Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH:11]1([C:17]2[C:18]3[CH:19]=[CH:20][C:21]([C:37]([O:39][CH3:40])=[O:38])=[CH:22][C:23]=3[N:24]3[CH2:30][CH:29]([CH2:31][OH:32])[CH2:28][C:27]4[CH:33]=[CH:34][CH:35]=[CH:36][C:26]=4[C:25]=23)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.CCN(CC)CC>C(Cl)Cl>[CH:11]1([C:17]2[C:18]3[CH:19]=[CH:20][C:21]([C:37]([O:39][CH3:40])=[O:38])=[CH:22][C:23]=3[N:24]3[CH2:30][CH:29]([CH:31]=[O:32])[CH2:28][C:27]4[CH:33]=[CH:34][CH:35]=[CH:36][C:26]=4[C:25]=23)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CO)Cc1ccccc1-3
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C=O)Cc1ccccc1-3
Temperature: -78 °C
Reaction time: 0.42 h

Procedure:
DMSO (5 eq.) was dissolved in DCM and the solution was cooled to −78° C. At this temperature a 2M solution of oxalylchloride in DCM (2.5 eq.) was added slowly and the mixture was left stirring for 25 min at −78° C. A solution of methyl 13-cyclohexyl-6-(hydroxymethyl)-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (1 eq.) in DCM (0.09M) was added slowly at −78° C. and stirring was continued for 25 min at this temperature. Then NEt3 (8 eq.) was added and the resulting slurry was placed into an ice bath at 0° C. The mixture was stirred for 90 min, then diluted with DCM and extracted with water, HCl 1N, sat. aq. NaHCO3 and brine. After drying over Na2SO4 all volatiles were evaporated in vacuo. After evaporation of the solvent the product was obtained as a yellowish solid (quant.). (ES+) m/z 402 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][CH2:12][C:13]1[C:14]([CH3:19])=[N:15][NH:16][C:17]=1[CH3:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH2:11][CH2:12][C:13]2[C:14]([CH3:19])=[N:15][NH:16][C:17]=2[CH3:18])=[C:2]([NH2:1])[CH:7]=1
Reactant: Cc1n[nH]c(C)c1CCBr
Reactant: Nc1cc(Cl)ccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1n[nH]c(C)c1CCSc1ccc(Cl)cc1N
Yield: 74.5 %

Procedure:
Following General Procedure A, the title compound (517 mg, 74%) was prepared from 2-Amino-4-chloro-benzenethiol (590 mg, 3.693 mmol) and 4-(2-bromo-ethyl)-3,5-dimethyl-1H-pyrazole (500 mg, 2.462 mmol), K2CO3 (1.7 g, 12.31 mmol) in DMF (20 ml).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:10]([Si:14]([CH3:17])([CH3:16])Cl)([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1>CN(C=O)C.C(OCC)C>[Si:14]([O:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([I:1])[CH:3]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc(O)cc1I
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3-iodo-4-methylphenol 1-1 (500 mg, 2.14 mmol), tert-butyldimethylchlorosilane (387 mg, 2.57 mmol) and imidazole (175 mg, 2.57 mmol) in 11 mL of DMF was stirred at rt for 16 h, and then diluted with diethylether, washed with water, brine, dried (MgSO4) and evaporated. The residue was subjected to MPLC on a 40 g column of SiO2 eluting with hexanes to provide 5-tert-butyldimethylsilyloxy-2-methylphenyliodide 1-2 as an oil. 1H NMR (300 MHz, DMSO-d6): δ 0.17 (s, 6H), 0.93 (s, 9H), 2.29 (s, 3H), 6.81 (dd, 1H, J=8, 2 Hz), 7.20 (d, 1H, J=8 Hz), 7.28 (d, 1H, J=2 Hz).
Reaction SMILES: C(P(C(C)(C)C)C1C(OC)=CC=C(OC)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC1CCCO1.FC(F)(F)C(F)(S(O[C:60]1[CH:69]=[CH:68][C:67]2[C:62](=[CH:63][CH:64]=[C:65]([C:70]3[CH:75]=[C:74]([N:76]4[CH:81]=[CH:80][C:79](=[O:82])[NH:78][C:77]4=[O:83])[CH:73]=[C:72]([C:84]([CH3:87])([CH3:86])[CH3:85])[C:71]=3[O:88][CH3:89])[CH:66]=2)[CH:61]=1)(=O)=O)C(F)(F)F.[CH3:93][S:94]([NH2:97])(=[O:96])=[O:95]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[C:84]([C:72]1[C:71]([O:88][CH3:89])=[C:70]([C:65]2[CH:66]=[C:67]3[C:62](=[CH:63][CH:64]=2)[CH:61]=[C:60]([NH:97][S:94]([CH3:93])(=[O:96])=[O:95])[CH:69]=[CH:68]3)[CH:75]=[C:74]([N:76]2[CH:81]=[CH:80][C:79](=[O:82])[NH:78][C:77]2=[O:83])[CH:73]=1)([CH3:86])([CH3:87])[CH3:85]
Reactant: CS(N)(=O)=O
Reactant: COc1c(-c2ccc3cc(OS(=O)(=O)C(F)(C(F)(F)F)C(F)(F)F)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Agent: [Pd]
Agent: COc1ccc(OC)c(P(C(C)(C)C)C(C)(C)C)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC1CCCO1
Solvent: CCOC(C)=O
Product: COc1c(-c2ccc3cc(NS(C)(=O)=O)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) (0.0071 g, 7.71 μmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.0089 g, 19.0 μmol) and milled potassium phosphate tribasic (0.360 g, 1.696 mmol) were charged to a 40-mL reaction vial inside an inert atmosphere glove box. 2-Methyltetrahydrofuran (4 mL) was added, and the closed vial and its contents were heated to 80° C. with magnetic stirring for 30 minutes. The reaction mixture was cooled down to room temperature. 6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,1,2,3,3,3-heptafluoropropane-2-sulfonate (1.0 g, 1.542 mmol, Example 3-4, compound (5c)), methanesulfonamide (0.176 g, 1.850 mmol) and ethyl acetate (8 mL) were added to the 40-mL reaction vial. The temperature of the closed vial and its contents was raised to 90° C. and stirred for 20 hours. HPLC analysis of the reaction mixture showed that the product was formed in 95 area % at 210 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:4]([CH:5]=[O:6])[C:3]=1[OH:11].[CH2:12](I)[CH:13]=[CH2:14]>CN(C=O)C>[CH2:14]([O:11][C:3]1[C:2]([Cl:1])=[CH:9][C:8]([Cl:10])=[CH:7][C:4]=1[CH:5]=[O:6])[CH:13]=[CH2:12]
Reactant: O=Cc1cc(Cl)cc(Cl)c1O
Reactant: C=CCI
Solvent: CN(C)C=O
Product: C=CCOc1c(Cl)cc(Cl)cc1C=O
Temperature: 65 °C
Yield: 90.9 %

Procedure:
A solution of 5.0 g of 3,5-dichlorosalicylaldehyde in 50 ml of DMF was treated with 3.23 g of potassium-tert.-butylate and 6.6 g of allyl iodide and stirred under argon at 65° C. After 2 hours the reaction mixture was concentrated, treated with ice-water and extracted with ethyl acetate. The organic phases were dried over sodium sulphate and concentrated. The residue was chrromatographed over silica gel and gave 5.5 g of 2-allyloxy-3,5-dichloro-benzaldehyde; MS (EI) m/z 230/232 M+.
Reaction SMILES: [CH2:1]([N:4]1[CH2:15][CH:14]2[CH2:16][CH:6]([C:7](=O)[C:8]3[C:9]([O:17]C)=[CH:10][CH:11]=[CH:12][C:13]=32)[CH2:5]1)[CH:2]=[CH2:3].Cl.[NH2:21][OH:22].C(=O)([O-])[O-].[Ba+2]>CO>[CH2:1]([N:4]1[CH2:15][CH:14]2[CH2:16][CH:6]([C:7](=[N:21][OH:22])[C:8]3[C:13]2=[CH:12][CH:11]=[CH:10][C:9]=3[OH:17])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: NO
Reactant: C=CCN1CC2CC(C1)c1cccc(OC)c1C2=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: C=CCN1CC2CC(C1)c1cccc(O)c1C2=NO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11-Allyl-6-methoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-trien-8-one (243 mg, 1.0 mmol), hydroxylamine hydrochloride (80 mg, 1.15 mmol) an barium carbonate (227 mg, 1.15 mmol) were stirred and warmed to reflux in methanol (10 mL) for 18 h. Additional hydroxylamine hydrochloride (30 mg, 0.43 mmol) an barium carbonate (70 mg, 0.35 mmol) were introduced and heating continued for 2 h. The mixture was cooled to ambient temperature and filtered through Celite™, rinsed with methanol, concentrated and the residue dissolved in dichloromethane (30 mL), H2O (30 mL) and saturated aqueous NaHCO3 solution (˜30 mL) to achieve pH 8.5. The layers were separated and the aqueous layer was extracted with dichloromethane (2×30 mL), dried through a cotton plug and concentrated to an oily solid (275 mg). This material was triturated with stirring for in dichloromethane (20 mL) for 60 h and the resulting orange solid filtered (100 mg, 39%). (TLC 20% EtOAc/Hex Rf 0.28); 1H NMR (400 MHz, CDCl3) δ 8.10 (br s, OH),), 7.11 (dd, J=8.3, 7.5 Hz, 1H), 6.76 (dd, J=8.3, 0.8 Hz, 1H), 6.64 (dd, J=7.5, 0.8 Hz, 1H), 5.63 (m, 1H), 5.02 (m, 2H), 3.61 (br s, 3H), 3.24 (d, J=10.8 Hz, 1H), 2.97 (br s, 3H), 2.94–2.85 (m, 2H), 2.35 (dd, J=10.8, 2.4 Hz, 1H), 2.24 (dd, J=10.8, 2.4 Hz, 1H), 1.96 (dd, J=12.5, 1.5 Hz, 1H), 1.74 (ddd, J=12.5, 5.6, 2.7 Hz, 1H).
Reaction SMILES: C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[CH:34]=[C:33]1[C:41]([OH:43])=O.Cl.[C:45]([O:49][C:50](=[O:60])[C:51]1[CH:56]=[CH:55][C:54]([C@H:57]([NH2:59])[CH3:58])=[CH:53][CH:52]=1)([CH3:48])([CH3:47])[CH3:46]>O.C(Cl)Cl>[O:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[CH:34]=[C:33]1[C:41]([NH:59][C@@H:57]([C:54]1[CH:55]=[CH:56][C:51]([C:50]([O:49][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:60])=[CH:52][CH:53]=1)[CH3:58])=[O:43]
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: C[C@@H](N)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)c1cc2ccccc2o1)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 2-dram vial was added triethylamine (0.10 mL, 0.72 mmol), HATU (0.068 g, 0.18 mmol), benzofuran-2-carboxylic acid (0.029 g, 0.18 mmol), and DCM (2 mL). The solution was stirred at rt for 30 min then transferred to another 2-dram vial containing solid tert-butyl-4-[(1R)-1-aminoethyl]benzoate hydrochloride. The mixture was stirred at rt for 16 h. To the reaction was then added DCM (3 mL) and water (1 mL). After separation, the aqueous layer was extracted with DCM (2×3 mL). The combined organic phases were concentrated to dryness to give crude tert-butyl 4-{(1R)-1-[(1-benzofuran-2-ylcarbonyl)amino]ethyl}benzoate as a brown solid. LC-MS: (FA) ES+ 366.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[N:10][N:11]([CH3:12])[C:7]=2[CH:6]=[C:5]([C:13]2[CH:32]=[CH:31][C:16]([O:17][CH2:18][CH2:19][CH:20]3[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]3)=[C:15]([C:33]([F:36])([F:35])[F:34])[CH:14]=2)[N:4]=1)#[N:2].[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>C(Cl)Cl.C(#N)C>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[NH:22]1[CH2:23][CH:20]([CH2:19][CH2:18][O:17][C:16]2[CH:31]=[CH:32][C:13]([C:5]3[N:4]=[C:3]([C:1]#[N:2])[C:8]4[N:9]=[N:10][N:11]([CH3:12])[C:7]=4[CH:6]=3)=[CH:14][C:15]=2[C:33]([F:36])([F:34])[F:35])[CH2:21]1
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CN(C(=O)OC(C)(C)C)C4)c(C(F)(F)F)c3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CNC4)c(C(F)(F)F)c3)cc21
Reaction time: 0.5 h
Yield: 62 %

Procedure:
tert-Butyl 3-(2-(4-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carboxylate (86 mg) was dissolved in DCM (2000 μl) and acetonitrile (500 μl). Trifluoroacetic acid (400 μl) was added and the reaction stirred for 30 minutes. Solvent was evaporated under reduced pressure and the resulting residue dissolved in a minimum volume of EtOAc. Ether was added dropwise until the solution clouded then the mixture was allowed to stand for 30 minutes and filtered. Solid was washed with ether and dried to afford the desired product 6-(4-(2-(azetidin-3-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile 2,2,2-trifluoroacetate (62% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:5]=1[C:19]1[N:23]([C@H:24]2[CH2:28][CH2:27][O:26][CH2:25]2)[N:22]=[CH:21][C:20]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])([O-:3])=[O:2].Br[C:35]1[C:36]([CH3:45])=[N:37][C:38]([O:42][CH2:43][CH3:44])=[CH:39][C:40]=1[CH3:41].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:43]([O:42][C:38]1[N:37]=[C:36]([CH3:45])[C:35]([C:8]2[CH:7]=[CH:6][C:5]([C:19]3[N:23]([C@H:24]4[CH2:28][CH2:27][O:26][CH2:25]4)[N:22]=[CH:21][C:20]=3[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=2)=[C:40]([CH3:41])[CH:39]=1)[CH3:44]
Reactant: CCOc1cc(C)c(Br)c(C)n1
Reactant: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1ccc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1ccc(-c2c(C)cc(OCC)nc2C)cc1[N+](=O)[O-]

Procedure:
Ethyl 5-[2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl][(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate obtained in Preparation Example 7-(2) (200 mg) was dissolved in a mixed solution of 1,4-dioxane (4 mL) and water (1 mL). 3-bromo-6-ethoxy-2,4-dimethylpyridine obtained in Preparation Example 51 (121 mg), Pd(PPh3)4 (25 mg) and cesium carbonate (428 mg) were added, and the mixture was reacted using a microwave reactor at 130° C. for three hours. The reaction mixture was returned to room temperature, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 30% to 100%) to give the title compound (97 mg).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].[C:22](O)([CH3:25])([CH3:24])[CH3:23].O>O1CCCC1.C(OCC)(=O)C>[C:22]([O:20][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][Br:14])([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C(O)CCCCBr
Reactant: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CCCCBr
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid anhydride (7.7 ml) was added dropwise to a solution of 5-bromovaleric acid (5 g) in tetrahydrofuran (25 ml) under nitrogen atmosphere at −40° C. and the solution was stirred at −40° C. for 30 minutes. To the mixture, was added tert-butanol (25 ml) at −40° C. and the stirring was continued for 3 hours while the temperature was gradually raised up to room temperature. Water and ethyl acetate were added to the mixture and the organic layer was separated, washed with a saturated sodium hydrogen carbonate aq. solution three times and then a saturated brine, dried over magnesium sulfate and concentrated in vacuo to give 5-bromovaleric acid tert-butyl ester (5.88 g). MS (m/z): 237/239 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[CH:18]=[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][C:12]2=[N:11]1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[CH:18]=[C:13]2[CH:14]=[N+:15]([O-:27])[CH:16]=[CH:17][C:12]2=[N:11]1
Reactant: Fc1cc(Cl)c(-n2cc3cnccc3n2)c(Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1ccc2nn(-c3c(Cl)cc(F)cc3Cl)cc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
To a cooled (0° C.) solution of 2-(2,6-dichloro-4-fluorophenyl)-2H-pyrazolo[4,3-c]pyridine (1.6 g, 5.67 mmol) in DCM (30 mL) under nitrogen, was added mCPBA (1.47 g, 8.51 mmol). The reaction mixture was stirred at 0° C. for 2 hours, warmed to room temperature, and stirred for a further 16 hours. Sodium thiosulfate (sat. aq.) was added and the organic layer was separated, washed with sodium hydrogen carbonate (sat. aq.) and brine, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel flash chromatography (5-10% methanol in DCM) to afford the title compound as a white solid (1.4 g, 83% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.90 (s, 1H), 8.82 (s, 1H), 7.98-7.87 (m, 3H), 7.83 (d, J=7.5 Hz, 1H).
Reaction SMILES: C(=O)([O-])[O-:2].[Li+:5].[Li+].[Cl:7]([OH:11])(=[O:10])(=[O:9])=[O:8].Cl([O-])(=O)(=O)=[O:13].[Li+]>>[OH2:2].[OH2:8].[OH2:13].[Cl:7]([O-:11])(=[O:10])(=[O:9])=[O:8].[Li+:5]
Reactant: O=C([O-])[O-]
Reactant: [O-][Cl+3]([O-])([O-])O
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: O

Procedure:
In the process (IV), lithium carbonate (Li2CO3) is added to an aqueous solution of perchloric acid, and lithium perchlorate is synthesized through a neutralization reaction. In addition, the aqueous solution of lithium perchlorate synthesized by the neutralization reaction is evaporated and crystallized so as to obtain lithium perchlorate trihydrate. The neutralization reaction in the process (IV) is expressed by the following chemical equation (E). 2HClO4+Li2CO3→2LiClO4+CO2+H2O  (D)
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][P:26]([O:31][CH2:32][CH3:33])(=[O:30])[O:27][CH2:28][CH3:29]>>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[N:12]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][P:26](=[O:30])([O:31][CH2:32][CH3:33])[O:27][CH2:28][CH3:29])[CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCOP(=O)(CCCCCBr)OCC
Reactant: CCCCn1c(=O)c2[nH]cnc2n(CCCC)c1=O
Product: CCCCn1c(=O)c2c(ncn2CCCCCP(=O)(OCC)OCC)n(CCCC)c1=O

Procedure:
The title substance was prepared from 1,3-dibutylxanthine and diethyl 5-bromopentanephosphonate analogously to Example 9.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[C:8]([CH3:17])[CH:9]=[C:10]([N+:14]([O-])=O)[C:11]=2[CH3:13])[N:6]=[CH:5][CH:4]=1)#[N:2].C(O)C.[OH-].[Na+]>O>[NH2:14][C:10]1[C:11]([CH3:13])=[C:12]2[C:7](=[C:8]([CH3:17])[CH:9]=1)[N:6]=[CH:5][CH:4]=[C:3]2[C:1]#[N:2]
Reactant: Cc1cc([N+](=O)[O-])c(C)c2c(C#N)ccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(N)c(C)c2c(C#N)ccnc12
Temperature: 60 °C

Procedure:
A mixture of 4-cyano-5,8-dimethyl-6-nitroquinoline (2.54 g, 11.2 mmol), stannous chloride dihydrate (12.6 g, 55.9 mmol) and ethanol (200 mL) is heated at 60° C. for 1.5 hours. The reaction is cooled to room temperature, and water (60 mL) is added. The mixture is basified with 10% aqueous sodium hydroxide solution (70 mL) and subsequently extracted with methylene chloride (3×150 mL). Drying (sodium sulfate) and evaporation provides 6-amino-4-cyano-5,8-dimethylquinoline.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])=[N:6][CH:5]=1.O.[OH-].[Li+].Cl>C1COCC1.CO.C(OCC)(=O)C>[F:26][C:21]1[CH:20]=[C:19]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:27])=[O:2])=[CH:5][N:6]=3)=[C:16]([CH2:17][OH:18])[O:15][N:14]=2)[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Yield: 88.2 %

Procedure:
6-[3-(3,4-Difluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (1.00 g, 2.66 mmol) in THF (6.25 mL), methanol (1.75 mL), and water (6.25 mL) was treated with lithium hydroxide (130 mg, 5.31 mmol) overnight at room temperature. Addition of aqueous hydrochloride solution (1 N, 100 mL) and extraction with ethyl acetate afforded the title compound (850 mg, 88%) as a white solid. MS: m/e=361.1 [M−H]−.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:12]([C:14]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17])[CH3:13]>>[CH2:12]([C:14]1[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:19][C:15]=1[C:16]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:17])[CH3:13]
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Reactant: CCc1cc(C(F)(F)F)ccc1C(=O)O
Product: CCc1cc(C(F)(F)F)ccc1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, white solid, MS: m/e=355.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-ethyl-4-(trifluoromethyl)-benzoic acid (CAS 854531-63-8).
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[N:7]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:24]2[C:32]3[C:27](=[N:28][CH:29]=[C:30]([Cl:33])[CH:31]=3)[N:26]([S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:25]=2)[OH:23])=[CH:18][N:17]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:1]([O:5][C:6](=[O:43])[N:7]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[C:32]3[C:27](=[N:28][CH:29]=[C:30]([Cl:33])[CH:31]=3)[N:26]([S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:35])=[O:36])[CH:25]=2)=[O:23])=[CH:18][N:17]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1F)c1ccc(C(O)c2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(Cc1ccccc1F)c1ccc(C(=O)c2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24.2 %

Procedure:
To 5-[(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-pyridin-2-yl-(2-fluoro-benzyl)-carbamic acid tert-butyl ester (582, 0.25 g, 0.40 mmol) in dichloromethane (5.0 mL) was added Dess-Martin periodinane (0.20 g, 0.48 mmol). The reaction was stirred at room temperature for 10 minutes, then poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (583, 0.060 g., 24%).
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].C(N(CC)CC)C.[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:26]=1[N:32]=[C:33]=[O:34])([CH3:24])[CH3:23]>O1CCCC1>[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:26]=1[NH:32][C:33](=[O:34])[O:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][CH2:5][N:4]2[CH2:1][C:2]#[CH:3])=[CH:9][CH:10]=1)([CH3:24])[CH3:23]
Reactant: Cc1cccc(C(C)C)c1N=C=O
Reactant: C#CCN1CCCc2ccc(O)cc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCN1CCCc2ccc(OC(=O)Nc3c(C)cccc3C(C)C)cc21
Temperature: 35 °C

Procedure:
A mixture of 1-(prop-2-ynyl)-1,2,3,4-tetrahydroquinolin-7-ol (400 mg, 2.14 mM) and triethylamine (0.6 mL) in dry tetrahydrofuran (THF, 5 mL) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, 2-isopropyl-6-methylphenyl isocyanate (558 mg/ml, 3.21 mM) was added at once and then the reaction mixture was further stirred for 30 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chloroform-hexane (1:19) to afford 10d as solid. Yield: 520 mg, 67.16%.