Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][CH2:4][CH:5]([NH:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:6]#[N:7].S(=O)(=O)(O)[OH:20].N>ClCCl>[F:1][C:2]([F:17])([F:18])[CH2:3][CH2:4][CH:5]([NH:8][CH:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:10])[C:6]([NH2:7])=[O:20]
Reactant: CC(NC(C#N)CCC(F)(F)F)c1ccccc1
Reactant: O=S(=O)(O)O
Agent: N
Solvent: ClCCl
Product: CC(NC(CCC(F)(F)F)C(N)=O)c1ccccc1
Temperature: -2.5 °C

Procedure:
5,5,5-Trifluoro-2-(1-phenylethylamino)pentanenitrile (crude mixture of diastereomers from Step B, 1.10 kg) was dissolved in dichloromethane (5.5 L) in a suitable vessel equipped with mechanical stirring, ice bath for cooling and maintained under a blanket of nitrogen. Stirring was started and the reaction mixture was cooled to 0 to −5° C. Concentrated sulfuric acid (1.75 L) was added dropwise over a period of 1 hour into the above mixture, maintaining the temperature below 0° C.; a clear solution was obtained after the addition was complete. The temperature of the reaction mixture was raised to 25 to 27° C. and stirred overnight (12-14 h). Completion of the reaction was determined by HPLC. The reaction mixture was poured slowly over crushed ice (˜15.0 kg) and was neutralized with aqueous ammonia (˜25% by volume). The aqueous layer was separated and extracted with dichloromethane (2×3.0 L). The combined dichloromethane layer was washed with water (1×12.0 L) followed by brine (1×3.0 L). The product rich organic layer was dried over sodium sulfate and concentrated under reduced pressure to yield 0.85 kg (72.0%) of the crude title compound 1H NMR (CDCl3) (400 MHz) (Mixture of diastereomers) δ 1.36 (d&m, 4H, CH3 (J=8.0 Hz & 1H of CH2), 1.90 (m, 1H of CH2), 2.15 & 2.35 (two m, 1H each of CH2—CF3), 2.80-2.90 (m, 1H, CH-Ph), 3.60-3.70 (m, 1H, —(CONH2)CH(NH), 5.90 & 6.45 (1H each of CONH2 with minor peaks for other diastereomer), 7.20-7.40 (m, 6H, Ar+NH).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[CH:6]1([CH2:9][NH2:10])[CH2:8][CH2:7]1>CS(C)=O>[CH:6]1([CH2:9][NH:10][CH2:3][CH2:2][C:1]([OH:5])=[O:4])[CH2:8][CH2:7]1
Reactant: C=CC(=O)O
Reactant: NCC1CC1
Solvent: CS(C)=O
Product: O=C(O)CCNCC1CC1

Procedure:
The above resin bound acrylic acid (50 mg) was treated with 300 μmol cyclopropylmethyl amine (21.3 mg) in 300 μL DMSO for 72 hours at 25° C. The excess reagent was filtered off and the resin was washed with 3×1 mL DMSO and 3×1 mL DMF.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:43]=[CH:44][CH:45]=1)[O:9][C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][C@H:27]([CH3:29])[N:26](C(OC(C)(C)C)=O)[C@H:25]([CH3:37])[CH2:24]3)=[CH:19][CH:18]=2)[C:13]([C:38](=[O:40])[NH2:39])=[N:12][C:11]=1[CH2:41][CH3:42])(=[O:4])[CH:2]=[CH2:3].O1CCOCC1.[ClH:52]>O1CCCC1>[ClH:52].[ClH:52].[ClH:52].[C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:43]=[CH:44][CH:45]=1)[O:9][C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][C@H:27]([CH3:29])[NH:26][C@H:25]([CH3:37])[CH2:24]3)=[CH:19][CH:18]=2)[C:13]([C:38]([NH2:39])=[O:40])=[N:12][C:11]=1[CH2:41][CH3:42])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Nc1cccc(Oc2nc(Nc3ccc(N4C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C4)cc3)c(C(N)=O)nc2CC)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: C=CC(=O)Nc1cccc(Oc2nc(Nc3ccc(N4C[C@@H](C)N[C@@H](C)C4)cc3)c(C(N)=O)nc2CC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl (2R,6S)-4-[4-({6-[3-(acryloylamino)phenoxy]-3-carbamoyl-5-ethylpyrazin-2-yl}amino)phenyl]-2,6-dimethylpiperazine-1-carboxylate (175 mg) and tetrahydrofuran (3 mL) was added a 4 M hydrogen chloride dioxane solution (3 mL), followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the obtained residue was washed with ethyl acetate and then dried at room temperature to obtain 5-[3-(acryloylamino)phenoxy]-3-({4-[(3R,5S)-3,5-dimethylpiperazin-1-yl]phenyl}amino)-6-ethylpyrazine-2-carboxamide trihydrochloride (157 mg) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:18]=[CH:17][C:10]([O:11][CH:12]([CH3:16])[C:13](Cl)=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.ClC1C=CC(OC2C=CC(OC(C)C(O)=O)=CC=2)=CC=1.S(Cl)(Cl)=O.[CH3:45][NH2:46]>C1C=CC=CC=1>[CH3:45][NH:46][C:13](=[O:14])[CH:12]([O:11][C:10]1[CH:17]=[CH:18][C:7]([O:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)[CH3:16]
Reactant: CN
Reactant: CC(Oc1ccc(Oc2ccc(Cl)cc2)cc1)C(=O)Cl
Agent: CC(Oc1ccc(Oc2ccc(Cl)cc2)cc1)C(=O)O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CNC(=O)C(C)Oc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
32 Grams of 4-(4-chlorophenoxy)-α-phenoxy-propionic acid chloride, prepared from 4-(4-chlorophenoxy)-α-phenoxypropionic acid (Example 5) and thionyl chloride, were dissolved in 150 ml of benzene and 7 grams of methyl amine were introduced at 15°C into the solution obtained. To complete the reaction the solution was stirred for 1 hour at 30°C, the precipitate formed was filtered off with suction, the benzenic solution was washed with water, dried over Na2SO4 and concentrated. The isolated crystals were recrystallized from petroleum ether. 28 Grams of 4-(4-chlorophenoxy)-α-phenoxypropionic acid methyl amide melting at 117° - 118°C were obtained. ##SPC6##
Reaction SMILES: [CH3:1][O:2][NH:3][C:4]([C:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:15]3[C:23]4[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=4)[N:17]([CH3:25])[N:16]=3)[N:13]=2)[N:8](COCC[Si](C)(C)C)[CH:7]=1)=[O:5].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[CH3:1][O:2][NH:3][C:4]([C:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:15]3[C:23]4[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=4)[N:17]([CH3:25])[N:16]=3)[N:13]=2)[NH:8][CH:7]=1)=[O:5]
Reactant: CONC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CONC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Reaction time: 2 h
Yield: 0.3 %

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid methoxy-amide (53 mg, 113 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.4 mL, 5.19 mmol) at 20° C. After 2 h, the mixture was concentrated in vacuo. The residue was diluted with dichloromethane and concentrated again. The residue was then suspended in dichloromethane (2 mL) and ethylenediamine (0.4 mL, 5.92 mmol) added. The mixture was stirred for 1 h, then concentrated in vacuo. To the residue was added ethyl acetate and water. The organic layer was then washed with brine then dried (sodium sulfate), filtered and concentrated in vacuo. Purification by chromatography (silica, 25 g pre-packed SiliCycle cartridge, 40-80% EtOAc in hexane gradient increasing over 15 min) gave 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid methoxy-amide (45 mg, 0.39 μmol, 39%) as a light yellow powder. MS (M+H)+=341; 1H NMR (DMSO-d6) δ: 12.87 (br. s., 1H), 10.97 (s, 1H), 9.09 (s, 1H), 8.66 (dd, J=8.8, 5.3 Hz, 1H), 8.45 (s, 1H), 7.67 (d, J=9.8 Hz, 1H), 7.24 (t, J=9.3 Hz, 1H), 4.15 (s, 3H), 3.84 (s, 3H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]([CH:17]1[CH2:22][CH2:21][S:20][CH2:19][CH2:18]1)=[O:16].[CH:23](=[O:25])[CH3:24]>O1CCCC1>[CH3:13][O:14][C:15]([C:17]1([CH:23]([OH:25])[CH3:24])[CH2:22][CH2:21][S:20][CH2:19][CH2:18]1)=[O:16]
Reactant: CC=O
Reactant: COC(=O)C1CCSCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(C(C)O)CCSCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
A solution of N,N-diisopropylamine (1.51 g, 2.1 mL, 15 mmol) in anhydrous tetrahydrofuran (10 mL) was stirred at −78° C. under nitrogen. n-Butyl lithium (6 mL, 15 mmol, 2.5 M solution in hexane) was added dropwise and the reaction mixture was stirred at −78° C. for 30 min. A solution of tetrahydro-thiopyran-4-carboxylic acid methyl ester (1.60 g, 10 mmol) in tetrahydrofuran (4 mL) was added and the reaction mixture was stirred at −78° C. for 20 min. Acetaldehyde (1.32 g, 1.7 mL, 30 mmol) was then added in one portion. The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0° C. and ice-cold hydrochloric acid (2 M) was added to acidify the reaction mixture to pH 2. Sodium chloride was added to saturate the aqueous phase and the mixture was extracted with diethyl ether. The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 3:1 to 1:3 to afford the title compound (1.77 g, 87%) as a yellow oil. 1H NMR (300 MHz, d6-DMSO): δ 0.96 (d, J=6.5 Hz, 3H), 1.46-1.73 (m, 2H), 2.12-2.28 (m, 2H), 2.43-2.57 (m, 4H), 3.50-3.58 (m, 1H), 3.63 (s, 3H), 4.85 (d, J=5.8 Hz, 1H). LCMS (m/z) 227.1 [M+Na], Tr=1.53 min.
Reaction SMILES: [Cl:1][CH:2]([Cl:26])[C:3]([NH:5][C@H:6]([CH2:24][F:25])[C@@H:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]([CH2:21][C:22]#[N:23])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)[OH:8])=[O:4].S(=O)(=O)(O)[OH:28].C(=O)(O)[O-].[Na+]>>[NH2:23][C:22](=[O:28])[CH2:21][C:18]1[N:17]=[CH:16][C:15]([C:12]2[CH:11]=[CH:10][C:9]([C@@H:7]([OH:8])[C@H:6]([NH:5][C:3](=[O:4])[CH:2]([Cl:1])[Cl:26])[CH2:24][F:25])=[CH:14][CH:13]=2)=[CH:20][CH:19]=1
Reactant: O=S(=O)(O)O
Reactant: N#CCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Product: NC(=O)Cc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cn1

Procedure:
The product of step 3 of Example 4 (10 mg, 0.025 mmol) is stirred with concentrated sulfuric acid (0.5 mL) at room temperature for 30 minutes. The solution is basified with saturated aqueous sodium bicarbonate (5 mL) and extracted with 10% methanol in CH2Cl2 (10 mL). The organics are concentrated and the residue purified by chromatography on a reverse phase C-18 column eluting with a gradient of neat water with 0.1% trifluoroacetic acid to neat acetonitrile with 0.1% trifluoroacetic acid to give the title compound (2 mg): m/z (Cl) 415 [M+H].
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:19][C:20]([CH:22]1[CH2:24][CH2:23]1)=[O:21]>CCO.O>[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14](/[CH:15]=[CH:19]/[C:20]([CH:22]2[CH2:24][CH2:23]2)=[O:21])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)C1CC1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(/C=C/c1ccc(OCc2ccccc2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
1M NaOH (4.8 ml) was added to a solution of 4-benzyloxybenzaldehyde (5 g) and cyclopropyl methyl ketone (3.96 g) in EtOH (24 ml) and the mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with H2O and EtOH. The mixture was stirred at ambient temperature for 20 minutes. Pale yellow crystals were collected and washed with H2O and 50% aqueous EtOH to give (2E)-3-[4-(benzyloxy)phenyl]-1-cyclopropyl-2-propen-1-one (6.29 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:36]=[CH:37][CH:38]=1)[CH2:8][N:9]1[C@@H:17]2[C@H:12]([C@H:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28](=O)[CH2:29][N:30]([CH3:32])[CH3:31])=[C:23]([F:34])[CH:22]=3)[CH2:14][S:15](=[O:19])(=[O:18])[CH2:16]2)[O:11][C:10]1=[O:35])([CH3:4])([CH3:3])[CH3:2].B.C1COCC1.Cl.[OH-].[Na+]>C1COCC1.CO>[C:1]([C:5]1[CH:6]=[C:7]([CH:36]=[CH:37][CH:38]=1)[CH2:8][N:9]1[C@@H:17]2[C@H:12]([C@H:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])=[C:23]([F:34])[CH:22]=3)[CH2:14][S:15](=[O:18])(=[O:19])[CH2:16]2)[O:11][C:10]1=[O:35])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CC(=O)Nc1ccc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc1F
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)CCNc1ccc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-{4-[(3aR*,7S*,7aS*)-3-(3-tert-butyl-benzyl)-2,5,5-trioxo-octahydro-1-oxa-5lambda*6*-thia-3-aza-inden-7-ylmethyl]-2-fluoro-phenyl}-2-dimethylamino-acetamide (example 6a), 0.055 g, 0.1 mmol) in THF (1.1 mL) was added borane THF-complex (1M in THF, 1 mL, 1 mmol) at 25° C. The mixture was stirred for 17 h at 25° C. and afterwards 3 h at reflux. The reaction mixture was evaporated and diluted with EtOAc; ice cold aq. H2SO4 was added carefully and the organic layer was washed with water, brine, dried over Na2SO4, filtered and evaporated to leave an amorphous powder which was dissolved in MeOH (3 mL). and 2N aq. HCl (2.5 mL) and the solution was kept at 80° C. for 17 h. The colorless solution was basified with aq. NaOH and extracted with EtOAc. Organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the title compound as a slight brownish foam: TLC (toluene-ETA 85:15) Rf=0.30; HPLC RtA=1.91 min; ESIMS [M+H]+=532; 1H NMR (600 MHz, DMSO-d6): δ 7.39 (s, 1H), 7.33 (m, 1H), 7.28 (t, 1H), 7.13 (d, 1H), 6.9 (d, 1H), 6.82 (d, 1H), 6.72 (t, 1H), 5.51 (d, 1H), 4.40 (d, 1H), 4.22 (d, 1H), 4.11 (t, 1H), 3.67 m, 2H), 3.44 (m, 3H), 3.01 (m, 2H), 2.84 (m, 3H), 2.55 (s, 6H), 2.46 (m, 2H), 1.25 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:39][C:38](Cl)=[N:37][CH:36]=1)(=[O:34])=[O:33])([CH3:30])[CH3:29]>>[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:39][C:38]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[N:37][CH:36]=1)(=[O:34])=[O:33])([CH3:30])[CH3:29]
Reactant: CC(C)(CO)NS(=O)(=O)c1cnc(Cl)s1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cnc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 2-Chloro-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.14) (244 mg, 0.9 mmol) according to general procedure II. Obtained as an orange solid (110 mg, 18%). MS (ISP) 590.3 [(M+H)+]; mp 252-253° C.
Reaction SMILES: Cl[C:2]1[C:3]([F:20])=[CH:4][N:5]2[C:10]([CH:11]=1)=[C:9]([NH:12][CH3:13])[CH:8]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]2=[O:19].[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>N1C=CC=CC=1>[F:20][C:3]1[C:2]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)=[CH:11][C:10]2[N:5]([C:6](=[O:19])[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][C:9]=2[NH:12][CH3:13])[CH:4]=1
Reactant: CCOC(=O)c1cc(NC)c2cc(Cl)c(F)cn2c1=O
Reactant: CN1CCNCC1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(NC)c2cc(N3CCN(C)CC3)c(F)cn2c1=O
Temperature: 70 °C

Procedure:
Ethyl 8-chloro-7-fluoro-1-methylamino-4H-quinolizin-4-one-3-carboxylate (899 mg, 3.0 mmol), the product of Step 6, is suspended in 12 mL of dry pyridine under a nitrogen atmosphere. To the resultant solution is added 6.0 mL (6.0 mmol) of N-methylpiperazine and the reaction mixture is heated at 70° C. for 8 hours. The reaction mixture is then concentrated in vacuo in order to remove all of the pyridine. The dry residue is dissolved in 125 mL of methylene chloride and the methylene chloride solution is washed with 125 mL of brine. The aqueous layer is extracted with 125 mL of methylene chloride and the combined methylene chloride solutions are dried over anhydrous sodium sulfate, filtered and concentrated and dried in vacuo to afford the title compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].Cl[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1[CH3:34]>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][C:29]=2[CH3:34])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: Cc1cnccc1Cl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(-c2ccncc2C)c1

Procedure:
By carrying out the operation analogously to example 49, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IX, and 4-chloro-3-methylpyridine, the desired product is obtained in the form of beige crystals (yield=15%).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([O:14]CC)=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH2:28][CH2:29][NH2:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1.[OH-].[Na+].O.CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH2:28][CH2:29][NH:30][C:12]([C:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][N:10]=1)=[O:14]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: CCOC(=O)c1noc(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1noc(-c2ccccc2)n1
Yield: 26.8 %

Procedure:
This compound was prepared according to method F with ethyl 5-phenyl-1,2,4-oxadiazole-3-carboxylate (0.075 g; 0.346 mmol) in THF (1 mL) and sodium hydroxide in water (2M, 1 mL); 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.080 g; 0.346 mmol), HATU (0.131 g; 0.346 mmol), N,N diisopropylethylamine (0.149 mL; 0.865 mmol), in DMF (4 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) and preparative HPLC method 2 to yield 0.034 g (24%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-phenyl-1,2,4-oxadiazole-3-carboxamide as a white solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:15])[CH2:13][CH3:14]>>[CH3:14][CH2:13][C:12]([C:7]1[CH:8]=[C:9]([N+:1]([O-:4])=[O:2])[CH:10]=[CH:11][C:6]=1[Cl:5])=[O:15]
Reactant: CCC(=O)c1ccccc1Cl
Reactant: O=[N+]([O-])O
Product: CCC(=O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
31 ml of 100% nitric acid (dl.52) are introduced into the reaction vessel, and 6 g of o-chloropropiophenone are added dropwise at -10° C. in the course of 15 minutes in such a way that the reaction temperature is between -5° C. and -10° C. To complete the reaction, stirring is continued at 0° C. for 45 minutes. The reaction mixture is subsequently poured onto 300 g of ice, and the aqueous mixture is extracted twice using 200 ml portions of diethyl ether. The organic phase is washed with 100 ml of water, twice with 100 ml portions of 2N potassium hydrogen carbonate solution and finally with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is recrystallised from diisopropyl ether/n-hexane; m.p.: 55°-56° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH3:22])[C:17](=[O:23])[CH2:16][CH2:15]3)[CH:9]=[N:10][CH:11]=1.[Cl:24][C:25]1[C:26]([C:31](O)=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=1>>[CH3:22][N:18]1[C:19]2[C:14](=[CH:13][C:12]([C:8]3[CH:7]=[C:6]([O:5][CH2:4][CH2:3][NH:2][C:31]([C:26]4[C:25]([Cl:24])=[CH:30][CH:29]=[CH:28][N:27]=4)=[O:32])[CH:11]=[N:10][CH:9]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:16][C:17]1=[O:23]
Reactant: CN1C(=O)CCc2cc(-c3cncc(OCCN)c3)ccc21
Reactant: O=C(O)c1ncccc1Cl
Agent: Cl
Product: CN1C(=O)CCc2cc(-c3cncc(OCCNC(=O)c4ncccc4Cl)c3)ccc21

Procedure:
In analogy to the procedure described for the preparation of example 75, 6-[5-(2-amino-ethoxy)-pyridin-3-yl]-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 42) has been coupled with 3-chloro-pyridine-2-carboxylic acid to give the title compound as a light yellow viscous oil. MS: 437.4 (M+H+).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)(C)C.[C:13]1([S:19]([NH:22][C:23]2[C:28](I)=[CH:27][C:26]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:25][CH:24]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(=O)C.[K+].O1CCOCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.O>[C:13]1([S:19]([N:22]2[C:23]3[C:24](=[CH:25][C:26]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:27][CH:28]=3)[CH:5]=[C:6]2[C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)(=[O:20])=[O:21])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)c1ccc(NS(=O)(=O)c2ccccc2)c(I)c1
Reactant: C[Si](C)(C)C#Cc1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc2c(c1)cc(-c1cccnc1)n2S(=O)(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 63 %

Procedure:
A mixture of 3-trimethylsilylethynylpyridine (1.07 g), 2-benzenesulfonylamino-3-iodo-5-methanesulfonylbenzene (1.75 g), potassium acetate (1.60 g), cuprous iodide (60 mg), dichlorobis(triphenylphosphine)palladium (0.20 g) and 1,4-dioxane (4 ml) was stirred at 100° C. for 12 hours under nitrogen atmosphere. To the reaction solution were added water and ethyl acetate. The insolubles were filtered off. The filtrate was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:3) to obtain 1.04 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[C:16](OC(=O)C)(=[O:18])[CH3:17]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(OC(C)=O)cc1
Temperature: 25 °C
Yield: 103.5 %

Procedure:
A mixture of 4-methoxyphenol (6.2 g, 50 mmol), K2CO3 (10 g, 72 mmol) and acetic anhydride (6.12 g, 60 mmol) in acetone (150 ml) was stirred at RT. over night. The solid was filtered off and washed with acetone (50 ml). After removal of acetone, 8.6 g of product was obtained. Yield: 100%.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH:19]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([CH2:27]Br)[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:26][C:22]1[C:23]([F:25])=[CH:24][CH:19]=[CH:20][C:21]=1[CH2:27][N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[CH:17][C:5]=2[C:1]([O:3][CH3:4])=[O:2]
Reactant: Fc1cccc(CBr)c1F
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(F)c2F)CCCC1=O
Temperature: 25 °C
Reaction time: 73 h
Yield: 70.4 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (973 mg, 4.0 mM), a-bromo-2,3-difluorotoluene (1.01 g, 4.8 mM), and potassium carbonate (553 mg, 4.0 mM) in 10 mL DMF was stirred at room temperature for 73 hours. The mixture was diluted with ethyl acetate, washed with H2O, 1 N HCl, H2O, saturated NaHCO3, H2O, and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated. The residue was purified by column chromatography on silica gel (elution with methylene chloride/ethyl acetate) to afford 1.04 g (70%) of the 9-[(2,3-difluorophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a tan solid. 1H NMR (CDCl3) δ 7.4 (d, 1H, J=8 Hz), 7.35 (d, 1H, J=8 Hz), 7.15-6.9 (m, 5H), 6.35 (t, 1H, J=8 Hz), 5.4 (s, 2H), 4.05 (s, 3H), 2.9 (t, 2H, J=6 Hz), 2.6 (t, 2H, J=6 Hz), and 2.25 (m, 2H). IR (KBr, cm−1) 1719 and 1650. MS (ES) m/e 368, 370.