Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[CH3:21].[C:22](=[O:25])([O-])[O-].[Na+].[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[Cl:40][C:41]1[N:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=1>ClCCl.O>[Cl:40][C:41]1[N:46]=[CH:45][C:44]([NH:47][C:22](=[O:25])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C@H:8]3[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:9]3)=[CH:4][C:3]=2[CH3:21])=[CH:43][CH:42]=1
Reactant: Cc1cc([C@@H]2CN(C(=O)OC(C)(C)C)CCO2)ccc1N
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(Cl)nc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc([C@@H]2CN(C(=O)OC(C)(C)C)CCO2)ccc1NC(=O)Nc1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a stirred solution of (+)-(R)-tert-butyl 2-(4-amino-3-methylphenyl)morpholine-4-carboxylate (99 mg) in dichloromethane (3 ml) was added a solution of sodium carbonate (72 mg) in water (3 ml). The reaction mixture was cooled to 0° C. and triphosgene (37 mg) was added. The reaction mixture was then stirred at 0° C. for 1 hour. TLC showed all the starting material had reacted. 6-Chloropyridin-3-amine (48 mg, CAS 5350-93-6) was then added and the reaction mixture was stirred at room temperature for a further hour. TLC showed the reaction was complete. The reaction mixture was poured into dichloromethane and extracted with water. The organic phase was separated, dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: 0% to 70% EtOAc in hexanes) to give (R)-tert-butyl 2-(4-(3-(6-chloropyridin-3-yl)ureido)-3-methylphenyl)morpholine-4-carboxylate (106 mg, 70%) as an off-white solid. MS (ISP): 449.2 ([{37Cl}M+H]+), 447.2 ([{35Cl}M+H]+).
Reaction SMILES: C([O:5][C:6](=[O:17])[C@@H:7]([NH:9][C:10]([C:12]1[NH:13][CH:14]=[CH:15][N:16]=1)=[O:11])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl>[NH:13]1[CH:14]=[CH:15][N:16]=[C:12]1[C:10]([NH:9][C@@H:7]([CH3:8])[C:6]([OH:17])=[O:5])=[O:11]
Reactant: C[C@H](NC(=O)c1ncc[nH]1)C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)c1ncc[nH]1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (2S)-2-[(1H-imidazole-2-carbonyl)-amino]-propionic acid tert-butyl ester (0.257 g) in dichloromethane (2 mL) was cooled to 0° C. before dropwise addition of trifluoroacetic acid and reaction mixture warmed to room temperature and stirred for 2 hr before evaporation under reduced pressure. The residue was co-evaporated with dichloromethane (twice) and toluene (twice) to leave the required (2S)-2-[(1H-imidazole-2-carbonyl)-amino]-propionic acid that was used without further purification (0.40 g).
Reaction SMILES: [CH:1]([S:4][C:5]1[S:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:7]2[CH2:15][CH2:16][CH2:17][C:18](=[O:19])[C:6]=12)([CH3:3])[CH3:2].[Br:20]Br.O>CO>[Br:20][CH:17]1[CH2:16][CH2:15][C:7]2=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:9][C:5]([S:4][CH:1]([CH3:2])[CH3:3])=[C:6]2[C:18]1=[O:19]
Reactant: BrBr
Reactant: CCOC(=O)c1sc(SC(C)C)c2c1CCCC2=O
Solvent: CO
Solvent: O
Product: CCOC(=O)c1sc(SC(C)C)c2c1CCC(Br)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
Ethyl 4,5,6,7-tetrahydro-3-isopropylthio-4-oxobenzo[c]thiophene-1-carboxylate (2.50 g) was dissolved in methanol (80 ml); a solution of bromine (1.34 g) in methanol (8.6 ml) was added dropwise at room temperature. After the reaction mixture was stirred at room temperature for 2 hours, it was poured over water and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium thiosulfate, a saturated aqueous solution of sodium hydrogen carbonate and water in that order, and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:5, v/v) to yield ethyl 5-bromo-4,5,6,7-tetrahydro-3-isopropylthio-4-oxobenzo[c]thiophene-1-carboxylate (2.65 g, 83.9%), which was then recrystallized from ethyl acetate-hexane. Colorless prisms. Melting point 107-108° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([N+:16]([O-])=O)[CH:10]=2)=[N:7][CH:8]=1>CO.CC(=O)OCC.[Pd]>[CH3:1][O:2][C:3]1[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[N:5][C:6]([C:9]2[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=2)=[N:7][CH:8]=1
Reactant: COc1cnc(-c2ccc(N)c([N+](=O)[O-])c2)nc1N1CCOCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cnc(-c2ccc(N)c(N)c2)nc1N1CCOCC1
Reaction time: 5 h

Procedure:
A mixture of 4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-2-nitro-phenylamine (0.69 g, 1.0 eq.) and Pd/C (Cat.) in MeOH/EA (10 ml/10 ml) was prepared. The mixture was sharked and H2 gas was injected to the mixture for 4-6 hrs at room temperature. The mixture was filtered with Celite 454 and dried in vacuo to give a black sold (0.65 g, 99.9%) as a product.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[CH:15][S:16][CH:17]=2)=[C:9]([F:18])[CH:8]=1)(=O)=O.C([Sn](CCCC)(CCCC)[C:26]([O:28]CC)=[CH2:27])CCC.[Cl-].[Li+]>O1CCOCC1.C(OCC)(=O)C.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>[F:18][C:9]1[CH:8]=[C:7]([C:26](=[O:28])[CH3:27])[CH:12]=[CH:11][C:10]=1[C:13]1[N:14]=[CH:15][S:16][CH:17]=1
Reactant: O=S(=O)(Oc1ccc(-c2cscn2)c(F)c1)C(F)(F)F
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)c1ccc(-c2cscn2)c(F)c1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
To a stirred solution of 3-fluoro-4-(1,3-thiazol-4-yl)phenyl trifluoromethanesulfonate (1.45 g, 4.43 mmol) in dioxane (42 ml) was added tributyl(1-ethoxyvinyl)tin (1.92 g, 5.32 mmol), tetrakis(triphenylphosphine)palladium (512 mg, 0.44 mmol), lithium chloride (466 mg, 11.0 mmol), and the mixture was heated at reflux temperature for 16 hours. The reaction mixture was cooled down to room temperature, and diluted with ethyl acetate. The whole was washed with saturated potassium fluoride aqueous solution, and the precipitate was removed by filteration through celite. The resulting solution was extracted with ethyl acetate. The organic layer was concentrated in vacuo. To the residue was added THF (20 ml), 2N HCl aqueous solution (20 ml), and the mixture was heated at reflux temperature for 8 hours. The reaction mixture was cooled down to room temperature, made neutral by addition of NaHCO3, and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:5) to give title compound (666 mg, 68% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:21][CH2:22][CH3:23])=[C:8]2[CH:14]=[N:13][N:12](CC3OC=CC=3)[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].[Se](=O)=O.O.N>COCCOCCOC.O.CO>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:21][CH2:22][CH3:23])=[C:8]2[CH:14]=[N:13][NH:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccco2)c1OCC
Agent: N
Agent: O=[Se]=O
Solvent: CO
Solvent: COCCOCCOC
Solvent: O
Product: CCOC(=O)c1cnc2[nH]ncc2c1OCC
Reaction time: 1.5 h
Yield: 67 %

Procedure:
31.5 g of 4-ethoxy-1-(2-furyl)methyl-1H-pyrazolo[3,4-b]pyridine- 5-carboxylic acid ethyl ester (0.1 mol) and 20 g of selenium dioxide (0.18 mol) are suspended in 100 ml diethyleneglycol dimethylether. The mixture is heated with stirring at 160° and a few drops of water are added. The temperature is held steady for 1.5 hours. After cooling, 100 ml of water is added and the mixture is neutralized with a dilute solution of aqueous ammonia. Yellow crystals are formed, which yield on recrystallization from methanol 15.8 g of 4-ethoxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (67%), m.p. 180°.
Reaction SMILES: S(=O)(=O)(O)[OH:2].N[C:7]1[C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][S:15](=[O:17])(=[O:16])[C:11]=2[CH:10]=[C:9]([C:24]([OH:26])=[O:25])[CH:8]=1.N([O-])=O.[Na+].[OH2:31]>>[C:13]([C:12]1[C:11]([S:15](=[O:17])(=[O:16])[NH2:14])=[CH:10][C:9]([C:24]([OH:26])=[O:25])=[CH:8][C:7]=1[OH:2])(=[O:31])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(O)O
Reactant: O
Reactant: Nc1cc(C(=O)O)cc2c1C(c1ccccc1)=NS2(=O)=O
Agent: O=N[O-]
Agent: [Na+]
Product: NS(=O)(=O)c1cc(C(=O)O)cc(O)c1C(=O)c1ccccc1

Procedure:
To a stirred mixture of conc. sulfuric acid (125 ml) and water (40 ml), 4-amino-6-carboxy-3-phenyl-1,2-benzisothiazole 1,1-dioxide (15.1 g) is added in portions. The resulting solution is cooled to 0° -5° C. and the amine is diazotized by the dropwise addition of a solution of sodium nitrite (3.8 g) in water (40 ml). The diazonium-mixture is then heated on a steam bath for 2-3 hours until the nitrogen evolution has ceased. After cooling and dilution with water (about 200 ml), the resulting precipitate is collected by filtration and washed with water. The material is dried and recrystallized twice from aqueous ethanol. The thus purified material is dissolved in 1 N sodium hydroxide and the solution is added to a slight excess of ice-cold 1 N hydrochloric acid. The resulting precipitate is collected by filtration, washed with water and dried in vacuo in the presence of P2O5 to give 4-benzoyl-3-hydroxy-5-sulfamylbenzoic acid as a hemihydrate.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].C(OC([N:67]([CH2:76][CH2:77][S:78][S:79][C:80]([CH3:83])([CH3:82])[CH3:81])[CH2:68][CH2:69][C:70](OCC#N)=[O:71])=O)(C)(C)C.C(N(CC)CC)C>CN(C=O)C>[C:80]([S:79][S:78][CH2:77][CH2:76][NH:67][CH2:68][CH2:69][C:70]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:71])([CH3:83])([CH3:82])[CH3:81]
Reactant: CC(C)(C)OC(=O)N(CCSSC(C)(C)C)CCC(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)SSCCNCCC(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.9 %

Procedure:
((2R,3S,5R)-5-(4-Amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate tetrabutylammonium salt (Compound 1h, 44.6 mg, 0.314 mmol) and cyanomethyl 3-((tert-butoxycarbonyl) (2-(tert-butyldisulfanyl)ethyl)amino)propanoate (Compound 6g-B, 236 mg, 0.628 mmol) were dissolved in DMF under ice-cooling, followed by addition of triethylamine (0.088 ml, 0.628 mmol). After stirring at room temperature for 1 hour, the reaction solution was purified by column chromatography (0.05% aqueous TFA solution:0.05% TFA-acetonitrile solution=70:30). TFA (1.5 ml) was added to the resulting residue, and the mixture was stirred at room temperature for 5 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (0.05% aqueous TFA solution:0.05% TFA-acetonitrile solution=80:20) to afford the title compound (66.9 mg, 25%).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH:25]([CH3:27])[CH3:26])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](O)(=[O:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH:25]([CH3:27])[CH3:26])[C:28](=[O:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCC(=O)O
Reactant: CC(C)NCCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Product: CCCCCCC(=O)N(CCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(C)C
Yield: 90.8 %

Procedure:
Following literature precedent,2 5-(tert-butyldiphenylsilyloxy)-N-isopropylpentan-1-amine (0.90 g, 2.30 mmol) was condensed with heptanoic acid (0.26 g, 2.0 mmol) to give the title amide (0.90 g, 79%) as a viscous oil. TLC: EtOAc/hexanes (3:8), Rf˜0.60; 1H NMR (300 MHz, 1:1 mixture of rotamers) δ 7.65-7.67 (m, 4H), 7.30-7.40 (m, 6H), 4.62-4.72 (m, 0.5H), 4.00-4.80 (m, 0.5H), 3.62 (t, J=4.8 Hz, 1H), 3.68 (t, J=4.8 Hz, 1H), 3.02 (t, J=5.2 Hz, 1H), 3.16 (t, J=5.2 Hz, 1H), 2.38 (t, J=5.3 Hz, 1H), 2.24 (t, J=5.3 Hz, 1H), 1.50-1.68 (m, 6H), 1.26-1.44 (m, 8H), 1.18 (d, J=7.3 Hz 3H), 1,12, (d, J=7.3 Hz 3H), 1.03 (s, 4.5H), 1.04 (s, 4.5H), 0.88 (t, J=7.3 Hz, 3H); 13C NMR (125 MHz) δ 173.38, 172.76, 135.80, 135.78, 134.36, 134.12, 129.85, 129.73, 127.88, 127.82, 64.22, 63.68, 48.43, 45.62, 43.64, 41.27, 34.13, 34.05, 32.61, 32.36, 31.96, 31.93, 31.51, 29.63, 29.47, 27.10, 27.03, 25.94, 25.78, 24.03, 23.77, 22.81, 21.63, 20.78, 19.47, 14.33, 14.28. HRMS calcd for C31HsoNO2Si [M+1]+ 496.3611. found 496.3615.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][CH:3]=1.[CH3:19][NH:20][CH3:21]>C(#N)C>[CH3:19][N:20]([CH3:21])[C:12](=[O:13])[C:11]1[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=1[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:18]
Reactant: CNC
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1
Solvent: CC#N
Product: CN(C)C(=O)C1=C(C(=O)Nc2ccc(Cl)cc2)CCCC1
Temperature: 25 °C

Procedure:
In 100 ml of acetonitrile is dissolved 3.0 g of N-(4-chlorophenyl)-3,4,5,6-tetrahydrophthalimide. To the solution is added 1.5 g of a 40% aqueous dimethylamine solution under stirring at room temperature, followed by further stirring for 30 minutes. The solution is concentrated to dryness under reduced pressure, the resulting oily substance is dissolved in 50 ml of ether and the solution is dried with sodium sulfate. The ether layer is concentrated to dryness under reduced pressure and the resultant oily substance is allowed to crystallize by adding 50 ml of n-hexane thereto. The resultant crystals are recovered by filtration and washed with a small amount of n-hexane, whereby to yield 2.5 g of the subject compound.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[CH3:9][O:10][C:11]1[C:12]([CH3:38])=[C:13]([C:20]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[NH:28][CH:27]=[C:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:25]3=[O:37])=[O:21])[N:14]2[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]2>CN(C=O)C>[CH3:9][O:10][C:11]1[C:12]([CH3:38])=[C:13]([C:20]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]([CH3:1])[CH:27]=[C:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:25]3=[O:37])=[O:21])[N:14]2[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]2
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c[nH]c2ccc(C(=O)c3c(C)c(OC)c4ccccn34)cc2c1=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c2ccc(C(=O)c3c(C)c(OC)c4ccccn34)cc2c1=O
Temperature: 90 °C
Yield: 93.6 %

Procedure:
3.8 g (27.89 mmol) of potassium carbonate and 1.74 ml (27.89 mmol) of methyl iodide are added, at ambient temperature under an inert atmosphere, to 10 g (23.24 mmol) of ethyl 6-[(1-methoxy-2-methylindolizin-3-yl)carbonyl]-4-oxo-1,4-dihydroquinoline-3-carboxylate in 100 ml of DMF. The reaction medium is heated at 90° C. for 1 h 30. The reaction medium is filtered through talc, diluted with dichloromethane, and then washed with water. The organic phase is dried with sodium sulphate and then concentrated under reduced pressure. The residue obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (90/10) mixture. 9.1 g of a yellow solid are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B(O)O)[CH:5]=[CH:4][N:3]=1.Br[C:12]1[N:17]2[CH:18]=[CH:19][N:20]=[C:16]2[C:15]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[CH:24][CH:23]=2)=[N:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[NH3:3].[F:1][C:2]1[CH:7]=[C:6]([C:12]2[N:17]3[CH:18]=[CH:19][N:20]=[C:16]3[C:15]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]4)=[CH:26][CH:27]=3)=[N:14][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CN1CCN(c2ccc(Nc3ncc(Br)n4ccnc34)cc2)CC1
Reactant: OB(O)c1ccnc(F)c1
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: [Na+]
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(Nc3ncc(-c4ccnc(F)c4)n4ccnc34)cc2)CC1
Product: N
Yield: 60.4 %

Procedure:
In the same way as described for Compound 127, step 4, using 2-fluoro-pyridine-4-boronic acid (44 mg, 0.310 mmol), (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-(4-(4-methylpiperazin-1-yl)phenyl)amine (60 mg, 0.155 mol), Pd(PPh3)4 (45 mg, 0.038 mmol) and 1.5M Na2CO3 (0.83 mL) in dioxane (2.2 mL). The residue is chromatographed on silica gel, eluting with DCM followed by 97:3 DCM:NH3 (7M in MeOH) affording the title compound (37.8 mg, 61%). LCMS: Rt 2.14 min (96%) m/z (APCI) 404 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.26 (3H, s), 2.49-2.54 (4H, t), 3.13-3.15 (4H, m), 6.97 (2H, d), 7.58 (1H, s), 7.71 (1H, s), 7.75 (2H, m), 7.89 (2H, d), 8.21 (1H, s), 8.43 (1H, d), 9.73 (1H, s).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH3:8][C:9]1[CH:10]=[C:11]([C:15]2[NH:19][C:18]([C:20]([F:23])([F:22])[F:21])=[N:17][C:16]=2[C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:12]=[CH:13][CH:14]=1.[CH3:34][Si:35]([CH3:42])([CH3:41])[CH2:36][CH2:37][O:38][CH2:39]Cl>CCCCCC>[CH3:8][C:9]1[CH:10]=[C:11]([C:15]2[N:19]([CH2:39][O:38][CH2:37][CH2:36][Si:35]([CH3:42])([CH3:41])[CH3:34])[C:18]([C:20]([F:22])([F:23])[F:21])=[N:17][C:16]=2[C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1cccc(-c2[nH]c(C(F)(F)F)nc2-c2ccc(S(C)(=O)=O)cc2)c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1cccc(-c2c(-c3ccc(S(C)(=O)=O)cc3)nc(C(F)(F)F)n2COCC[Si](C)(C)C)c1
Reaction time: 0.25 h
Yield: 79.5 %

Procedure:
Sodium hydride (60% in oil, 1.06 mmol, 42 mg) was washed with hexane (ca 2×1 ml), then covered with N,N-dimethyformamide (2.1 ml). 5-(3-Methylphenyl)-4-[4-(methylsulfonyl)phenyl]-2-trifluoromethyl-1H-imidazole (Example 59) (0.70 mmol, 268 mg) was added, with stirring. After 15 minutes, 2-(trimethylsilyl)ethoxymethyl chloride (SEM-Cl) (1.06 mmol, 0.19 ml) was added and the mixture was stirred overnight. The reaction was quenched with saturated ammonium chloride (ca. 4 drops), and concentrated in vacuo. The residue was subjected to chromatography (2:1 hexane: ethyl acetate) and concentrated to afford the title compound (284 mg, 79%) as an oil as a mixture of the two possible N alkylated isomers (by NMR).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[OH-].[K+].Cl[C:13]1[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][N:14]=1>CO.C1(C)C=CC=CC=1>[NH2:19][C:18]1[C:13]([O:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: COc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc(Oc2ncccc2N)cc1
Reaction time: 2 h
Yield: 108.5 %

Procedure:
5.87 g of 4-methoxyphenol were dissolved in 8 ml of methanol; 2.61 g of KOH were added, the whole was stirred for 2 hours, and the solvent was evaporated. The solid obtained was dissolved in 150 ml of anhydrous toluene. With stirring, 5 g of 2-chloro-3-nitropyridine were added at 70°-80° C. in the course of 4 hours under a nitrogen atmosphere. The whole was then stirred at ambient temperature for 2 hours. It was washed with 10% aqueous NaOH and then with plenty of water. The organic phase was treated with active carbon at room temperature for 60 minutes. It was filtered and the filtrate was dried with anhydrous magnesium sulphate. After evaporation of the solvent at low pressure, 7.4 g of 3-amino-2-(4-methoxyphenoxy)pyridine (95% yield) were obtained as a pale yellow solid which melted at 105°-107° C. with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][CH2:7][CH2:6]2.C(N(C(C)C)CC)(C)C.Br[CH2:25][C:26](Cl)=[O:27].C(=O)([O-])[O-].[K+].[K+].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[N:8]([C:26](=[O:27])[CH2:25][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[CH2:7][CH2:6]2
Reactant: O=C(Cl)CBr
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCC2
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CN1CCOCC1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
To a solution of 5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (0.5 g, 2.57 mmols) and polymer-bound diisopropyl ethylamine (2.10 g, 7.73 mmol) in dichloromethane (50 mL) was added bromoacetyl chloride (0.49 g, 3.11 mmol) via a dropwise addition. After stirring for 2 hrs at room temperature the solids were removed by vacuum filtration. The filtrate was concentrated under reduced pressure, maintained under high vacuum for several hours, redissolved in THF (20 mL) and to this crude mixture was added potassium carbonate (1.06 g, 7.68 mmols), catalytic Kl, and morpholine (0.67 g, 7.68 mmols). After overnight stirring, the reaction was diluted with dichloromethane (50 mL), washed with water (25 mL), filtered through a cotton plug and concentrated by rotary evaporation to provide 5-(methyloxy)-1-(4-morpholinylacetyl)-6-nitro-2,3-dihydro-1H-indole (0.56 g, 67% over two steps). ESIMS (M+H)+=322.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[CH2:8]O.C(N(CC)CC)C.C(Cl)(=O)C=CC1C=CC=CC=1.[C:28]([O:31]CC)(=[O:30])[CH3:29]>C1COCC1>[CH:1]12[CH2:7][CH:4]([CH:3]=[CH:2]1)[CH2:5][CH2:6]2.[CH3:8][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH:7]=[CH:29][C:28]([O-:31])=[O:30]
Reactant: OCC1CC2C=CC1C2
Reactant: CCOC(C)=O
Agent: O=C(Cl)C=Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C1=CC2CCC1C2
Product: Cc1ccccc1C=CC(=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
After 5-norbornene-2-methanol (15 g, 0.121 mol), which was synthesized as described above, triethylamine (Aldrich, 61.2 g, 0.605 mol), and 20 ml of THF were put into a 250 ml two-neck flask, agitation was conducted in an ice-water bath at 0° C. Cinnamoyl chloride (22.1 g, 0.133 mol) was dissolved in 60 ml THF, and then slowly added to the reactants using an additional flask. After 10 min, the reactants were heated to room temperature, and agitation was conducted for an additional time of 1 hour. The solution was diluted using ethyl acetate, moved to a separatory funnel, washed with water and NaHCO3 a few times, and distilled under reduced pressure to remove the solvent. Purification was conducted using column chromatography (hexane:ethyl acetate=20:1) to obtain a product. (yield: 88%)