Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([CH3:7])[S:4][C:3]=1[CH:8]=O.[NH2:10]OS(O)(=O)=O>O>[Br:1][C:2]1[CH:6]=[C:5]([CH3:7])[S:4][C:3]=1[C:8]#[N:10]
Reactant: Cc1cc(Br)c(C=O)s1
Reactant: NOS(=O)(=O)O
Solvent: O
Product: Cc1cc(Br)c(C#N)s1
Temperature: 50 °C
Yield: 83.2 %

Procedure:
To a suspension of 3-bromo-5-methyl-2-thiophenecarboxaldehyde (500 mg) in water (10 ml) was added hydroxylamine-O-sulfonic acid (330 mg). The mixture was heated to 50° C. for 12 h and allowed to cool. The mixture was then extracted with ethyl acetate (3×50 ml). The combined organic layers were washed (brine), dried (MgSO4), filtered and evaporated to leave the sub-title compound (410 mg) as a brown solid.
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][CH:12]([CH:16]([S:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=2)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13](O)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[O:51][NH2:52]>C(Cl)Cl>[OH:51][NH:52][C:13](=[O:14])[CH:12]([CH2:11][CH2:10][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])[CH:16]([S:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(SC(CCCCc2ccccc2)C(CCS(=O)(=O)c2ccccc2)C(=O)O)cc1OC
Reactant: C[Si](C)(C)ON
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(SC(CCCCc2ccccc2)C(CCS(=O)(=O)c2ccccc2)C(=O)NO)cc1OC
Reaction time: 0.5 h
Yield: 189.5 %

Procedure:
To a solution containing (-)-2-(2-benzenesulfonylethyl)-3-(3,4-dimethoxyphenylsulfanyl)-7-phenylheptanoic acid (285 mg, 0.53 mmol) in anhydrous CH2Cl2 (10 mL) under nitrogen atmosphere is added anhydrous DMF (41 μL, 0.53 mmol) followed by oxalyl chloride (2 M in CH2Cl2, 0.66 mL, 1.31 mmol). The yellow solution is stirred for 30 minutes then O-(trimethylsilyl)hydroxylamine (0.32 mL, 2.65 mmol) is added dropwise. The resulting white precipitate is stirred for 10 minutes then partitioned between 1 N HCl (50 mL) and ethyl acetate (50 mL). The aqueous layer is extracted with ethyl acetate (2×20 mL) and the combined organic extracts are washed with water (30 mL), brine (30 mL), dried over anhydrous MgSO4, filtered and concentrated to afford a pale yellow oil. The crude product is combined with the product of a reaction performed on identical scale and chromatographed on silica gel (CH2Cl2 →CH2Cl2 :MeOH, 19:1) to afford (-)-N-hydroxy-2-(2-benzenesulfonylethyl)-3-(3,4-dimethoxyphenylsulfanyl)-7-phenylheptanamide (560 mg, 95%) as a cream-colored foam. TLC analysis [pet-ether/EtOAc, 1:2, Rf (carboxylic acid)=0.45, Rf (hydroxamate)=0.40]. [α]23D -28° (c 1.1, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.40-1.80 (m, 6H), 2.10 (m, 1H), 2.22 (m, 1H), 2.60 (m, 2H), 2.68 (m, 1H), 3.05 (broad s, 3H), 3.83 (s, 3H), 3.84 (s, 3H), 6.76 (d, J=8.7 Hz, 1H), 6.98 (m, 2H), 7.12 (m, 3H), 7.28 (m, 2H), 7.52 (m, 2H), 7.64 (t, J=7.3 Hz, 1H), 7.84 (d, J=7.4 Hz, 2H), 8.85 (broad s, 1H) ppm. Mass spectrum (FAB) m/z 557 (M)+.
Reaction SMILES: [CH3:1][N:2]([CH:9]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[S:24][C:23]3[C:18](=[N:19][CH:20]=[CH:21][C:22]=3Cl)[CH:17]=2)=[O:15])[CH2:10]1)[C:3]([CH:5]1[CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:26][C:27]1[NH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][C:32]([NH2:36])=[CH:31][CH:30]=2>>[CH3:1][N:2]([CH:9]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[S:24][C:23]3[C:18](=[N:19][CH:20]=[CH:21][C:22]=3[NH:36][C:32]3[CH:33]=[C:34]4[C:29](=[CH:30][CH:31]=3)[NH:28][C:27]([CH3:26])=[CH:35]4)[CH:17]=2)=[O:15])[CH2:10]1)[C:3]([CH:5]1[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: CN(C(=O)C1CCC1)C1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CCC(N(C)C(=O)C6CCC6)C5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from (+/−)-cyclobutane carboxylic acid methyl-{1-[7-chloro-thieno[3,2-b]pyridine-2-carbonyl]-pyrrolidin-3-yl}-amide and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C. MS: 488 (MH+); HPLC Rf: 4.84 min.; HPLC purity 95%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[NH:4][C@H:5]([C:10]([NH:12][NH:13][CH2:14][CH2:15][C@:16]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([OH:33])[C:17]([N:19]1[C@H:23]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[CH2:30][C@H:22]2[O:21]C1(C)C)=[O:18])=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7].C([O-])([O-])=O.[K+].[K+].[Br:48][C:49]1[CH:56]=[CH:55][C:52]([CH2:53]Br)=[CH:51][CH:50]=1>CC(=O)CC>[CH3:1][O:2][C:3](=[O:41])[NH:4][C@@H:5]([C:10]([NH:12][N:13]([CH2:53][C:52]1[CH:55]=[CH:56][C:49]([Br:48])=[CH:50][CH:51]=1)[CH2:14][CH2:15][C@@:16]([OH:33])([C:17](=[O:18])[NH:19][C@H:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30][C@H:22]1[OH:21])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:11])[C:6]([CH3:7])([CH3:9])[CH3:8]
Reactant: COC(=O)N[C@H](C(=O)NNCC[C@@](O)(Cc1ccccc1)C(=O)N1[C@H]2c3ccccc3C[C@H]2OC1(C)C)C(C)(C)C
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)N[C@@H](C(=O)NN(CC[C@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)Cc1ccc(Br)cc1)C(C)(C)C
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Compound 21i (0.105 g) was dissolved in 2-butanone (10 mL) and added K2CO3 (0.045 g, 0.32 mmol), and 4-bromobenzyl bromide (0.054 g, 0.21 mmol) and stirred at 80° C. for 3 h. Solvent was evaporated and the residue was dissolved in dichloromethane (15 mL), washed with water, brine and cooled to 0° C. TFA (1.0 mL) was added slowly and stirred for 30 min then evaporated. Residue dissolved in dichloromethane (10 mL) and washed with NaHCO3 solution, water, brine and dried. Residue was purified by analytical preparative LCMS to yield 0.023 g (15% overall yield) of the title compound.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[N:42]=5)=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[N+:42]=5[O-:58])=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc(C)n4)cc2)CCN3C(=O)C(F)(F)F)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc(C)[n+]4[O-])cc2)CCN3C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.3 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(6-methylpyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (340 mg) in dichloromethane (10 ml) was added 3-chloroperbenzoic acid (70%, 0.15 g) at 0° C. and the mixture was stirred at room temperature for 20 hours. To the reaction solution was added sodium thiosulfate solution and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:19) and further recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(6-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 96) (262 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:8][C:7](=[O:9])[C:6]1[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=1)[OH:11])[CH3:18]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(Cl)ccc1O

Procedure:
A solution of 5-chlorosalicylic acid (5.0 g) in ethanol (50 mL) was added with concentrated sulfuric acid (2.0 mL), and heated under reflux for 24 hours. After the ethanol was evaporated under reduced pressure, the resultant oil was dissolved in ethyl acetate, and the solution was washed with saturated aqueous solution of sodium hydrogencarbonate. The ethyl acetate layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure to obtain roughly purified 5-chlorosalicylic acid ethyl ester (5.3 g). This product was treated with 70% nitric acid (7.2 mL, d=1.42) in acetic anhydride (40 mL) under ice cooling. The reaction mixture was stirred at the same temperature for 6 hours, and poured into iced water, and the deposited crystals were collected by filtration. The crystals were washed with water, and dried under reduced pressure to obtain the title compound (1.48 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N+:10]([O-])=[C:9]([CH3:14])[CH:8]=1.C([OH:17])C>C(OC(=O)C)(=O)C>[OH:17][CH2:14][C:9]1[CH:8]=[C:7]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:12]=[CH:11][N:10]=1
Reactant: CCO
Reactant: COCCCOc1cc[n+]([O-])c(C)c1
Solvent: CC(=O)OC(C)=O
Product: COCCCOc1ccnc(CO)c1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
4.05 g (0.02 mol) of 4-methoxypropoxy-2-methylpyridine 1-oxide was dissolved in 50 ml of acetic anhydride to obtain a solution. This solution was stirred at 90° C. for 0.5 hour and cooled, followed by the addition of ethanol. The obtained mixture was concentrated under a reduced pressure, followed by the addition of 150 ml of 1N hydrochloric acid. The obtained mixture was stirred at 100° C. for one hour, cooled, neutralized with sodium hydrogencarbonate and, extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. Thus, 3.64 g of the title compound was obtained as a crude product.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:25])[N:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:29]([O:31][CH2:32][C:33]([Cl:36])([Cl:35])[Cl:34])=[O:30]>CCOC(C)=O>[Cl:34][C:33]([Cl:36])([Cl:35])[CH2:32][O:31][C:29](=[O:30])[NH:25][C:7]1[N:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[CH:11]=2)[N:9]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2cc(Cl)cc(O[Si](C)(C)C(C)(C)C)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cc(Cl)cc(O[Si](C)(C)C(C)(C)C)c2)n1
Reaction time: 5 h
Yield: 107.9 %

Procedure:
To a bi-phasic mixture of Intermediate 62c (807 mg, 2.12 mmol) in EtOAc (7.5 mL) and 1N NaOH solution (1.38 ml, 1.38 mmol) at 0° C. was added 2,2,2-trichloroethyl chloroformate (0.35 mL, 2.54 mmol) and the mixture stirred for 5 h. The layers were separated and the organic layer was washed with brine, dried and concentrated in vacuo to give the title compound (1.27 g, 99%). LCMS (Method 3): Rt 5.66 min, m/z 553, 555, 557 [MH+].
Reaction SMILES: [Li]CCCC.Br[C:7]1[N:11]([CH3:12])[C:10]([CH3:13])=[N:9][CH:8]=1.CON(C)[C:17]([CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:18]>C1COCC1>[CH3:12][N:11]1[C:7]([C:17]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])=[CH:8][N:9]=[C:10]1[CH3:13]
Reactant: Cc1ncc(Br)n1C
Reactant: CON(C)C(=O)C1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ncc(C(=O)C2CCOCC2)n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of n-BuLi (4.0 mL, 10 mmol, 2.5 M solution in hexane) was slowly added to a solution of 5-bromo-1,2-dimethyl-1H-imidazole (1.77 g, 10.2 mmol) in THF (70 mL) at −78° C. After addition, stirring was continued for an additional 30 minutes and N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide (1.76 g, 10.1 mmol, Intermediate 1: step a, Procedure A) dissolved in THF (25 mL) was slowly added. An additional 6 mL of THF was used to complete the quantitative addition. The mixture was stirred at −78° C. for 5 minutes then warmed to room temperature and stirred for 1 hour. The solution was quenched with water and layers were separated. The aqueous layer was extracted with DCM and the combined organic extracts washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The crude product was purified using flash column chromatography (0 to 6% MeOH/DCM) to provide the title compound.
Reaction SMILES: [F:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.S(=O)(=O)(O)O.[CH3:20]O>>[F:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([O:8][CH3:20])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: O=C(O)c1cc(O)c(F)cc1[N+](=O)[O-]
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(O)c(F)cc1[N+](=O)[O-]
Temperature: 12.5 °C
Reaction time: 13.5 h
Yield: 85 %

Procedure:
Starting material 4-fluoro-5-hydroxy-2-nitrobenzoic acid, 68 g, 0.34 mol, 1.0 eq) and methanol (140 mL) were charging into a reactor under nitrogen. The solution was cooled to 10-15° C. Sulfuric acid (120 g, 1.2 mol, 3.5 eq) was added at a rate that the internal temperature was below 30° C. The reaction mixture was'refluxed at 65-75° C. for 12-15 hour until HPLC sample showed the conversion was higher than 96%. The mixture was concentrated to minimum volume and the residue was charged into cold water (400 mL) slowly so that the batch was kept below 25° C. The resulting suspension was stirred at 10-15° C. for about 2 hours. The slurry was filtered. The desired product, methyl 4-fluoro-5-hydroxy-2-nitrobenzoate, was obtained as a light brown solid after drying under vacuum (62 g, 85% yield). 1H NMR (CDCl3, 400 MHz) δ 7.84 (d, J=9.7 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 6.66 (s, 1H), 3.93 (s, 3H). 13C NMR (DMSO-4, 100 MHz) δ 165.3, 157.6, 151.9, 151.0, 150.8, 149.4, 138.0, 137.9, 125.9, 117.4, 114.1, 113.8, 53.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[N:9]=[CH:8][NH:7][C:6]2=O.S(Cl)([Cl:24])=O>CN(C=O)C>[Cl:24][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COCCOCCOc1cc2nc[nH]c(=O)c2cc1OC
Solvent: CN(C)C=O
Product: COCCOCCOc1cc2ncnc(Cl)c2cc1OC
Yield: 87 %

Procedure:
A solution of 6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-3,4-dihydroquinazolin-4-one (930 mg, 3.16 mmol) in thionyl chloride (15 ml) and DMF (150 μl) was heated at 60° C. for 1.5 hours. The mixture was allowed to cool and the volatiles were removed by evaporation and by azeotroping with toluene. The residue was dissolved in methylene chloride and 5% aqueous sodium hydrogen carbonate solution was added until the aqueous layer was at pH8. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash chromatography eluting with ethyl acetate to give 4-chloro-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline (863 mg, 87%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[N:15]=[C:16]([NH:19][C:20]4[CH:21]=[C:22]([CH2:26][CH2:27]OS(C)(=O)=O)[CH:23]=[CH:24][CH:25]=4)[N:17]=[CH:18][C:13]=3[CH:12]([CH3:33])[N:11]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[C:10]2=[O:42])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:43]([NH:45][CH2:46][CH3:47])[CH3:44]>>[CH2:43]([N:45]([CH2:46][CH3:47])[CH2:27][CH2:26][C:22]1[CH:21]=[C:20]([NH:19][C:16]2[N:15]=[C:14]3[N:9]([C:5]4[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=4)[C:1]#[N:2])[C:10](=[O:42])[N:11]([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)[CH:12]([CH3:33])[C:13]3=[CH:18][N:17]=2)[CH:25]=[CH:24][CH:23]=1)[CH3:44]
Reactant: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4cccc(CCOS(C)(=O)=O)c4)ncc3C2C)cc1
Reactant: CCNCC
Product: CCN(CC)CCc1cccc(Nc2ncc3c(n2)N(c2cccc(C#N)c2)C(=O)N(c2ccc(OC)cc2)C3C)c1
Temperature: 100 °C

Procedure:
A mixture of (±)-methanesulfonic acid (2-{3-[8-(3-cyano-phenyl)-6-(4-methoxy-phenyl)-5-methyl-7-oxo-5,6,7,8-tetrahydro-pyrimido[4,5-d]pyrimidin-2-ylamino]-phenyl}-ethyl)-ester (1.18 g; 2.02 mmol) (from Example 5a supra) and diethylamine (1.5 mL; 14.5 mmol) (Aldrich) in a pressure bottle and heated at 100° C. for 100 minutes. Upon cooling, the mixture was concentrated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. Purification by flash chromatography (Biotage 40S; 100:0 to 50:50 ethyl acetate-methanol) followed by crystallization from ethyl acetate and hexanes gave (±)-3-[7-[3-(2-diethylamino-ethyl)-phenylamino]-3-(4-methoxy-phenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile. (Yield 0.66 g; 57.9%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.C([Sn](CCCC)(CCCC)[C:15]1[N:19]2[CH:20]=[CH:21][C:22]([C:24]([F:27])([F:26])[F:25])=[N:23][C:18]2=[N:17][CH:16]=1)CCC>>[CH3:9][O:8][C:4]1[N:3]=[C:2]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([F:25])([F:26])[F:27])=[N:23][C:18]3=[N:17][CH:16]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: COc1cccc(Cl)n1
Product: COc1cccc(-c2cnc3nc(C(F)(F)F)ccn23)n1
Yield: 10.4 %

Procedure:
2-Chloro-6-methoxypyridine (305 mg, 2.1 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.4 mmol) by the method of Example 1 to give 3-(6-methoxypyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (43 mg) as a white solid: δH (400 MHz, DMSO) 4.04 (3H, s), 6.84 (1H, d, J 8.2), 7.73 (2H, t, J 6.7), 7.88 (1H, t, J 7.8), 8.81 (1H, s), 10.37 (1H, d, J 7.0); m/z (ES+) 295 (M++H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9](OS(C)(=O)=O)[CH2:8][C@H:7]1[C:16]([N:18]1[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19]1)=[O:17])=[O:5])[CH3:2].[SH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:8][C@H:7]1[C:16]([N:18]1[CH2:22][CH2:21][C:20]([F:23])([F:24])[CH2:19]1)=[O:17])=[O:5])[CH3:2]
Reactant: Sc1ccccn1
Reactant: CCOC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)N1CCC(F)(F)C1
Product: CCOC(=O)[C@@H]1CC(Sc2ccccn2)C[C@H]1C(=O)N1CCC(F)(F)C1

Procedure:
The title compound was prepared in analogy to example 68/69 step 8 using (1R,2R,4R)-2-(3,3-Difluoro-pyrrolidine-1-carbonyl)-4-methanesulfonyloxy-cyclopentanecarboxylic acid ethyl ester (example 186 step 3) and 2-mercaptopyridine. Light brown semi-solid (74%). MS (EI): 385.3 (M+H)+.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([O:10][C@@H:11]([CH3:15])[C:12]([OH:14])=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:17][C:18](=[CH2:20])[CH3:19].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:1]1([CH3:16])[CH:2]=[CH:3][C:4]([S:7]([O:10][C@@H:11]([CH3:15])[C:12]([O:14][C:18]([CH3:20])([CH3:19])[CH3:17])=[O:13])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: C=C(C)C
Reactant: Cc1ccc(S(=O)(=O)O[C@@H](C)C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@@H](C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Add 2(S)-(p-toluenesulfonyloxy)propionic acid (4.4 g) to a cold solution of 10 ml of isobutylene and 0.4 ml of concentrated sulfuric acid in 30 ml of methylene chloride in a pressure vessel, seal, and agitate at room temperature for 48 hours. Pour into 50 ml of 15% sodium carbonate solution, dry over magnesium sulfate and concentrate to obtain t-butyl 2(S)-(p-toluenesulfonyloxy)propionate as an oil (NMR δ1.37). Distilled material (Kugelrohr, 120°) has [α]D26 =-45.9° (EtOH, c=1).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[N:5][N:4]=1.[F:14][B-:15]([F:18])([F:17])[F:16].[CH2:19]([O+](CC)CC)[CH3:20]>ClCCl>[F:14][B-:15]([F:18])([F:17])[F:16].[CH2:19]([N:5]1[N:4]=[C:3]([S:2][CH3:1])[N+:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6]1)[CH3:20]
Reactant: CC[O+](CC)CC
Reactant: CSc1nnnn1-c1ccccc1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCn1nc(SC)[n+](-c2ccccc2)n1

Procedure:
A process which comprises reacting 5-methylthio-1-phenyltetrazole and triethyloxonium fluoroborate at a temperature of between about 15° and 40° C. in anhydrous dichloromethane to yield 3-ethyl-5-methylthio-1-phenyltetrazolium fluoroborate and isolating said fluoroborate.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6](=[O:11])[CH2:7][C:8](=O)[CH3:9].[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C(O)(=O)C>C1C=CC=CC=1>[F:12][C:13]([F:21])([F:22])[C:14]1[CH:15]=[C:16]([NH:17][C:8]([CH3:9])=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[O:11])[CH:18]=[CH:19][CH:20]=1
Reactant: COCCOC(=O)CC(C)=O
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COCCOC(=O)C=C(C)Nc1cccc(C(F)(F)F)c1

Procedure:
To a solution of 4.81 g (30 mmol) 2-methoxyethyl-3-oxobutanoate in 90 ml benzene are added 4.83 g (30 mmol) 3-(trifluoromethyl)aniline and 1.80 g (30 mmol) acetic acid. The mixture is stirred under reflux for four hours using a Dean-Stark trap to remove water. After removal of the solvent in vacuo, the residue is purified by preparative HPLC (column: YMC C18 ODS-AQ 250 mm×30 mm, 11 μm; solvent A: acetonitrile, solvent B: water; gradient: 0 min 10% A, 3 min 10% A, 11 min 90% A, 13 min 90% A, 13.2 min 10% A, 15 min 10% A; wavelength: 220 nm; injection volume: ca. 900 μl ethanol solution; number of injections: 9). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)C.[OH-].[Li+].O>O1CCOCC1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:8]2[CH:7]=[C:6]([CH2:5][C:4]([OH:29])=[O:3])[CH:11]=[CH:10][C:9]=2[O:12][CH3:13])=[C:16]([CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:17]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Cl)cc2CN2CCOC2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CC(=O)O)cc1Oc1ccc(Cl)cc1CN1CCOC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To {3-[4-chloro-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester (0.36 mmol) in 1,4-dioxane was added lithium hydroxide and H2O, and the reaction was stirred overnight at room temperature. The mixture was worked-up, and the residue was purified by preparative HPLC to give the title compound.