Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C@H:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH:20]=[O:21])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.C[Si]([C:35]([F:38])([F:37])[F:36])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C@H:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH:20]([OH:21])[C:35]([F:38])([F:37])[F:36])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCCC[C@H](C=O)NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCC[C@@H](NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12)C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
430 mg of 8-[(2,6-difluorobenzyl)oxy]-2-methyl-N-[(2R)-1-oxohexan-2-yl]imidazo[1,2-a]pyridine-3-carboxamide (1.05 mmol) were initially charged in 30 ml of dry THF, and 194 μl of trimethylsilyl trifluoromethane (1.24 mmol) and 621 μl of tetrabutylammonium fluoride solution (1.0 M in THF; 0.62 mmol) were successively added dropwise at 0° C. The reaction mixture was slowly warmed to RT, and stirring was continued overnight. The mixture was then concentrated and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, dried, filtered and concentrated. Preparative HPLC separation (Method 9) afforded 41 mg of the target compound, which was once more purified by HPLC (Method 10). This gave 28.4 mg of the target compound. The diastereomer ratio was about 3:1 (1H NMR integration).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH2:17][CH2:18][S:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([Cl:31])=[C:27]([NH2:30])[CH:28]=2)[NH:23][C:22](=[O:32])[C:21]=1[C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[C:35]([CH3:40])[CH:34]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:41]1[CH:46]=C[CH:44]=[CH:43][CH:42]=1.C(Cl)(Cl)=[O:48].C1(N)CC1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH2:17][CH2:18][S:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([Cl:31])=[C:27]([NH:30][C:46]([NH:41][CH:42]3[CH2:44][CH2:43]3)=[O:48])[CH:28]=2)[NH:23][C:22](=[O:32])[C:21]=1[C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[C:35]([CH3:40])[CH:34]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccncc1
Reactant: Cc1cc(C)cc(-c2c(SCCC3CCCCN3C(=O)OCc3ccccc3)c3cc(N)c(Cl)cc3[nH]c2=O)c1
Reactant: O=C(Cl)Cl
Agent: NC1CC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(-c2c(SCCC3CCCCN3C(=O)OCc3ccccc3)c3cc(NC(=O)NC4CC4)c(Cl)cc3[nH]c2=O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-{2-[6-amino-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-ylsulfanyl]-ethyl }-piperidine-1-carboxylic acid benzyl ester (23 mg in 1.0 mL methylene chloride) at 0° C. was added 0.01 mL pyridine followed by phosgene (0.03 mL of a 1.93M solution in toluene) and the mixture allowed to stir at 0° C. for 1 hour. At this time 0.02 mL of cyclopropylamine was added via syringe and the reaction mixture warmed to room temperature. After 4 hours, the mixture was diluted with ethyl acetate and washed sequentially with 10% aqueous sodium bisulfate, water and brine. The organic portion was dried over magnesium sulfate then concentrated in vacuo. Purification of the crude material by flash chromatography on silica gel (chloroform:methanol, 95:5) gave the title compound (18 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C@@H:9]1[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH3:28])=[CH:23][CH:22]=1)=O)(C)(C)C.Cl>ClCCl.C(OCC)(=O)C>[CH:29]1([N:27]([C:24]2[CH:25]=[CH:26][C:21]([C@H:9]3[CH2:10][NH:11][CH2:12][CH2:13][NH:8]3)=[CH:22][CH:23]=2)[CH3:28])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CN(c1ccc([C@H]2CN(C(=O)OC(C)(C)C)CCN2C(=O)OC(C)(C)C)cc1)C1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(c1ccc([C@H]2CNCCN2)cc1)C1CCCCC1
Reaction time: 0.67 h
Yield: 8 %

Procedure:
To a solution of (S)-1,4-di(t-butoxycarbonyl)-2-(4-(N-cyclohexyl-N-methylamino)phenyl)piperazine in dichloromethane (4 mL) was added 4 N hydrogen chloride in ethyl acetate (4 mL). After stirring for 40 min, the white precipitate was collected, which included impurities. The mixture was purified by a reverse phase chromatography eluting 0.05% TFA in water-acetonitrile to afford (S)-2-(4-(N-cyclohexyl-N-methylamino)phenyl)piperazine (59 mg 8% in 2 steps) as a clear oil.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33].CC(C)=O>O.CO>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Solvent: O
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 8.2 %

Procedure:
Fluvastatin methyl ester (3.0 g) was added to a solution of NaOH (1 eq.) in water (0.75 ml) and methanol (7.5 ml). The mixture was stirred at about 65EC for 3.5 h. Then, another portion of NaOH (0.5 eq.) in water (0.4 ml) was added. After another 40 min the starting material was no longer detectable by HPLC. Acetone (58 ml) was dripped into the solution over 25 min. Turbidity appeared in the solution. The mixture was cooled slowly to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with acetone (20 ml) and dried at 50EC in a vacuum oven for 24 h to obtain 0.25 g (8.2%) of fluvastatin sodium Form XXX.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]2[O:8][C@@H:4]([CH2:5][CH2:6]2)[C@@H:3]1[C:9]([O:11][CH3:12])=[O:10].CCN(CC)CC.[O:20](C(OC(C)(C)C)=O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O>C(#N)C>[C:24]([O:23][C:21]([NH:1][C@@H:2]1[C@@H:7]2[O:8][C@@H:4]([CH2:5][CH2:6]2)[C@@H:3]1[C:9]([O:11][CH3:12])=[O:10])=[O:20])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H]1[C@H](N)[C@H]2CC[C@@H]1O2
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1[C@H](NC(=O)OC(C)(C)C)[C@H]2CC[C@@H]1O2
Temperature: 80 °C
Yield: 92.1 %

Procedure:
A solution of (1S,2R,3S,4R)-methyl 3-amino-7-oxabicyclo[2.2.1]heptane-2-carboxylate (11) (500 mg, 2.4 mmol), Et3N (0.85 ml, 6 mmol) and BOC2O (0.66 ml, 2.88 mmol) in acetonitrile was stirred at rt for 2 h and then heated at 80° C. for 30 min when TLC confirmed completion of reaction. Acetonitrile was removed and the crude product was purified by column chromatography using silica gel (100-200 mesh) to afford the desired compound (600 mg, 92%) as a colourless oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[C:28]([CH3:36])=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:70][C:71]1[CH:77]=[CH:76][C:74]([NH2:75])=[CH:73][CH:72]=1>CN(C=O)C>[CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[C:28]([CH3:36])=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:75][C:74]2[CH:76]=[CH:77][C:71]([F:70])=[CH:72][CH:73]=2)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:2]
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: Nc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)Nc3ccc(F)cc3)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-2-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and 4-fluoroaniline (9.6 uL, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (14 mg, 46%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([C:10]2[CH:20]=[C:19]([CH3:21])[C:13]3[N:14]([CH3:18])[C:15](=[O:17])[O:16][C:12]=3[CH:11]=2)=[O:9])[CH:3]=1.BrN1C(=O)CCC1=O.[N:30]([C:37]([CH3:41])(C)C#N)=[N:31][C:32](C)(C)C#N.N1C=CC=N1.CCN(C(C)C)C(C)C>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([C:10]2[CH:20]=[C:19]([CH2:21][N:31]3[CH:32]=[CH:41][CH:37]=[N:30]3)[C:13]3[N:14]([CH3:18])[C:15](=[O:17])[O:16][C:12]=3[CH:11]=2)=[O:9])[CH:3]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Agent: c1cn[nH]c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1c(=O)oc2cc(C(=O)c3cc(Cl)ncn3)cc(Cn3cccn3)c21

Procedure:
Under a nitrogen atmosphere 0.15 g (0.49 mmol) 6-(6-chloropyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one, 95 mg (0.53 mmol) N-bromosuccinimide and 5.0 mg (30 mmol) 2,2′-azobis-isobutyronitrile (AIBN) in 15 mL carbon tetrachloride were combined and refluxed for 4 h. The precipitate formed was filtered off and the filtrate was combined with 20 μL isopropanol. After brief stirring 36 mg (0.53 mmol) pyrazole and 0.17 mL (0.99 mmol) DIPEA were added and the mixture was refluxed for 6 h. Then the reaction mixture was filtered through silica gel and washed with DCM/EtOAc (1/1). The filtrate was evaporated down i. vac. and the residue was reacted further as the crude product.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]2[C:11]([CH2:12]Br)=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:9][N:8]=2)=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22](=[O:36])[CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35])[CH3:20].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[Br:1][C:2]1[O:6][C:5]([C:7]2[C:11]([CH2:12][N:24]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=3[O:34][CH3:35])[CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:36])=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1onc(-c2ccc(Br)o2)c1CBr
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1c(-c2ccc(Br)o2)noc1C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.4 %

Procedure:
Ethyl 3-(5-bromofuran-2-yl)-4-(bromomethyl)isoxazole-5-carboxylate (1.8 g, 4.75 mmol) was dissolved in 20 mL of DMF. N-(2,4-dimethoxybenzyl)glycine ethyl ester (1.2 g, 4.75 mmol) and potassium carbonate (1.3 g, 9.50 mmol) were added, and the mixture was stirred at room temperature for 16 h. EtOAc (50 mL) and water (50 mL) were added and the aqueous layer was extracted with additional EtOAc. The combined organic layer was washed with water and brine, and dried over MgSO4. After solvent was removed in vacuo, the crude was purified by flash chromatography (0-40% EtOAc/hexanes) to give 1.53 g of the title compound. MS: (+) m/z 551.44, 553.35 (M+1, 79Br/81Br).
Reaction SMILES: CN(C1C=CC=CC=1)/[CH:3]=[CH:4]/[CH:5]=[CH:6]/[CH:7]=[O:8].[CH2:15]([N:19]([CH2:26][CH2:27][CH2:28][CH3:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:16][CH2:17][CH3:18].P(Cl)(Cl)(Cl)=O>C1COCC1>[CH2:15]([N:19]([CH2:26][CH2:27][CH2:28][CH3:29])[C:20]1[CH:25]=[CH:24][C:23](/[CH:3]=[CH:4]/[CH:5]=[CH:6]/[CH:7]=[O:8])=[CH:22][CH:21]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCN(CCCC)c1ccccc1
Reactant: CN(/C=C/C=C/C=O)c1ccccc1
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCN(CCCC)c1ccc(/C=C/C=C/C=O)cc1
Temperature: 50 °C
Reaction time: 0.58 h
Yield: 13 %

Procedure:
To a solution of the vinylogous amide 2 (1.135 g, 6.06 mmol) and dibutylaniline (1.43 g) in dry THF (6 ml) at −20° C. was added a solution of phosphorus oxychloride (1.08 g, 1.17 eq.) and dibutylaniline (1.03 g, 1.98 eq. for the sum) in THF (3.6 ml) dropwise at such a rate as to keep the mixture between −10° C. and −20° C. Following the addition, the mixture was stirred at room temperature for 2 hours and at 50° C. for 35 minutes. To the reaction mixture (a dark blue-green oil) was added petroleum ether (25 ml) and the mixture was triturated; the ether was separated and discarded. Methanol (4 ml) was then added and the mixture was neutralized with 2N NaOH. Silicagel was then added, the suspension was diluted with ethyl acetate and methanol and dried to a solid on the rotovap. The crude product was purified by MPLC using hexanes-ethyl acetate 5-30% gradient to give the desired aldehyde as an intense yellow oil (225 mg, 13%). MS (EI): 285 (M+, 45%); 242 (100%); 200 (85%); 128 (30%); 118 (40%). H-NMR (CDCl3): 0.95 (t, J=12 Hz, 6H); 1.35 (m, 4H); 1.45 (m, 4H); 3.8 (t, J=9 Hz, 4H); 6.4, (d, J=17 Hz, 1 H); 6.5-6.8 (m, 3H); 7.1 (d, J=15 Hz,1 H); 7.5 (d, J=17 Hz,1 H); 7.8 (d, J=11 Hzm 2H); 9.8 (s,1 H).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:25])[NH:6][C:7]2[C:12]([C:13]=1C)=[C:11](OS(O)(=O)=O)[C:10]([Cl:20])=[CH:9][C:8]=2[C:21]([F:24])([F:23])[F:22])(=[O:3])[CH3:2].[CH2:26]([NH2:28])[CH3:27]>>[C:1]([C:4]1[C:5](=[O:25])[NH:6][C:7]2[C:12]([C:13]=1[NH:28][CH2:26][CH3:27])=[CH:11][C:10]([Cl:20])=[CH:9][C:8]=2[C:21]([F:24])([F:22])[F:23])(=[O:3])[CH3:2]
Reactant: CCN
Reactant: CC(=O)c1c(C)c2c(OS(=O)(=O)O)c(Cl)cc(C(F)(F)F)c2[nH]c1=O
Product: CCNc1c(C(C)=O)c(=O)[nH]c2c(C(F)(F)F)cc(Cl)cc12
Yield: 75.7 %

Procedure:
3-Acetyl-6-chloro-8-trifluoromethyl-4-methylsulfoxy-2-quinolinone (3.5g, 0.01 mol) and ethylamine(70 wt % solution; 0.65g, 0.01 mol) were used, but the reaction was carried out as the above process of example 37 to obtain the desired product (2.52g, yield: 76%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=[O:23])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21][CH3:22])[CH:15]=2)=[C:5]([O:24][CH2:25][C:26]([O:28]C)=[O:27])[C:4]=1[CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33].[OH-].[K+].Cl>CO>[C:26]([CH2:25][O:24][C:5]1[C:4]([CH2:30][CH2:31][CH:32]([CH3:33])[CH3:34])=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[C:6]=1[C:11](=[O:23])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21][CH3:22])[CH:15]=1)([OH:28])=[O:27]
Reactant: COC(=O)COc1c(CCC(C)C)c(OC)cc(OC)c1C(=O)CCc1ccc(O)c(OC)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(CCC(=O)c2c(OC)cc(OC)c(CCC(C)C)c2OCC(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
Then, 12.0 g of 1-(4,6-dimethoxy-2-methoxycarbonylmethoxy-3-isopentylphenyl)-3-(4-hydroxy-3-methoxyphenyl)-1-propanone was dissolved in 120 ml of methanol, and 70 ml of a 5% aqueous solution of potassium hydroxide was added to the solution and the mixture was stirred at room temperature for 20 minutes. Then, the reaction mixture was made weakly acidic by addition of dilute hydrochloric acid, and the solvent was removed by distillation and the residue was crystallized from ethyl acetate/diethyl ether/hexane to obtain 9.7 g (yield=85% of 1-(2-carboxymethoxy-4,6-dimethoxy-3-isopentylphenyl)-3-(4-hydroxy-3-methoxyphenyl)-1-propanone in the form of a white solid.
Reaction SMILES: [F:1][C:2]1([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[N+:20]([O-:22])=[O:21])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[F:23][CH2:24][C:25](=O)[CH2:26][F:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CN(C)C=O>ClCCl>[F:23][CH2:24][CH:25]([N:5]1[CH2:6][CH2:7][C:2]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[N+:20]([O-:22])=[O:21])([F:1])[CH2:3][CH2:4]1)[CH2:26][F:27]
Reactant: NS(=O)(=O)c1ccc(OCC2(F)CCNCC2)c([N+](=O)[O-])c1
Reactant: O=C(CF)CF
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(OCC2(F)CCN(C(CF)CF)CC2)c([N+](=O)[O-])c1
Reaction time: 0.25 h

Procedure:
To a suspension of EXAMPLE 341C (0.100 g) and 1,3-difluoropropan-2-one (0.025 g) in dichloromethane (2 mL) was added sodium triacetoxyborohydride (0.071 g). After 15 minutes, N,N-dimethylformamide was added dropwise until an orange solution resulted (˜15 drops). After stirring overnight additional 1,3-difluoropropan-2-one and sodium triacetoxyborohydride were added. After 3 hours, the reaction was loaded onto silica gel (Reveleris 40 g) and eluted with a gradient of 0.5-5% methanol/dichloromethane over 30 minutes (flow=40 ml/minutes) to provide the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][P:24]([O:29][CH2:30][CH3:31])(=[O:28])[O:25][CH2:26][CH3:27]>>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:21][CH2:22][CH2:23][P:24](=[O:28])([O:29][CH2:30][CH3:31])[O:25][CH2:26][CH3:27])[C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Reactant: CCOP(=O)(CCCBr)OCC
Product: CCOP(=O)(CCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O)OCC

Procedure:
The title substance was prepared from 7-benzyl-3-methylxanthine, (0.04 mol) and diethyl 3-bromopropanphosphonate (0.046 mol) analogously to Example 23.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH3:7][C@@H:8]1[O:13][S:12](=[O:14])[N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]1.Cl.CC[O:25]C(C)=O>C(#N)C.O>[CH3:7][C@@H:8]1[O:13][S:12](=[O:25])(=[O:14])[N:11]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:10][CH2:9]1
Reactant: C[C@H]1CCN(C(=O)OC(C)(C)C)S(=O)O1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: C[C@H]1CCN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
Sodium periodate (341 g, 1.6 mol) is added to a solution of tert-butyl (6S)-6-methyl-1,2,3-oxathiazinane-3-carboxylate 2-oxide (250 g, 1062 mmol) in acetonitrile (2.5 L) and water (1.5 L) at 0° C. The pH of the mixture is adjusted to 7 by the addition of saturated Na2HPO4 solution. A solution of RuCl33H2O (2.20 g, 10.62 mmol) is added at 5° C. and the pH of mixture is kept at 7 by addition of saturated Na2HPO4 solution. The reaction is stirred at room temperature for 2 h. Water is added and pH is adjusted to 6 by addition of 2.0 M HCl solution. EtOAc (1.0 L) is added and the aqueous layer is separated and extracted with EtOAc (2×500 mL). The organic layers are combined, washed with saturated NaHCO3 solution and brine, dried (Na2SO4) and concentrated to afford the crude compound which is purified by flash column chromatography using EtOAc in hexane to afford the title compound (140 g, 52%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[C:13](Cl)(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCOCC1.C(Cl)Cl>[C:14]1([C:13]2[O:12][C:3]3[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=3[N:1]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(-c3ccccc3)oc2c1
Temperature: 210 °C
Yield: 85.6 %

Procedure:
A mixture of methyl 4-amino-3-hydroxy-benzoate 25a (0.3 g, 1.8 mmol) and benzoyl chloride 25b (0.23 mL, 2.0 mmol) in dioxane (2.5 mL) was heated at 210° C. under microwave for 15 min. The reaction mixture was diluted with CH2Cl2 and washed with aq. NaHCO3. The organic solution was dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, 20% EtOAc/heptane) to give 25c (0.39 g).
Reaction SMILES: [CH:1]12[O:9][CH:5]([CH2:6][NH:7][CH2:8]1)[CH2:4][N:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:2]2.Cl[CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.BrBr.C([O-])([O-])=O.[K+].[K+]>>[N:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][CH2:19][CH2:18][N:7]2[CH2:6][CH:5]3[O:9][CH:1]([CH2:2][N:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4]3)[CH2:8]2)=[CH:23][CH:24]=1
Reactant: ClCCCCc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CC2CN(CCCCc3ccncc3)CC(C1)O2
Yield: 45.5 %

Procedure:
tert-Butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (1.35 g, 5.9 mmol, see Preparation A and Preparation C(iii) above) was mixed with 4-(4-chlorobutyl)pyridine (1.35 g, 7.37 mmol, see Example 10(i) above), Br2 (0.094 g, 0.59 mmol ) and K2CO3 (3.26 g, 23.6 mmol). The mixture was refluxed under argon for 3 days. The reaction mixture was filtered, evaporated and purified by chromatography (DCM, 2-5% MeOH) giving 0.97 g (44%) of the sub-title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH2:30])[N:17]=[CH:16]2.CCN(C(C)C)C(C)C.[C:40](Cl)(=[O:43])[CH:41]=[CH2:42]>ClCCl>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH:30][C:40](=[O:43])[CH:41]=[CH2:42])[N:17]=[CH:16]2
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4CCCC[C@@H]4N)ncc3c2)c1Cl
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N[C@H]1CCCC[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ccc2n1
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of (1R,2S)—N1-(6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)cyclohexane-1,2-diamine (0.94 g, 2.1 mmol) in dichloromethane (25 mL) at 0° C. was added DIEA (0.37 mL, 2.1 mmol) and acryloyl chloride (0.17 mL, 2.1 mmol) and the reaction was stirred for 3 h. LC-MS indicated complete consumption of SM. The reaction mixture was purified by silica gel chromatography to yield N-((1S,2R)-2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)cyclohexyl)acrylamide (0.8 g, 76%). MS (ES+) C25H26Cl2N4O3 requires: 500, found: 501.
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].C(N(CC)CC)C.ClC(OCC(C)C)=O.Cl.[CH3:25][NH:26][O:27][CH3:28]>C(Cl)(Cl)Cl>[CH3:28][O:27][N:26]([CH3:25])[C:1](=[O:8])[CH2:2][CH2:3][C:4](=[O:5])[CH3:6]
Reactant: CC(=O)CCC(=O)O
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CON(C)C(=O)CCC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of levulinic acid (30 g, 0.258 mol) in 850 mL CHCl3 at 0° C. was added triethylamine (43.2 mL, 0.310 mol), followed by isobutyl chloroformate (37 mL, 0.284 mol) over 15 minutes. After 30 minutes, triethylamine (57.6 mL, 0.413 mol) was added, followed by N,O-dimethylhydroxylamine hydrochloride (37.8 g, 0.387 mol) in 5 portions over 5 minutes. Vigorous bubbling ensued, and the mixture was allowed to warm to RT and stir for 1 h. The mixture was reduced to a moist solid by rotary evaporation under reduced pressure, slurried in 500 mL EtOAc, washed with 10% K2CO3, brine, and dried over Na2SO4. Evaporative removal of the solvent gave 4-1 as a yellow oil.