Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1.[CH:16]#[C:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CCN(CC)CC.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.[Cu]I>[C:16]([C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1)#[C:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: C#CCCCCCCCC
Reactant: CN1CCC[C@H]1COc1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCC#Cc1cncc(OC[C@@H]2CCCN2C)c1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (544 mg, 2.00 mmol), bis(triphenylphosphine)palladium(II) chloride (28 mg, 0.038 mmol) and copper (I) iodide (5 mg, 0.038 mmol) in CH2Cl2 (3.0 mL) and NEt3 (1.0 mL) was added 1-decyne (0.553 mL, 3.00 mmol). The mixture was refluxed overnight then cooled to room temperature. Water (2 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with NH4OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford an oil (543 mg, 85%). MS (CI/NH3) m/z 329 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ0.90 (t, J=6.9 Hz, 3H), 1.23-2.10 (m, 14H), 2.25-2.41 (m, 1H), 2.41 (t, J=7.3 Hz, 2H), 2.50 (s, 3H), 2.60-2.75 (m, 1H), 3.08-3.21 (m, 1H),, 3.89-4.06 (m, 2H), 7.19 (s, 1H), 8.15-8.28 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:19]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:20][CH:21]=C)=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].I([O-])(=O)(=O)=[O:32].[Na+].N1C(C)=CC=CC=1C>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[C:1]([C:3]1[C:4]([CH:19]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:20][CH:21]=[O:32])=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCC(c1ccc(Cl)c(Cl)c1)c1c(C(=O)OCC)sc(N2CCOCC2)c1C#N
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1C(CC=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 43.5 %

Procedure:
To a suspension of ethyl 4-cyano-3-[1-(3,4-dichlorophenyl)but-3-en-1-yl]-5-(morpholin-4-yl)thiophene-2-carboxylate (247 mg, 0.531 mmol) in 1,4-dioxane (6.00 mL) and water (2.00 mL) was added sodium metaperiodate (454 mg, 2.12 mmol), 2,6-lutidine (246 uL, 2.12 mmol), and 4% osmium tetroxide in water (4:96, osmium tetraoxide:water, 64.9 uL, 0.0106 mmol). The reaction was vigorously stirred at rt for 5 hrs. The mixture was filtered over a celite pad and the filtered solid was rinsed with EtOAc. The filtrate was washed with NaHCO3(aq) saturated solution and the aqueous layer was extracted with EtOAc (×2). The combined organic layer was washed with 1N HCl soln and brine, dried, and concentrated. Purification on a silica gel column (gradient elution 5-50% EtOAc/hexanes) provided ethyl 4-cyano-3-[1-(3,4-dichlorophenyl)-3-oxopropyl]-5-(morpholin-4-yl)thiophene-2-carboxylate as a yellow syrup (108 mg, 43.5% yield). 1H NMR (400 MHz, CDCl3) δ 9.84-9.73 (d, J=1.3 Hz, 1H), 7.48-7.42 (d, J=2.1 Hz, 1H), 7.42-7.32 (d, J=8.4 Hz, 1H), 7.30-7.18 (m, 1H), 6.06-5.94 (t, J=−7.7 Hz, 1H), 4.38-4.26 (q, J=7.1 Hz, 2H), 3.86-3.77 (t, J=4.9 Hz, 4H), 3.62-3.51 (dd, J=5.7, 4.0 Hz, 4H), 3.50-3.42 (m, 2H), 1.41-1.29 (m, 3H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(CC(O)=O)(CCC=C(C)C)(C=C)C.[C:23]([O:26][C:27]([CH3:36])([CH2:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[CH:28]=[CH2:29])(=[O:25])[CH3:24].[CH:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][C:38]=1[C:47](Cl)=[O:48]>C1COCC1>[CH:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][C:38]=1[C:47](=[O:48])[CH2:24][C:23]([O:26][C:27]([CH3:36])([CH2:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[CH:28]=[CH2:29])=[O:25]
Reactant: C=CC(C)(CCC=C(C)C)OC(C)=O
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: C=CC(C)(CCC=C(C)C)CC(=O)O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC(C)(CCC=C(C)C)OC(=O)CC(=O)c1ccc2ccccc2c1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide (101.0 mL of a 2.0M solution, 0.202 mol) is placed into a 500 mL three-necked round-bottomed flask fitted with a magnetic stirrer, internal thermometer, argon inlet, and addition funnel. The flask is placed in a dry ice-acetone bath. 3,7-Dimethyl-1,6-octadien-3-yl acetate (linalyl acetate) in the amount of (18.66 g, 0.095 mol) is dissolved in THF (5 mL) and the resulting solution added to the flask over 45 min. Once addition is complete, the mixture is stirred for an additional 15 min before being treated with a solution of 2-naphthoyl chloride in the amount of (17.43 g, 0.090 mol) dissolved in THF (25 mL) over 30 min. The mixture is warmed to -20° C. and stirred at that temperature for 18 h. After warming to 0° C., the mixture is quenched with 20% HCl (53 mL). The mixture is poured into a separatory funnel containing ether (150 mL) and water (250 mL). The aqueous layer is extracted with ether (150 mL). The combined organic layers are washed with saturated NaHCO3 solution (2×100 mL), water (2×150 mL) and brine (150 mL), dried over MgSO4 and filtered. The solvent is removed by rotary evaporation to give an orange/red oil. The oil is purified by column chromatography (elution with 5% ethyl acetate dissolved in petroleum ether) to give an oil. Purity of the product is determined by thin layer chromatography and GC analysis and the structure confirmed by mass spectrometry, 1H and 13C NMR.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH:16]=1)[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:21]([C:17]1[CH:16]=[C:15]([CH:13]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH3:14])[CH:20]=[CH:19][CH:18]=1)[CH:22]([CH3:24])[CH3:23]
Reactant: COC(=O)c1cccc(O)c1
Reactant: CC(C)Cc1cccc(C(C)Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C(C)c2cccc(CC(C)C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
A mixture of methyl 3-hydroxybenzoate (939 mg), 1-(1-bromoethyl)-3-isobutylbenzene (1.49 g) and potassium carbonate (1.71 g) in N,N-dimethylformamide (20 ml) was stirred at 25° C. overnight. The mixture was partitioned between ether and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel (30 g) eluting with a mixture of ethyl acetate and hexane (1:10) to give methyl 3-[1-(3-isobutylphenyl)ethyl]benzoate (1.45 g) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11]([C:14]1[C:15]([C:20]([F:23])([F:22])[F:21])=[N:16][CH:17]=[CH:18][CH:19]=1)=[CH:10][C:9]2=[O:24])([O-])=O.[NH4+].[Cl-].CO>[Fe].CCOC(C)=O>[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11]([C:14]1[C:15]([C:20]([F:23])([F:22])[F:21])=[N:16][CH:17]=[CH:18][CH:19]=1)=[CH:10][C:9]2=[O:24]
Reactant: O=c1cc(-c2cccnc2C(F)(F)F)oc2c([N+](=O)[O-])cccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cccc2c(=O)cc(-c3cccnc3C(F)(F)F)oc12
Temperature: 90 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
A mixture of 8-nitro-2-(2-(trifluoromethyl)pyridin-3-yl)-4H-chromen-4-one 27 (118 mg, 0.38 mmol), Fe (96 mg, 1.7 mmol), sat. aq NH4Cl (7 mL) and MeOH (14 mL) was stirred at 90° C. for 2 h. After cooling to room temperature the reaction mixture was poured into EtOAc and the layers separated. The organic layer was dried (MgSO4) and concentrate to give 28 as a yellow solid (90 mg, 77% yield over two steps).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:22])[O:20][CH3:21])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12][CH2:11]1.[CH3:23][C:24]([CH3:29])([CH3:28])[C:25](Cl)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:24]([C:29]1[N:8]([CH2:9][CH:10]2[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12][CH2:11]2)[C:7]2[CH:6]=[CH:5][C:4]([NH:18][C:19](=[O:22])[O:20][CH3:21])=[CH:3][C:2]=2[N:1]=1)([CH3:28])([CH3:25])[CH3:23]
Reactant: COC(=O)Nc1ccc(NCC2CCC(F)(F)CC2)c(N)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl (3-amino-4-{[(4,4-difluorocyclohexyl)methyl]amino}phenyl)carbamate (185 mg, 0.590 mmol) and DMAP (15 mg, 0.118 mmol) were dissolved in 10 mL of DCM. Trimethylacetyl chloride (0.080 mL, 0.649 mmol) was added dropwise and the solution was stirred at rt for 2 h. The solution was washed with aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The solvent was concentrated. The residue was dissolved in 4 mL of DCE and P2O5 (catalytic) was added and the solution was heated at 125° C. for 1 h using a Personal Chemistry microwave apparatus. The solution was washed with aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by silica gel flash chromatography using 50 to 75% EtOAc/hexanes. Yield: 122 mg (54%); 1H NMR (400 MHz, CHLOROFORM-D): δ 1.43-1.52 (m, 2H), 1.55 (s, 9H), 1.57-1.66 (m, 2H), 1.67-1.74 (m, 2H), 2.08-2.18 (m, 3H), 3.79 (s, 3H), 4.19 (d, J=7.42 Hz, 2H), 6.63 (br.s, 1H), 7.23 (d, J=8.79 Hz, 1H), 7.37-7.46 (m, 1H), 7.62 (d, J=1.76 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:21]([C:23]2([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24]2)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.CS(O[CH2:40][CH2:41][CH2:42][N:43]1[CH2:49][CH:48]([OH:50])[C:45]2([CH2:47][CH2:46]2)[CH2:44]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[OH:50][CH:48]1[C:45]2([CH2:47][CH2:46]2)[CH2:44][N:43]([CH2:42][CH2:41][CH2:40][O:19][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][C:7]4[CH:6]=[CH:5][C:4]([N:20]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[C:21]([C:23]5([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24]5)=[O:22])=[CH:3][C:2]=4[F:1])=[CH:10][CH:11]=[N:12]3)=[CH:17][CH:16]=2)[CH2:49]1
Reactant: CS(=O)(=O)OCCCN1CC(O)C2(CC2)C1
Reactant: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(OCCCN5CC(O)C6(CC6)C5)ccc34)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
To a solution of N-(3-fluoro-4-(7-hydroxyquinolin-4-yloxy)phenyl)-N-phenylcyclopropane-1,1-dicarboxamide (240 mg, 0.525 mmol) in DMA (3 mL) was added 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (261 mg, 1.05 mmol) and Cs2CO3 (512 mg, 1.575 mmol). The reaction was then stirred at rt for 24 hrs. The solvent was removed and the residue was partioned between saturated NaHCO3 (10 mL) aqueous solution and CHCl3 (30 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (100:15:1(v/v/v)EtOAc/CH3OH/Et3N) to afford the desired compound as a white solid (170 mg, 53%).
Reaction SMILES: C(O)C.[OH-].[K+].[C:6]1([CH2:12][CH2:13][N:14]2[C:18]([Br:19])=[C:17]([C:20]([O:22]CC)=[O:21])[C:16]([N:25]([CH2:44][CH2:45][CH3:46])[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]4[NH:43][N:42]=[N:41][N:40]=4)=[CH:29][CH:28]=3)=[N:15]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O>[C:6]1([CH2:12][CH2:13][N:14]2[C:18]([Br:19])=[C:17]([C:20]([OH:22])=[O:21])[C:16]([N:25]([CH2:44][CH2:45][CH3:46])[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]4[NH:43][N:42]=[N:41][N:40]=4)=[CH:29][CH:28]=3)=[N:15]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1nn(CCc2ccccc2)c(Br)c1C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1nn(CCc2ccccc2)c(Br)c1C(=O)O
Yield: 94.1 %

Procedure:
5 ml of ethanol, 5 ml of water and 226 mg of potassium hydroxide were added to 206 mg of N-[1-(2-phenylethyl)-4-ethoxycarbonyl-5-bromopyrazol-3-yl ]-N-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-n-propylamine, and heated under reflux for 5 hours. Ethanol was distilled off under reduced pressure, and 10 ml of water were added to the reaction mixture, which was then made acidic with concentrated hydrochloric acid. The resultant was extracted with 50 ml of dichloromethane. After dried over magnesium sulfate, the extract was concentrated under reduced pressure and dried to obtain 185 mg of the intended compound as a pale yellow, amorphous solid.
Reaction SMILES: P(O)(O)(O)=O.[Cl:6][C:7]1[CH:8]=[C:9]([C:19]([C:22]2[N:26]([CH3:27])[N:25]=[CH:24][C:23]=2[CH2:28][NH2:29])=[CH:20][CH:21]=1)[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])=O>[OH-].[Na+].C(Cl)Cl>[Cl:6][C:7]1[CH:21]=[CH:20][C:19]2[C:22]3[N:26]([CH3:27])[N:25]=[CH:24][C:23]=3[CH2:28][N:29]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:9]=2[CH:8]=1
Reactant: Cn1ncc(CN)c1-c1ccc(Cl)cc1C(=O)c1ccccc1F
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cn1ncc2c1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reaction time: 0.08 h

Procedure:
The suspension of 0.5 g of 3-chloro-6-(1-methyl-4-aminomethyl-5-pyrazolyl)-2'-fluorobenzophenone monophosphate in 20 ml of 0.5N aqueous sodium hydroxide and 50 ml of methylene chloride is shaken for 5 min., the organic layer separated, dried and evaporated, to yield the 8-chloro-6-(2-fluorophenyl)-1-methyl-1H,4H-pyrazolo[4,3-d](2)benzazepine melting at 128°; it is identical with that obtained according to Example 2.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([C:14]2[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([C:22]([OH:24])=O)[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])(C)(C)C.C([O:27][C:28](=[O:41])[C@H:29]([OH:40])[C@H:30]([NH2:39])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:38])C.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>C(Cl)Cl>[C:28]([C@H:29]([OH:40])[C@H:30]([NH:39][C:22]([C:16]1[CH:17]=[C:18]([F:21])[C:19]([F:20])=[C:14]([C:9]2[C:8]([C:6]([OH:5])=[O:7])=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=1)=[O:24])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:38])([OH:41])=[O:27]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1cc(C(=O)O)cc(F)c1F
Reactant: CCOC(=O)[C@H](O)[C@H](N)Cc1ccccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H](Cc1ccccc1Cl)[C@@H](O)C(=O)O)c1cc(F)c(F)c(-c2ccccc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 6.6 %

Procedure:
5′,6′-Difluoro-biphenyl-2,3′-dicarboxylic acid 2-t-butyl ester (60 mg, 180 μmol, 1.0 eq.), (2R,3R)-3-amino-4-(2-chloro-phenyl)-2-hydroxy-butyric acid ethyl ester (46.3 mg, 180 μmol, 1.0 eq.), DIPEA (94 μL), and HATU (68.4 mg, 180 μmol) were combined in DCM (2 mL) and was stirred for 45 minutes at room temperature. The reaction was quenched with saturated NH4Cl and extracted with DCM, dried and evaporated. 1:1 DCM:TFA (0.5 mL each) was added and the mixture was stirred for 30 minutes. The solvent was evaporated under vacuum. THF (2 mL) and 10N NaOH (0.3 mL) were added and the mixture was stirred for 2 hours. The reaction was quenched with AcOH and the product was purified by preparative HPLC to yield the title compound (5.8 mg, 97% purity). MS m/z [M+H]+ calc'd for C24H18ClF2NO6, 490.08. found 491.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:11])=[CH:8][CH:7]=1.[CH3:19]O>>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([CH2:12][CH2:13][C:14]([O:16][CH3:19])=[O:15])=[O:11])=[CH:17][CH:18]=1
Reactant: CO
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)CCC(=O)c1ccc(Cl)cc1
Yield: 97 %

Procedure:
Thionyl chloride (2.4 ml, 33 mmol) was added dropwise to a stirred solution of 3-(4-chlorobenzoyl)propionic acid (5.0 g, 24 mmol) in dry methanol (50 ml) at 0° C. The mixture was heated at reflux for 2 h, cooled and the solvent removed under reduced pressure to give methyl 3-(4-chlorobenzoyl)propionate (5.3 g, 97%) as a colourless oil. deltaH (250 MHz, CDCl3) 7.93 (2H, d, J 8.5 Hz), 7.45 (2H, d, J 8.6 Hz), 3.72 (3H, s), 3.29 (2H, t, J 6.6 Hz), 2.78 (2H, t, J 6.6 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:10])[C:7]=1[CH:8]=[O:9].Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=1>>[NH2:21][C:17]1[N:18]=[C:19]([C:4]2[CH:3]=[C:2]([F:1])[C:7]([CH:8]=[O:9])=[C:6]([F:10])[CH:5]=2)[CH:20]=[CH:15][N:16]=1
Reactant: Nc1nccc(Cl)n1
Reactant: O=Cc1c(F)cc(B(O)O)cc1F
Product: Nc1nccc(-c2cc(F)c(C=O)c(F)c2)n1
Yield: 91.3 %

Procedure:
The title compound was prepared following the General Procedure A using: (3,5-difluoro-4-formylphenyl)boronic acid (4.93 g, 26.5 mmol) and 4-chloro-2-pyrimidinamine (3.44 g, 26.5 mmol). Flash chromatography on SiO2 (gradient: 100% CHCl3 to 10% THF/90% CHCl3) afforded the title compound (5.69 g, 75%) as an off-white solid. LC-MS (ES) m/z=236 [M+H]+.
Reaction SMILES: [Na].CS([O:6][CH2:7][C@@H:8]1[O:25][CH2:24][C@:11]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:12]=[C:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[S:14][CH2:15][C@@H:10]2[CH2:9]1)(=O)=O.[Cl-].[NH4+].[CH3:35][CH:36](O)[CH3:37]>>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C@:11]12[CH2:24][O:25][C@@H:8]([CH2:7][O:6][CH:36]([CH3:37])[CH3:35])[CH2:9][C@H:10]1[CH2:15][S:14][C:13]([NH:16][C:17](=[O:18])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:12]2
Reactant: CC(C)O
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)CO[C@@H](COS(C)(=O)=O)C[C@H]2CS1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Product: CC(C)OC[C@H]1C[C@H]2CSC(NC(=O)OC(C)(C)C)=N[C@@]2(c2ccccc2F)CO1
Reaction time: 18 h

Procedure:
The sodium salt of 2-propanol (34 mg, 0.41 mmol) was dissolved in 2-propanol (1.5 mL), and this was added to a solution of [(4aR,6R,8aS)-2-[(tert-butoxycarbonyl)amino]-8a-(2-fluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-6-yl]methyl methanesulfonate (C19) (40 mg, 0.084 mmol) in 2-propanol (0.5 mL). After 18 hours, additional sodium salt (34 mg, 0.41 mmol) was added, and stirring was continued for 66 hours. After addition of aqueous ammonium chloride solution, the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with water, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification was carried out via preparative thin layer chromatography on silica gel (Eluent: 1:1 ethyl acetate/heptane) to provide the product as a white foam. Yield: 11.2 mg, 0.255 mmol, 30%. LCMS m/z 439.4 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.19 (br d, J=6.2 Hz, 6H), 1.54 (s, 9H), 1.63-1.71 (br m, 1H), 1.83-1.97 (br m, 1H), 2.50-2.59 (m, 1H), 2.93 (dd, J=13, 4 Hz, 1H), 3.07-3.18 (br m, 1H), 3.41 (dd, J=9.9, 4.8 Hz, 1H), 3.58-3.68 (m, 2H), 3.72-3.89 (m, 2H), 4.20 (br d, J=12 Hz, 1H), 7.05-7.12 (m, 1H), 7.17-7.23 (m, 1H), 7.30-7.40 (m, 2H).
Reaction SMILES: [S].[NH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[O-:12].Cl>>[NH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[OH:12]
Reactant: Nc1cc([N+](=O)[O-])ccc1[O-]
Agent: Cl
Agent: [S]
Product: Nc1cc([N+](=O)[O-])ccc1O

Procedure:
The preparation of sodium 2,4-dinitrophenolate and the hydrosulphide reduction to give sodium 2-amino-4-nitrophenolate is carried out in accordance with the statements of Example 8. When the reduction has ended, the sulphur-containing 2-amino-4-nitrophenolate solution is added to 310 parts of 30% strength aqueous hydrochloric acid. The sulphur is filtered off from the solution of 2-amino-4-nitro-phenol hydrochloride and 8 parts of concentrated hydrosulphite (sodium dithionite) are added to the filtrate. A pH value of 3.9 is then established with 30% strength sodium hydroxide solution and the 2-amino-4-nitrophenol suspension is cooled to 0°-5° C. After filtration, 190 g of 74.8% strength 2-amino-4-nitrophenol, corresponding to 142.1 g of 100% pure 2-amino-4-nitrophenol (92% of theory, relative to 2,4-dinitrochlorobenzene) are obtained.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH:10](=[O:18])[CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[CH2:13]([CH:12]1[C:11]([CH:10]=[O:18])=[CH:1][C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[O:4]1)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=Cc1ccccc1O
Reactant: CCCCCC=CC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCCCCC1Oc2ccccc2C=C1C=O
Yield: 48 %

Procedure:
A mixture of 22.0 g (0.18 mol) of salicylaldehyde, 25.0 g (0.198 mol) of 2-octenal and 24.8 g (0.18 mol) of potassium carbonate in 200 ml of dioxane, maintained under an inert atmosphere, is heated at reflux for 2.5 h. The reaction mixture is subsequently brought to room temperature (20-25° C.) and then diluted by addition of 1.5 litres of water. The formation of an oil is observed, which oil is extracted with methylene chloride. The organic phase is dried over anhydrous sodium sulphate and then concentrated under reduced pressure. The title compound is thus obtained in a form of an orange oil, which oil is distilled under reduced pressure (B.p. (0.44 mm Hg): 132-140° C.). 20 g of the title product are obtained by distillation (48% yield).
Reaction SMILES: [C:1]([C:7]1[O:8][CH:9]=[CH:10][C:11]=1[NH:12]C(=O)OC(C)(C)C)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl>C(OCC)(=O)C>[NH2:12][C:11]1[CH:10]=[CH:9][O:8][C:7]=1[C:1](=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5]
Reactant: CC(C)(C)OC(=O)Nc1ccoc1C(=O)C(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)c1occc1N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of t-butyl (2-pivaloylfuran-3-yl)carbamate (2.15 g, 8.0 mmol) in ethyl acetate (25 ml) was saturated With anhydrous hydrogen chloride gas at 0° C. The solution was stirred at ambient temperature for 5 hours. and then was evaporated to dryness in vacuo. The residual solid was taken up in ethyl acetate (50 ml) and saturated NaHCO3 (20 ml). Additional solid NaHCO3 was added to basify the mixture. The ethyl acetate extract was separated, washed with saturated NaCl, dried over Na2SO4, filtered and concentrated in vacuo to an amber liquid (1.34 g).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5]I)[CH2:3][CH2:2]1.C([Li])(C)(C)C.[Cl:12][C:13]1[CH:22]=[CH:21][C:20]2[N:19]=[C:18]3[C:23](=[O:27])[NH:24][CH:25]=[N:26][C:17]3=[C:16]([C:28]([F:31])([F:30])[F:29])[C:15]=2[CH:14]=1>CCOCC.C1COCC1>[Cl:12][C:13]1[CH:22]=[CH:21][C:20]2[NH:19][C:18]3[C:23](=[O:27])[NH:24][CH:25]=[N:26][C:17]=3[C:16]([CH2:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)([C:28]([F:30])([F:29])[F:31])[C:15]=2[CH:14]=1
Reactant: ICCC1CC1
Reactant: O=c1[nH]cnc2c(C(F)(F)F)c3cc(Cl)ccc3nc12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=c1[nH]cnc2c1Nc1ccc(Cl)cc1C2(CCC1CC1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 61.7 %

Procedure:
To a stirred solution of 1-cyclopropyl-2-iodoethane (12.5g, 63.9 mmol, 5 equiv) in anhydrous Et2O (128 mL) at −78° C. was added tert-butyl lithium (1.7M in pentane, 75 mL, 128 mmol, 10 equiv). The resulting white suspension was stirred at −78° C. for 50 min and added via cannula to a suspension of 7 (3.83 g, 12.8 mmol) in THF (64 mL) at −78° C. The resulting dark yellow mixture was stirred at −78° C. for 30 min and then allowed to warm to 0° C. over 5 h. The reaction was quenched with satd. NH4Cl (100 mL) and H2O (100 mL). The reaction mixture was extracted with EtOAc (3×100 mL) and the combined organic layers washed with brine and dried (MgSO4). Chromatography (SiO2, 40 to 50% EtOAc-hexane) provided the desired product as a yellow solid (2.92 g, 62%). ESI HRMS m/z 370.1735 (M++H, C17H16ClF3N3O requires 370.0934).