Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([OH:7])[CH2:5][OH:6].[CH3:8][C:9]1([CH3:34])[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[C:15]2[CH:14]=[C:13]([C:21]3[N:26]=[C:25]([N:27]4[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]4)[CH:24]=[CH:23][CH:22]=3)[CH:12]=[CH:11][C:10]1=2.Cl>>[CH3:8][C:9]1([CH3:34])[CH2:18][CH2:17][C:16]([CH3:19])([CH3:20])[C:15]2[CH:14]=[C:13]([C:21]3[N:26]=[C:25]([N:27]4[CH2:32][CH2:31][CH:30]([NH:1][CH2:2][CH2:3][C@H:4]([OH:7])[CH2:5][OH:6])[CH2:29][CH2:28]4)[CH:24]=[CH:23][CH:22]=3)[CH:12]=[CH:11][C:10]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCC(=O)CC4)n3)ccc21
Reactant: NCC[C@H](O)CO
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCC(NCC[C@H](O)CO)CC4)n3)ccc21

Procedure:
The preparation is carried out analogously to FS1008 starting from 21 mg (0.199 mmol) of (S)-4-aminobutane-1,2-diol and 80 mg (0.199 mmol) of 6′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2,3,5,6-tetrahydro-1,2′-bipyridinyl-4-one. The product is in the form of the hydrochloride.
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=O)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1.COC1C=CC(P2SP(C3C=CC(OC)=CC=3)S2)=CC=1>C(COC)OC>[N:1]1([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[S:32])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CCCN1S(=O)(=O)c1ccc(N2CCCCCC2)cc1
Agent: COc1ccc(P2SP(c3ccc(OC)cc3)S2)cc1
Solvent: COCCOC
Product: O=S(=O)(c1ccc(N2CCCCCC2)cc1)N1CCCC1=S
Yield: 57.3 %

Procedure:
A mixture comprising 5 g of 1-[4-(1-hexahydroazepinyl)benzenesulphonyl]-2-pyrrolidinone, prepared as in Example 18 of the European Patent Application published under No. 0,033,578, and 3.13 g of Lawesson reagent (or 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane in 100 cm3 of dimethoxyethane is heated to reflux for 3 hours. The mixture is allowed to return to room temperature and is evaporated to dryness, and the residue is chromatographed on silica (eluant: benzene). 2 g of product are recovered. M.p. 168°-170° C. After crystallization in methanol, 1.5 g of expected product are obtained. M.p. 172°-173° C.
Reaction SMILES: O1C2C=CC(C(Cl)=O)=CC=2OC1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.[O:35]1[C:39]2[CH:40]=[CH:41][C:42]([C:44]([N:46]=[C:47]=[S:48])=[O:45])=[CH:43][C:38]=2[O:37][CH2:36]1>C1(C)C=CC=CC=1.C(O)C>[O:35]1[C:39]2[CH:40]=[CH:41][C:42]([C:44]([N:46]=[C:47]=[S:48])=[O:45])=[CH:43][C:38]=2[O:37][CH2:36]1.[O:35]1[C:39]2[CH:40]=[CH:41][C:42]([C:44]([NH:46][C:47]([NH:32][C:31]3[CH:33]=[CH:34][C:28]([O:27][C:18]4[C:17]5[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][CH3:13])[CH:16]=5)[N:21]=[CH:20][CH:19]=4)=[CH:29][CH:30]=3)=[S:48])=[O:45])=[CH:43][C:38]=2[O:37][CH2:36]1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccc2c(c1)OCO2
Agent: O=C(N=C=S)c1ccc2c(c1)OCO2
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc5c(c4)OCO5)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
1,3-Benzodioxole-5-carbonyl isothiocyanate was prepared using commercially available 1,3-benzodioxole-5-carbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 1,3-benzodioxole-5-carbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (68 mg, yield 86%).
Reaction SMILES: [CH:1]([C:3]1([O:8][Si:9]([CH2:14][CH3:15])([CH2:12][CH3:13])[CH2:10][CH3:11])[CH2:7][CH2:6][CH2:5][CH2:4]1)=[CH2:2].B.[OH2:17]>C1COCC1>[CH2:12]([Si:9]([CH2:10][CH3:11])([CH2:14][CH3:15])[O:8][C:3]1([CH2:1][CH2:2][OH:17])[CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:13]
Reactant: C=CC1(O[Si](CC)(CC)CC)CCCC1
Reactant: O
Agent: B
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC1(CCO)CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Vinyl-1-triethylsilanyloxy-cyclopentane (9.06 g; 40.0 mmole) was dissolved in dry THF (100 ml); at 0° C. borane (1M in THF; 40.0 ml; 40.0 mmole) was added dropwise and the reaction mixture was stirred for one hour at ambient temperature. At 0° C. water (50 ml)was added dropwise, followed by NaBO3.4H2O (7.69 g; 50.0 mmole) and the mixture was stirred for additional 16 hours at ambient temperature; after filtration the organic layer was removed and concentrated in vacuo; the aqu. layer was extracted with tert.-BuOMe (2×50 ml); all organic layers were combined, washed with sat. aqu. NaCl (50 ml) and dried over MgSO4. After filtration the solvent was removed in vacuo, the crude product was chromatographed on silica gel (hexane:ethyl acetate--4:1). 2-(1-Triethylsilanyloxy-cyclopentyl)-ethanol (D1) was obtained as colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=O)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]([F:37])([F:36])[C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:32][C:31]3[CH:33]=[CH:34][CH:35]=[C:29]([C:28]([F:27])([F:36])[F:37])[CH:30]=3)=[O:21])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(C)cccc3Cl)[nH]c2=O)cc1OC
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(C)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)(F)F)c1
Yield: 22.3 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2-chloro-6-methylphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-27, 0.100 g, 0.268 mmol), 3-(trifluoromethyl)aniline (0.040 g, 0.403 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.030 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 2.33 (s, 3H), 3.95 (s, 3H), 7.41-7.59 (m, 4H), 7.68 (t, J=6.9 Hz, 1H), 7.75 (d, 1H), 7.77-7.82 (m, 2H), 7.95 (d, J=8.4 Hz, 1H), 8.25 (s, 1H), 10.36 (s, 1H), 12.53 (br s, 1H); MS (m/z): 503.17 (M+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][CH:11]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: c1ccc2[nH]ccc2c1
Product: Fc1cnc(Cl)nc1-c1c[nH]c2ccccc12

Procedure:
Starting materials: 2,4-dichloro-5-fluoropyrimidine and 1H-indole. m/z 248.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[N:25][CH:26]=1.O>CN(C)C=O>[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]4[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=4)=[N:25][CH:26]=3)=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=[N:4]1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc(-c2ccc(COc3ccc(CCCCn4ccnn4)cc3)cn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
23 mg (0.90 mmol) of 95% sodium hydride were added at 0° C. to a solution of 163 mg (0.75 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 4.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 204 mg (0.75 mmol) 5-chloromethyl-2-(4-trifluoromethyl-phenyl)-pyridine (WO 2005/049573) were given to the reaction mixture and stirring continued at r.t for 2 days. After addition of 8 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, methanol/water 1:1, and a small amount of ether. The residue was purified by chromatography on silica (eluent: ethyl acetate) to give 240 mg 71% of the title compound as white powder.
Reaction SMILES: [Mg].Cl[Si:3]([CH3:6])([CH3:5])[CH3:4].CN(C=O)C.Cl[C:13]([F:20])([F:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>O>[CH2:17]([O:16][C:14](=[O:15])[C:13]([F:20])([F:19])[Si:3]([CH3:6])([CH3:5])[CH3:4])[CH3:18]
Reactant: CCOC(=O)C(F)(F)Cl
Reactant: C[Si](C)(C)Cl
Agent: [Mg]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(F)(F)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
According to the above-described scheme, magnesium (243 mg, 10.0 mmol), chlorotrimethylsilane (Me3SiCl; 2.17 g, 20.0 mmol) and DMF (15 mL) were put into a two-neck reaction tube under nitrogen atmosphere. Ethyl chlorodifluoroacetate (Compound 3; 793 mg, 624 μL, 5.0 mmol) was added thereto with the reaction container being cooled in water bath, and then the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was extracted with diethyl ether and washed with water, and an organic layer was dried with anhydrous sodium sulfate. Diethyl ether was distilled away under reduced pressure, and by carrying out the production by silica gel column chromatography, difluorotrimethylsilanylacetic acid ethyl ester (Compound 3a) was obtained with a yield of 43%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Br-].[C:31]([C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][Zn+])#[N:32]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:36][C:35]5[CH:38]=[CH:39][CH:40]=[C:33]([C:31]#[N:32])[CH:34]=5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Reactant: N#Cc1cccc(C[Zn+])c1
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Br-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Cc3cccc(C#N)c3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-cyano-benzylzinc bromide following a procedure analogous to that described in Step 6 of Intermediate 1; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II) dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 6): tR=1.23 min; Mass spectrum (ESI+): m/z=508 [M+H]+.
Reaction SMILES: C([O:8][CH2:9][C:10]1([CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[O:14][C:13](=[O:15])[CH2:12][CH2:11]1)C1C=CC=CC=1.C(O)C.[H][H]>[Pd].O>[OH:8][CH2:9][C:10]1([CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[O:14][C:13](=[O:15])[CH2:12][CH2:11]1
Reactant: CCCCCCCCCCCCCCCCCCOCC1(COCc2ccccc2)CCC(=O)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCOCC1(CO)CCC(=O)O1

Procedure:
A mixture containing 10.7 g (21.83 mmol) of the compund prepared in (e) above, 300 ml of a mixture of ethyl alcohol and water in a ratio of 9:1 and 1.5 g of 5% palladium on carbon (50% water content) was placed in a pressure bottle and hydrogenated at b 40° C. under a pressure of 50 lbs. of hydrogen until uptake was complete. The catalyst was then filtered off and the filtrate concentrated in vacuo. The residue was crystallized from methanol to yield a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[C:13](=[O:26])[NH:14][C:15]3[C:20]([N:21]=1)=[CH:19][C:18]([C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=3)[CH2:7][CH2:6][CH2:5]2.N1C=CC=CC=1.[O:33](S(C(F)(F)F)(=O)=O)[S:34]([C:37]([F:40])([F:39])[F:38])(=O)=[O:35]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[C:13]([O:26][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:35])=[O:33])=[N:14][C:15]3[C:20]([N:21]=1)=[CH:19][C:18]([C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=3)[CH2:7][CH2:6][CH2:5]2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4cc(F)ccc43)nc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCc4cc(F)ccc43)nc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 3-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (150 mg, 0.43 mmol) in dichloromethane (30 mL) was added pyridine (136 mg, 1.72 mmol) and then Tf2O (243 mg, 0.86 mmol) was added dropwise with stifling at 0° C. The resulting solution was stirred for 4 h at room temperature and then washed with water (3×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford methyl 3-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (200 mg, crude).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][N:7]=1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>O1CCCC1>[C:17]([NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][N:7]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCOc1cc(-c2ccccc2)on1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCOc1cc(-c2ccccc2)on1)c1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
3-(2-Aminoethoxy)-5-phenylisoxazole hydrochloride (240 mg) was suspended in anhydrous tetrahydrofuran (5 ml), and the suspension was cooled to 5° C. Benzoyl chloride (168 mg) and triethylamine (243 mg) were added thereto, followed by stirring of the resulting mixture at the same temperature for 30 minutes. At the end of this time, the reaction mixture was added to ice-cold water (40 ml) and extracted with ethyl acetate (40 ml×2). Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain the title compound (276 mg, 90%) as colorless crystals.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]3[CH:12]=[N:11][NH:10][C:8]=3[N:9]=2)[CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[NH2:24]OC(C1C=CC(OC)=CC=1)=O.COC1C=CC(C(ON)=O)=CC=1>CN1CCCC1=O.CCOC(C)=O>[NH2:24][N:10]1[C:8]2[N:9]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]=2[CH:12]=[N:11]1
Reactant: CCOC(=O)c1cc(C2CC2)nc2[nH]ncc12
Reactant: COc1ccc(C(=O)ON)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cc(C2CC2)nc2c1cnn2N
Reaction time: 0.33 h

Procedure:
Ethyl 6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (200 mg, 0.865 mmol) was dissolved in N-Methyl-2-pyrrolidone (NMP) (8 mL), followed by addition of potassium tert-butoxide (116 mg, 1.038 mmol). After 20 minutes stirring, O-{[4-(methyloxy)phenyl]carbonyl}hydroxylamine 1-[(aminooxy)carbonyl]-4-(methyloxy)benzene (289 mg, 1.730 mmol) was added and the mixture stirred at room temperature for 16 h. The contents were diluted with EtOAc, and then washed with brine, and saturated NaHCO3. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography (eluent: 0 to 50% EtOAc). The final product as collected as 106 mg (50%). LCMS E-S (M+H)=274.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00-1.14 (m, 4 H), 1.41 (t, J=7.07 Hz, 3 H), 2.34-2.47 (m, 1 H), 4.44 (q, J=7.07 Hz, 2 H), 6.39 (s, 2 H), 7.64 (s, 1 H), 8.09 (s, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C@@H:17]([NH:26][C:27](=[O:40])[CH2:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:31])[CH3:30])[C:16]2=[O:41])=[CH:10][CH:9]=1.[CH3:42][N:43]=[C:44]=[O:45].N12CCCN=C1CCCCC2>C(Cl)Cl>[CH3:42][NH:43][C:44]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C@@H:17]([NH:26][C:27](=[O:40])[CH2:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:31])[CH3:30])[C:16]2=[O:41])=[CH:12][CH:13]=1)=[O:45]
Reactant: CN=C=O
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3O)cc2)C1=O)NC(=O)OC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CNC(=O)Oc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC(=O)OC(C)(C)C)CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 100 mg (approx. 0.2 mmol) of the crude intermediate obtained in Step G in 5 mL of methylene chloride was treated with 1.0 mL of methyl isocyanate (17 mmol) and 0.1 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 10 minutes and then evaporated under vacuum to give 146 mg ofo crude product. 1H NMR (400 MHz, CDCl3): 1.32 (s, 3H), 1.33 (s, 3H), 1.39 (s, 9H), 2.12 (m, 1H), 2.33 (m, 1H), 2.52 (dd, 1H), 2.57 (m, 2H), 2.59 (s, 3H), 4.38 (dd, 1H), 4.8 (d, 1H), 5.26 (d, 1H), 7.10 (d, 1H), 7.36 (m, 11H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][CH2:23][NH:24]C(OCC2C=CC=CC=2)=O)[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2].[BrH:35].CCOCC>C(O)(=O)C>[BrH:35].[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][CH2:23][NH2:24])[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCNC(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCN
Reaction time: 2 h

Procedure:
4.8 G. of 2-{2-[(benzyloxycarbonyl)amino]-ethyl}-5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester are dissolved in 10 ml. of glacial acetic acid; 15 ml. of a solution of 33% hydrobromic acid in glacial acetic acid are added. The mixture is left to stand for 2 hours at room temperature with occasional shaking and then poured into 150 ml. of ether. The precipitated crystals are removed by filtration under suction and washed with ether. Recrystallization from ethanol yields 2-(2-aminoethyl)-5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester hydrobromide; melting point 230°-234° C. (decomposition).
Reaction SMILES: [S:1]1(=[O:12])(=[O:11])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[NH:2]1.FC(F)(F)C([O-])=[O:16].[Na+].O>FC(F)(F)C(O)=O>[OH:16][C:9]1[C:4]2[C:3](=[O:10])[NH:2][S:1](=[O:11])(=[O:12])[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1NS(=O)(=O)c2cccc(O)c21
Yield: 18.5 %

Procedure:
4.6 g (25 mmol) of 1,2-benzisothiazol-3(2H)-one-1,1-dioxide (Saccharin®) were dissolved in 30 ml of trifluoroacetic acid and mixed with 4 g of sodium trifluoroacetate. The solution was electrolysed analogously to Example 1. After a charge quantity of 0.4 Ah had been used up the solution was added to water. It was extracted with chloroform and worked up as in Example 1. In addition to 3.3 g of starting material, 0.92 g of 4-hydroxy-1,2-benzisothiazol-3(2H)-one-1,1-dioxide were obtained after recrystallisation from water. This corresponds to a yield of 61% based on the starting material reacted;
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[C:7]([NH2:9])[N:6]=[C:5]([NH2:10])[N:4]=1.[CH2:11]([OH:13])[CH3:12]>>[NH2:10][C:5]1[N:4]=[C:3]([O:13][CH2:11][CH3:12])[CH:8]=[C:7]([NH2:9])[N:6]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: CCO
Agent: [Na]
Product: CCOc1cc(N)nc(N)n1
Temperature: 160 °C
Yield: 72 %

Procedure:
To a solution of sodium (1.05 g) in ethanol (50 ml) was added 4-chloro-2,6-diaminopyrimidine (6 g, 41.4 mmoles). The resulting solution was heated in a reactor for 6 hours at 160° C. The reaction mixture was cooled down and the precipitated sodium chloride was filtered off. The filtrate was concentrated and precipitated from ethanol (two times), affording the pure title compound as a white solid (4.53 g, 72% yield). The spectral data are identical to those described e.g. by W. Pfleiderer et al. in Chem. Ber. (1961) 94, 12.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:31][CH3:32].[N:33]1([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.[I-].[Na+]>COCCOC>[N:33]1([CH:39]2[CH2:44][CH2:43][N:42]([CH2:2][CH2:3][O:4][C:5]3[CH:14]=[C:13]4[C:8]([C:9]([NH:17][C:18]5[CH:23]=[CH:22][C:21]([O:24][C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)=[CH:20][CH:19]=5)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]4)=[CH:7][C:6]=3[O:31][CH3:32])[CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: COc1cc2c(Nc3ccc(Oc4ccccc4)cc3)c(C#N)cnc2cc1OCCCl
Reactant: C1CCN(C2CCNCC2)CC1
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2c(Nc3ccc(Oc4ccccc4)cc3)c(C#N)cnc2cc1OCCN1CCC(N2CCCCC2)CC1
Temperature: 137.5 °C
Yield: 47.7 %

Procedure:
A mixture of 222.5 mg (0.5 mmol) of 7-(2-chloroethoxy)-6-methoxy-4-(4-phenoxyphenylamino)quinoline-3-carbonitrile, 841.4 mg (5.0 mmol) of 4-piperidinopiperidine and 49.5 mg (0.33 mmol) of sodium iodide in 6.0 mL of ethylene glycol dimethyl ether are heated in a sealed tube at 135-140° C. for 17 hours to yield the crude product. Solvents are removed in vacuo. Purification of the oily residue is carried out by preparative thin layer chromatography (eluting with 85:15 dichloromethane/methanol) to provide 137.7 mg of 7-(2-[1,4′]bipiperidinyl-1′-yl-ethoxy)-6-methoxy-4-(4-phenoxy-phenylamino)-quinoline-3-carbonitrile as a light yellow solid, mp 141° C. (decompose).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:15])[NH:9]2)(=[O:3])[CH3:2].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:15])[NH:9]2)(=[O:3])[CH3:2]
Reactant: ClCc1ccccc1
Reactant: CC(=O)c1ccc(O)c2[nH]c(=O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Yield: 46.1 %

Procedure:
15.23 g of 5-acetyl-8-hydroxycarbostyril and 15.7 g of benzyl chloride are added to a mixture of 200 ml of acetone and 90 ml of water, and 10.35 g of potassium carbonate are added thereto. The mixture is refluxed for 12 hours under stirring. Then, the mixture is evaporated under reduced pressure to remove acetone, and the residue is extracted with chloroform. The extract is washed with water, dried and evaporated under reduced pressure to remove chloroform. The residue is recrystallized from a mixture of ethyl acetate and n-hexane. 10.14 g of 5-acetyl-8-benzyloxycarbostyril are obtained as prisms. 1.58 g of said product are further recovered from the mother liquor.