Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([O:10][CH3:11])=[N:8][C:7]([Br:12])=[CH:6][N:5]=1.[C:13]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=1.Cl>C(COC)OC.O>[Br:12][C:7]1[N:8]=[C:9]([O:10][CH3:11])[C:4]([NH:3][S:19]([C:14]2[C:13]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:21])=[O:20])=[N:5][CH:6]=1
Reactant: COc1nc(Br)cnc1N
Reactant: O=S(=O)(Cl)c1ccccc1-c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1nc(Br)cnc1NS(=O)(=O)c1ccccc1-c1ccccc1
Reaction time: 0.25 h
Yield: 55.3 %

Procedure:
Sodium hydride (60% dispersion in oil; 0.198 g) was suspended in dimethoxyethane (5 ml) and 2-amino-5-bromo-3-methoxypyrazine (0.405 g) was added with stirring. After 15 minutes, 2-biphenylsulphonyl chloride (0.5 g) was added and the mixture was stirred for 18 hours. The reaction mixture was poured into water (20 ml) and acidified to pH2 with concentrated hydrochloric acid and extracted with ethyl acetate (3×25 ml). The combined organic extracts were evaporated and the residue was purified by flash chromatography on silica gel (30 g), eluting with hexane/ethyl acetate/glacial acetic acid (160/40/1 v/v), to give N-(5-bromo-3-methoxy-2-pyrazinyl)-2-biphenylsulphonamide (0.46 g); 1H NMR (d6 -DMSO): 3.82(s,3H), 7.2-7.4(m,6H), 7.53-7.7(m,2H), 7.78(s,1H), 8.08(dd,1H), 10.33(br,1H); mass spectrum (+ve FAB, methanol/NBA): 420(M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])/[C:3](/[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=[CH:4]\[C:5]([O:7][CH3:8])=[O:6]>CCOC(C)=O.CO>[F:1][C:2]([F:17])([F:18])[CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)/C=C(/c1cccc(OC)c1)C(F)(F)F
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CC(c1cccc(OC)c1)C(F)(F)F
Reaction time: 8 h
Yield: 98.3 %

Procedure:
A 250 mL flask containing a solution of 6.1 (2.20 g, 8.5 mmol) in 1:1 EtOAc/MeOH (40 mL) was purged with N2. To the mixture was added palladium, 10 wt. % (dry), on carbon powder, wet (0.90 g, 0.85 mmol). The vial was then purged with H2, and the contents were stirred overnight under a H2 balloon. The black mixture was filtered through a pad of Celite and concentrated to afford 6.2 (2.19 g, 99% yield).
Reaction SMILES: CO[C:3]1[CH:8]=[N:7][N:6]([CH3:9])[C:5](=[O:10])[CH:4]=1.P(Cl)(Cl)([Cl:13])=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.O>[Cl:13][C:3]1[CH:8]=[N:7][N:6]([CH3:9])[C:5](=[O:10])[CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cnn(C)c(=O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cn1ncc(Cl)cc1=O
Temperature: 110 °C
Yield: 58.4 %

Procedure:
A mixture of 1.50 g (10.70 mmol) of 5-methoxy-2-methyl-2H-pyridazin-3-one and 7.8 ml (13.1 g, 85.6 mmol) of phosphorus oxychloride was heated at 110° C. for 2 h. After allowing to cool to room temperature, the mixture was poured into 100 ml of ice/water with vigourous stirring. After neutralization by addition of saturated sodium carbonate solution, the compound was worked up with methylene chloride/water, dried over magnesium sulfate and concentrated in vaccuo. The crude material was purified by flash chromatography on silicagel using a 80:20 mixture of ethyl acetate and heptane as eluant to yield 904 mg (6.25 mmol, 58%) of the title compound as a crystalline white solid, MS: 141.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[F:14].[Cl:15][S:16](O)(=[O:18])=[O:17]>C(Cl)Cl>[Cl:1][C:2]1[S:3][C:4]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:5][C:6]=1[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[F:14]
Reactant: O=S(=O)(O)Cl
Reactant: Fc1ccc(F)c(-c2ccsc2Cl)c1
Solvent: ClCCl
Product: O=S(=O)(Cl)c1cc(-c2cc(F)ccc2F)c(Cl)s1
Yield: 82.6 %

Procedure:
To a solution of 2-chloro-3-(2,5-difluorophenyl)thiophene (0.73 g, 3.2 mmol) in CH2Cl2 (100 mL), cooled on ice, chlorosulfonic acid (0.37 g, 3.2 mmol) in CH2Cl2 (50 mL) was added dropwise over 1 h. The reaction was refluxed over night. The reaction mixture was cooled and washed with water (2×100 mL) and brine, dried over MgSO4, filtered and concentrated to a dark brown oil. The oil was dissolved in heptane (50 mL) and stored in the fridge over the weekend. A black tar precipitated. The solution was decanted and concentrated to give the title compound as a light brown oil (0.87 g, 21% over two steps). MS (ESI+) m/z 293 [M−Cl]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:14]1=[O:25].[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:26]([N:16]1[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][CH:6]=2)[C:14](=[O:25])[CH:15]1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CC1NCCN(CCc2c[nH]c3ccc(Cl)cc23)C1=O
Product: CCOC(=O)CC1C(=O)N(CCc2c[nH]c3ccc(Cl)cc23)CCN1C(=O)c1ccccc1

Procedure:
Using the procedure of Step D of Example 1, 11 g of the product of Step C and 3.5 ml of benzoyl chloride were reacted to obtain 13 g of the expected product.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Cl[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC([O-])(C)C.[K+].CN(C=O)C>[Cu]I.C(OCC)(=O)C>[C:11]1([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc2ocnc2c1
Reactant: Clc1ccccc1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc(-c2nc3ccccc3o2)cc1
Yield: 10 %

Procedure:
Copper(I) iodide (19.1 mg, 0.1 mmol), benzoxazole (119 mg, 10.0 mmol), chlorobenzene (450 mg, 4.0 mmol), t-BuOK (336 mg, 3.0 mmol), and DMF (1.0 mL). After column chromatography (hexanes, then 10% ethyl acetate in hexanes) and preparative HPLC (5% ethyl acetate in hexanes) 78 mg (40%) of 2-phenylbenzoxazole is obtained. Table I, entry 1.
Reaction SMILES: [I-:1].[Na+].Cl[CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]>CC(C)=O>[I:1][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C(CCCCl)c1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(CCCI)c1ccccc1
Temperature: 25 °C
Yield: 58.6 %

Procedure:
Sodium iodide (1.64 g, 10.95 mmol, 2 equiv) was added to a solution of 4-chloro-1-phenylbutan-1-one (1 g, 5.475 mmol, 1 equiv) in acetone. The reaction mixture was refluxed for 16 h. After cooling to ambient temperature, it was evaporated under reduced pressure to remove all the acetone. The residue was worked up using ethyl acetate and sodium bisulfite, followed by a wash with brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified using the Biotage flash chromatography system (SNAP 50 g cartridge, Rf=0.4, 5%-30% ethyl acetate in hexanes) to afford the title compound as white solid (880 mg, 59%). The bottle containing the compound was wrapped in aluminium foil to stored in the freezer to avoid further darkening of the mixture; 1H NMR (400 MHz, DMSO-d6): δ 2.06-2.16 (m, 2H); 3.14 (t, 2H, J=3.2 and 4 Hz); 3.34 (t, 2H, J=6.8 and 7.2 Hz); 7.51-7.55 (m, 2H); 7.62-7.67 (m, 2H); 7.95-7.98 (m, 2H); MS for C10H11IO m/z 274.99 (M+H)+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].C[O-].[Na+].Cl>O.CN(C)P(N(C)C)(N(C)C)=O>[O:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: Oc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(O)CCCCCCCCCCOc1ccccc1
Temperature: 100 °C

Procedure:
To a mixture of 9.4 g of phenol, 26.5 g of 11-bromoundecanoic acid and 250 ml of hexamethylphosphoramide chilled in an ice bath is added 10.5 g of sodium methoxide. A viscous mass developes and the mixture is stirred and heated at 100° C. for 20 hours. The mixture is diluted with cold water, acidified with concentrated hydrochloric acid, filtered and the solid washed with water to give gray crystals. Recrystallization from acetone gives pale gray crystals, mp 76°-78° C. A second crop of crystals is obtained from mother liquors, mp 75°-77° C.
Reaction SMILES: [CH3:1][CH:2]([C:8]([C:10]([F:13])([F:12])[F:11])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])(=O)C.[NH4+:18].C(O)C>O>[NH2:18]/[C:8](/[C:10]([F:13])([F:12])[F:11])=[C:2](/[CH3:1])\[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: [NH4+]
Reactant: CCOC(=O)C(C)C(=O)C(F)(F)F
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)/C(C)=C(\N)C(F)(F)F
Temperature: 25 °C
Yield: 88 %

Procedure:
Ethyl 2-methyl-4,4,4-trifluoroacetoacetate (10.2 g, 51 mmoles), ammonium acetate (11.9, 150 mmoles), ethanol (20 g), and water (1 g) were combined in a 100 mL round-bottom flask. The mixture was heated for 6 hr. at 70° C. The mixture was then cooled to room temperature and poured into water (50 mL). The aqueous mixture was extracted with ethyl acetate (approximately 40 mL) and the layers were separated. The ethyl acetate layer was dried over anhydrous magnesium sulfate and evaporated to give an 88% yield of ethyl 3-amino-2-methyl-4,4,4-trifluorocrotonate.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[CH2:18]([O:9][C:8](=[O:10])[CH2:7][O:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=1)[CH3:19]
Reactant: CCO
Reactant: O=C(O)COc1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)COc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 50 g (0.29 moles) of p-fluorophenoxy acetic acid in one liter of absolute ethanol is added 10 ml of sulfuric acid. The mixture is heated to reflux for 18 hours, cooled to room temperature, and evaporated under vacuum. It is then poured onto 300 g of ice, extracted twice with 500 ml of ether, washed twice with 250 ml of a saturated solution of sodium bicarbonate, 100 ml of saturated sodium chloride solution, dried with magnesium sulfate, filtered and evaporated under vacuum giving 58 g of an oil. This is crystallized from 50 ml of hexane at -25° C. to give 55 g (90%) of the subject product as colorless crystals, mp 32°-33° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][C:24]=1[CH3:32]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:26]4[CH:27]=[CH:28][C:23]([Cl:22])=[C:24]([CH3:32])[CH:25]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Reactant: Cc1cc(B(O)O)ccc1Cl
Product: COc1ccc(-c2nc3cc(-c4ccc(Cl)c(C)c4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 4-chloro-3-methylphenylboronic acid (145 mg, 0.85 mmol) the subtitle compound was obtained (85 mg, 25%). MS 395 m/z (M+H)+.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.C([O-])(O)=O.[Na+]>CCO>[C:11]1([N:17]2[C:5]([NH2:6])=[CH:4][C:3]([C:2]([F:9])([F:8])[F:1])=[N:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#CCC(=O)C(F)(F)F
Reactant: NNc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(C(F)(F)F)nn1-c1ccccc1
Temperature: 90 °C
Yield: 90.6 %

Procedure:
A mixture of 4,4,4-trifluoro-3-oxobutanenitrile (2.056 g, 15 mmol) and phenylhydrazine hydrochloride (2.169 g, 15 mmol) in EtOH was heated at 90° C. for 8 hours. The reaction was quchened with water, basified with saturated NaHCO3 solution, and extracted with CH2Cl2. Extracts were dried over MgSO4, concentrated under reduced pressure, and dried under vacuum to afford 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-amine as yellow solid (3.089 g, 91%). 1H NMR (300 MHz, CDCl3) δ 7.54 (m, 5H), 5.85 (s, 1H), 3.95 (br, 2H); LC-MS (ESI) m/z 228 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[N:12]=1.[B-](F)(F)(F)[F:23].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:21])[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[C:8]1[S:9][C:10]([F:23])=[C:11]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[N:12]=1
Reactant: F[B-](F)(F)F
Reactant: CC1(C)CCC(=O)N1c1nc(-c2ccc(C#N)cc2)cs1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1(C)CCC(=O)N1c1nc(-c2ccc(C#N)cc2)c(F)s1
Reaction time: 16 h
Yield: 32 %

Procedure:
4-[2-(2,2-Dimethyl-5-oxopyrrolidin-1-yl)-1,3-thiazol-4-yl]benzonitrile (0.50 g, 1.7 mmol), prepared in step 2 of Example 88, was dissolved in acetonitrile (16 mL) and the Selectfluor® reagent (0.65 g, 1.9 mmol) was added. The mixture was stirred for 16 h, diluted with ethyl acetate, washed with H2O, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (10% acetone/hexane) afforded the title compound (0.17 g, 32%) as colorless crystals. HRMS: calcd for C16H14FN3OS+H+, 316.09144; found (ESI-FT/MS, [M+H]1+), 316.0916; Analytical HPLC purity 100% at 210-370 nm, 10.6 min; 98.4% at 296 nm, 10.6 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:5].Cl[C:21]1[N:26]([CH3:27])[C:25](=[O:28])[CH:24]=[C:23]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][C:30]=2[F:35])[N:22]=1.C(N(CC)CC)C>O1CCCC1>[CH3:1][N:2]([CH3:19])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C@@H:13]2[O:18][CH2:17][CH2:16][N:15]([C:21]3[N:26]([CH3:27])[C:25](=[O:28])[CH:24]=[C:23]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][C:30]=4[F:35])[N:22]=3)[CH2:14]2)=[CH:11][CH:12]=1)=[O:5]
Reactant: CN(C)CC(=O)Nc1ccc([C@H]2CNCCO2)cc1
Reactant: Cn1c(Cl)nc(-c2ccncc2F)cc1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)CC(=O)Nc1ccc([C@H]2CN(c3nc(-c4ccncc4F)cc(=O)n3C)CCO2)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
A solution of N2,N2-dimethyl-N1-(4-((2S)-morpholin-2-yl)phenyl)glycinamide obtained in Reference Example 13 (0.21 g, 0.8 mmol), 2-chloro-6-(3-fluoropyridin-4-yl)-3-methyl-3H-pyrimidin-4-one (0.15 g, 0.64 mmol), and triethylamine (0.40 g, 4 mmol) in tetrahydrofuran (10 ml) was stirred at 95° C. for one hour. The solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to afford N2,N2-dimethyl-N1-(4-((2S)-4-(3-methyl-4-oxo-3,4-dihydro-6-(3-fluoropyridin-4-yl)pyrimidin-2-yl)-morpholin-2-yl)phenyl)glycinamide (0.15 g, 50%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:23])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][C:9]=2[C:16]2[C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH:17]=2)[CH:7]=1.CN(C=O)C.S(Cl)([Cl:31])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:23])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][Cl:31])=[CH:10][C:9]=2[C:16]2[C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH:17]=2)[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CC1(C)CCC=C1c1cc(CO)ccc1-c1cc(Cl)ccc1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)CCC=C1c1cc(CCl)ccc1-c1cc(Cl)ccc1F
Reaction time: 1 h
Yield: 143.2 %

Procedure:
To a stirred solution of 78.9B (0.048 g, 0.1 mmol) in DCM (2.00 mL) at 23° C. was added DMF (0.001 mL) followed by thionyl chloride (0.02 mL, 0.3 mmol). The reaction was stirred for one hour and then concentrated in vacuo. The product was purified on silica gel (0-10% EtOAc in hexanes) to yield 78.9C as a colorless oil (0.05 g, 99% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[CH2:19]([OH:23])[CH2:20][CH2:21][CH3:22].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([O:23][CH2:19][CH2:20][CH2:21][CH3:22])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CCCCO
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCOc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, butanol and DBU in DME. EI-MS m/e (%): 258 (M+, 20), 202 ([M—C4H8]+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:17])[C:12](=[CH2:16])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[O:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[C:39]([CH2:41][NH2:42])[CH:38]=[C:37]([C:43]3[CH:48]=[CH:47][C:46]([O:49][C:50]([F:53])([F:52])[F:51])=[CH:45][CH:44]=3)[N:36]=2)[CH2:31][CH2:30]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH3:17])[C:12](=[CH2:16])[C:13]([NH:42][CH2:41][C:39]2[CH:38]=[C:37]([C:43]3[CH:48]=[CH:47][C:46]([O:49][C:50]([F:53])([F:51])[F:52])=[CH:45][CH:44]=3)[N:36]=[C:35]([N:32]3[CH2:31][CH2:30][O:29][CH2:34][CH2:33]3)[CH:40]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: C=C(C(=O)O)N(C)S(=O)(=O)c1ccc(Cl)cc1
Reactant: NCc1cc(-c2ccc(OC(F)(F)F)cc2)nc(N2CCOCC2)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1cc(-c2ccc(OC(F)(F)F)cc2)nc(N2CCOCC2)c1)N(C)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27.1 %

Procedure:
A solution of acid 4C (0.40 g, 1.45 mmol) in THF (25 mL) was added with DEPC (0.28 mL, 1.3 mol eq) and the mixture was stirred at room temperature for about 5 minutes. Then [2-morpholino-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 27D (0.56 g, 1.1 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was suspended in EtOAc and washed with water and brine. After drying over Na2SO4, the separated organic phase was evaporated under reduced pressure and the residue was purified by flash chromatography (7:3 EtOAc:Petroleum ether) to afford a pale yellow solid (0.24 g) after crystallization from a mixture of diethyl ether/petroleum ether. Yield=36%, 1HNMR (DMSO, 200 MHz) δ 2.95 (s, 3H), 3.55 (m, 4H), 3.70 (m, 4H), 4.40 (d, 2H, J=6), 5.12 (s, 1H), 5.87 (s, 1H), 6.82 (s, 1H), 7.29 (s, 1H), 7.43 (d, 2H, J=8.2), 7.83-7.74 (m, 4H), 8.17 (d, 2H, J=8), 8.86 (t, 1H); [M+1] 611.03 (C27H26ClF3N4O5S requires 610.13).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH2:8]P(OCC)(OCC)=O)=[O:7].[CH:17]12[CH2:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][C:19](=O)[CH2:18]2.O>COCCOC>[CH:17]12[CH2:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][C:19](=[CH:8][C:6]([O:5][CH2:4][CH3:3])=[O:7])[CH2:18]2
Reactant: O=C1CC2CCC(C1)C2
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C=C1CC2CCC(C1)C2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (1.55 g, 38.7 mmol, 60% dispersion in oil) in 1,2-dimethoxy ethane (70 mL) at 0° C., triethyl phosphono acetate (8.38 mL, 41.9 mmol) was added. The resulting mixture was stirred 15 minutes at 0° C., 15 minutes at room temperature, and cooled to 0° C. Then, a solution of bicyclo[3.2.1]octan-3-one (Biogene, 4.0 g, 32.2 mmol) in 1,2-dimethoxy ethane (20 mL) was added and the resulting solution was stirred for 5 minutes at 0° C. and then stirred at room temperature overnight. Water was added and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with H2O (50 mL), brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using an Analogix® Intelliflash280™ (Hex-EtOAc, 0 to 25%) to give the title compound. MS (DCI/NH3) m/z 212 (M+NH4)+
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15](=[O:17])[CH3:16])[CH:8]=[C:9]([CH2:11][O:12][CH2:13][CH3:14])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br-:18].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>CO.C1COCC1>[Br:18][CH2:16][C:15]([C:7]1[CH:8]=[C:9]([CH2:11][O:12][CH2:13][CH3:14])[CH:10]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[CH:6]=1)=[O:17]
Reactant: [Br-]
Reactant: CCOCc1cc(C(C)=O)cc(C(C)(C)C)c1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: CCOCc1cc(C(=O)CBr)cc(C(C)(C)C)c1
Yield: 132.8 %

Procedure:
1-(3-tert-Butyl-5-ethoxymethylphenyl)ethanone (O2.008; 550 mg) was dissolved in methanol/THF (10 ml/10 ml), admixed with phenyltrimethylammonium tribromide (882 mg) while stirring and stirred at RT for 2 h. Subsequently, the reaction mixture was poured onto DCM (200 ml) and washed thoroughly once with 5% sodium thiosulfate solution and once with water. Then the DCM phase was dried and concentrated. The residue was purified using silica gel (40 g cartridge, n-heptane/EA gradient of 0-50% in 30 min). 566 mg of the title compound were obtained. LC-MS rt: 1.83 min [M+H]+: 313.2 (met. a)
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].N1C=CC=CC=1.[C:17]([O:21][C:22](=[O:29])[NH:23][C@@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:5]1([O:4][C:2]([N:26]2[CH2:27][CH2:28][C@@H:24]([NH:23][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:29])[CH2:25]2)=[O:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)Oc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Phenyl chloroformate (1 eq.) is added dropwise to a solution of pyridine in DCM. The reaction mixture is cooled to 0° C. and a solution of (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (1 eq.) in DCM is added dropwise. The reaction mixture is stirred at RT for 1 hour. The reaction mixture is partitioned between (0.2 M) HCl)(aq) and DCM. The organics are washed with water, (sat)NaHCO3(aq) and brine. The organics are dried (MgSO4), filtered and reduced in vacuo to yield the title compound.