.3 g of the aimed 2-phenyl-1,3-dioxolane was obtained by vacuum distillation (89% yield).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](O)[C:6]([CH3:15])=[C:5]([C:16]([F:19])([F:18])[F:17])[N:4]=1.N1C(C)=CC=CC=1C.P(Cl)(Cl)([Cl:32])=O>>[F:1][C:2]([F:21])([F:20])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([Cl:32])[C:6]([CH3:15])=[C:5]([C:16]([F:19])([F:18])[F:17])[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C)c1O
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C)c1Cl
Yield: 57.8 %

Procedure:
A mixture of 5.0 g (0.016 mol) of product of Example 35, 4.52 g (0.0362 mol) of 2,6-lutidine and 34 ml of phosphorus oxychloride was held at reflux for 20 hours and concentrated in vacuo. The residue was quenched with water and extracted with ether. The ether extract was washed successively with 10% K2CO3 and water, dried (CaSO4) and concentrated in vacuo to give 3.06 g (57.8%) of product as a brown oil, nD25 1.4313.
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH2:7])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+].[F:25][C:26]([F:36])([F:35])[CH2:27][CH2:28][S:29][CH2:30][CH2:31][C:32](Cl)=[O:33]>O>[Cl:1][C:2]1[C:6]([NH:7][C:32](=[O:33])[CH2:31][CH2:30][S:29][CH2:28][CH2:27][C:26]([F:25])([F:35])[F:36])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1
Reactant: O=C(Cl)CCSCCC(F)(F)F
Reactant: Nc1cn(-c2cccnc2)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCSCCC(F)(F)F)Nc1cn(-c2cccnc2)nc1Cl
Yield: 71.9 %

Procedure:
A 100-mL, three-neck round bottom flask was charged with 3-chloro-(pyridin-3-yl)-1H-pyrazol-4-amine (1.00 g, 5.14 mmol) and ethyl acetate (10 mL). Sodium bicarbonate (1.08 g, 12.9 mmol) was added, followed by dropwise addition of 3-((3,3,3-trifluoropropyl)thio)-propanoyl chloride (1.36 g, 6.17 mmol) at <20° C. The reaction was stirred at 20° C. for 2 hours, at which point thin layer chromatography analysis [Eluent: ethyl acetate] indicated that the reaction was complete. The reaction was diluted with water (50 mL) and the layers separated. The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers were concentrated to dryness to afford a light brown oil. The residue was purified by flash column chromatography using 30-60% ethyl acetate/hexanes. The fractions containing pure product were concentrated to dryness to afford a white solid (1.40 g, 72%): mp 99-102° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.05 (d, J=2.7 Hz, 1H), 8.86 (s, 1H), 8.54 (dd, J=4.5, 1.4 Hz, 1H), 8.21 (ddd, J=8.4, 2.7, 1.4 Hz, 1H), 7.54 (dd, J=8.4, 4.7 Hz, 1H), 2.86 (t, J=7.3 Hz, 2H), 2.74 (td, J=6.5, 5.6, 4.2 Hz, 4H), 2.59 (ddd, J=11.7, 9.7, 7.4 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ 169.32, 147.49, 139.44, 135.47, 133.40, 126.60 (q, J=296 Hz), 125.49, 124.23, 122.30, 120.00, 35.18, 33.42 (q, J=27.2 Hz), 26.77, 23.05 (q, J=3.3 Hz); EIMS m/z 378 ([M]+).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8](=[O:16])[C:9]([CH2:14][CH3:15])([CH3:13])[CH2:10][CH2:11][Cl:12])=[CH:4][CH:3]=1.[Br:19]Br>C(Cl)(Cl)Cl>[Br:19][CH:7]([O:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:18][CH:17]=1)[C:8](=[O:16])[C:9]([CH2:14][CH3:15])([CH3:13])[CH2:10][CH2:11][Cl:12]
Reactant: CCC(C)(CCCl)C(=O)COc1ccc(Cl)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCC(C)(CCCl)C(=O)C(Br)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
110 g (0.38 mole) of 1-(4-chlorophenoxy)-5-chloro-3-ethyl-3-methyl-2-pentanone are dissolved in 400 ml of chloroform. 60.8 g (0.38 mole) of bromine are added dropwise at room temperature such that the solution is always decolorized. The reaction mixture is then subsequently stirred at room temperature for 30 minutes and concentrated by distilling off the solvent. 138.5 g (99% of theory) of 1-bromo-1-(4-chlorophenoxy)-5-chloro-3-ethyl-3-methyl-2-pentanone of refractive index nD20 1.5250 are obtained. ##STR100##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9]O.P(Br)(Br)[Br:12].C(=O)(O)[O-].[Na+]>ClCCl>[Br:12][CH2:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: OCc1cc(F)ccc1Cl
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc(Cl)c(CBr)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
To a solution of (2-chloro-5-fluoro-phenyl)-methanol (5.0 g, 31.1 mmol) in dichloromethane (40 mL) was added drop wise phosphorus tribromide (87 g, 31.1 mmol). The mixture was stirred at room temperature for 16 h. The reaction was poured onto ice/water. The aqueous phase was made basic with sodium bicarbonate. The aqueous phase was extracted with dichloromethane. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with (hexanes/ethyl acetate 90:10) to give the title compound (5.75 g, 82.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.[I:14]I>CO.[O-]S([O-])(=O)=O.[Ag+].[Ag+]>[I:14][C:8]1[CH:7]=[C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: II
Reactant: COC(=O)Cc1ccc(OC)cc1
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COC(=O)Cc1ccc(OC)c(I)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl (4-methoxyphenyl)acetate (1 mL, 6.3 mmol) in MeOH (40 mL) was added Ag2SO4 (1.96 g, 6.3 mmol) followed by I2 (1.6 g, 6.3 mmol). The reaction was stirred vigorously at room temperature for 1 hour and then the solids were removed by filtration. The filtrate was diluted with EtOAc (200 mL), and washed with aq. NaHSO3 (2×50 mL) and brine (2×50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford methyl (3-iodo-4-methoxyphenyl)acetate. Rf=0.27 (15% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3) δ 7.68 (d, J=2.0 Hz, 1H), 7.21 (dd, J=8.2, 1.8 Hz, 1H), 6.76 (d, J=8.4 Hz, 1H), 3.85 (s, 3H), 3.68 (s, 3H), 3.52 (s, 2H).
Reaction SMILES: [C:1]([Mg]Cl)([CH3:4])([CH3:3])[CH3:2].[F:7][C:8]([F:19])([F:18])[O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.S(=O)(=O)(O)O.CCOCC>C1COCC1>[F:7][C:8]([F:18])([F:19])[O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]([OH:15])[C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:12][CH:11]=1
Reactant: CC(C)(C)[Mg]Cl
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)C(O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of commercially available t-butyl magnesium chloride in THF (1.0 mol) is added at 38°-40° C. a solution of 4-trifluoromethoxybenzaldehyde (56 g, 0.4 mol) in THF (50 ml) under nitrogen atmosphere. The reaction solution is stirred at room temperature overnight and cautiously acidified with dilute sulfuric acid at 15°-20° C. Ether is added and the organic phase is washed with water, dried (Na2SO4) and evaporated to a gummy solid. The crude material is purified by silica gel chromatography to give the alcohol which is used in Example 25.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[N:5].C(N(CC)CC)C.Cl[C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15]>C(#N)C>[CH2:17]([O:16][C:14](=[O:15])[NH:5][CH2:4][C:3]#[N:2])[CH:18]=[CH2:19]
Reactant: C=CCOC(=O)Cl
Reactant: N#CCN
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=CCOC(=O)NCC#N
Temperature: 20 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
To a suspension of 110 g of aminoacetonitrile hydrochloride in 1.2 l of acetonitrile were added at 20° C. 121.5 g of triethylamine. The mixture was cooled in an acetone-ice bath and 144.7 g of allyl chloroformate were added slowly, the temperature being maintained below 20° C. Subsequently, 121.5 g of triethylamine were added at such a rate that the temperature did not rise above 20° C. The mixture was stirred at 20° C. for 2 h and then, the solids were removed by filtration. The mother liquor was concentrated in vacuo and the oily residue was partitioned between ethyl acetate and water. The organic layer was washed successively with saturated potassium hydrogen sulfate solution, saturated potassium hydrogen carbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. The residual oil was distilled in vacuo to yield 132.6 g of cyanomethylcarbamic acid allyl ester as a colorless oil, b.p. 100° C./0.07 mbar.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N:10]1([C:15]2[N:20]=[C:19]([CH:21]3[CH:25]([C:26](=[S:28])[NH2:27])[CH2:24][CH2:23][N:22]3[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:18]=[C:17]([CH3:36])[N:16]=2)[CH:14]=[CH:13][N:12]=[CH:11]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:7]([O:6][C:4]([C:3]1[N:27]=[C:26]([CH:25]2[CH2:24][CH2:23][N:22]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:21]2[C:19]2[CH:18]=[C:17]([CH3:36])[N:16]=[C:15]([N:10]3[CH:14]=[CH:13][N:12]=[CH:11]3)[N:20]=2)[S:28][CH:2]=1)=[O:5])[CH3:8]
Reactant: Cc1cc(C2C(C(N)=S)CCN2C(=O)OC(C)(C)C)nc(-n2ccnc2)n1
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)C2c2cc(C)nc(-n3ccnc3)n2)n1
Temperature: 100 °C
Yield: 57.6 %

Procedure:
Ethyl 3-bromo-2-oxopropanoate (350 mg, 1.79 mmol) was added to a solution of tert-butyl 2-(2-(1 H-imidazol-1-yl)-6-methylpyrimidin-4-yl)-3-carbamothioylpyrrolidine-1-carboxylate (700 mg, 1.80 mmol) in DCM (20 mL) at rt under an atmosphere of N2. The reaction mixture was heated to 100° C. for 2 h then cooled to rt. Sodium bicarbonate (20 mL, sat. aq.) was added and the mixture extracted with DCM (2×20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was then purified using column chromatography (DCM to 9:1 DCM/MeOH) to afford 500 mg (80%) of 2-[1-tert-butoxycarbonyl-2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidin-3-yl]-thiazole-4-carboxylic acid ethyl ester as a yellow oil.
Reaction SMILES: [CH3:1][O:2][N:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH:6]([CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:5][C:4]1([CH3:17])[CH3:16].[N:18]1[C:25]([Cl:26])=[N:24][C:22](Cl)=[N:21][C:19]=1[Cl:20].[OH-].[Na+]>C1(C)C(C)=CC=CC=1.O>[Cl:20][C:19]1[N:18]=[C:25]([Cl:26])[N:24]=[C:22]([NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:6]2[CH2:7][C:8]([CH3:10])([CH3:9])[N:3]([O:2][CH3:1])[C:4]([CH3:17])([CH3:16])[CH2:5]2)[N:21]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CON1C(C)(C)CC(CCCCN)CC1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: CON1C(C)(C)CC(CCCCNc2nc(Cl)nc(Cl)n2)CC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
39.7 g (163 mmoles) of N-(1-methoxy-2,2,6,6-tetramethyl-4-piperidyl)butylamine are slowly added to a solution of 30 g (163 mmoles) of cyanuric chloride in 180 ml of xylene, maintained at room temperature. After the addition, the mixture is stirred for ½ hour at room temperature and subsequently, a solution of 6.8 g (170 mmoles) of sodium hydroxide in 45 ml of water is slowly added, maintaining the temperature at room temperature.