Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=2[C:8](=[O:16])[NH:7][C:6]2[CH:17]=[CH:18][CH:19]=[N:20][C:5]1=2)=[O:3].[N:21]1([CH2:27][CH2:28][CH:29]2[O:34][CH2:33][CH2:32][NH:31][CH2:30]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.Cl>>[CH3:15][C:13]1[CH:12]=[CH:11][C:10]2[N:4]([C:2]([N:31]3[CH2:32][CH2:33][O:34][CH:29]([CH2:28][CH2:27][N:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)[CH2:30]3)=[O:3])[C:5]3[N:20]=[CH:19][CH:18]=[CH:17][C:6]=3[NH:7][C:8](=[O:16])[C:9]=2[CH:14]=1
Reactant: C1CCN(CCC2CNCCO2)CC1
Reactant: Cc1ccc2c(c1)C(=O)Nc1cccnc1N2C(=O)Cl
Agent: Cl
Product: Cc1ccc2c(c1)C(=O)Nc1cccnc1N2C(=O)N1CCOC(CCN2CCCCC2)C1
Yield: 79 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-5,11-dihydro-8-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-(1-piperidinyl)ethyl]morpholine in a yield of 79% of theory. Rf 0.43 (conditions as in Example 58). The colourless hydrochloride melted at 272°-273° C. with decomposition.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:13]([O-])([OH:15])=[O:14]>>[N+:13]([C:4]1[CH:5]=[CH:6][C:1]([C@@H:7]2[CH2:9][C@H:8]2[C:10]([OH:12])=[O:11])=[CH:2][CH:3]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Product: O=C(O)[C@@H]1C[C@H]1c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 78.2 %

Procedure:
To a 1000 mL RB flask fitted with magnetic stirrer was charged with 150 mL of HNO3, cooled to 0° C., was added (1R,2R)-2-phenylcyclopropanecarboxylic acid (15 g, 92.593 mmol) portion wise for half an hour, RM brought to RT and stirred for 3 h. After the completion of reaction, RM was poured into ice cold water, stirred for 30 min and filtered off the product and dried under vacuum. The obtained product was white color solid (15 g, yield: 78.2%).
Reaction SMILES: [CH2:1]([O:5][C:6]([CH:8]([N:12]1[CH:15]([S:16][N:17]2[C:21](=[O:22])[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:27])[CH:14]([NH:28][C:29](=[O:38])[CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:13]1=[O:39])[C:9]([CH3:11])=[CH2:10])=[O:7])[CH2:2][CH2:3][CH3:4].[Br:40]N1C(C)(C)C(=O)N(Br)C1=O.C1OC1C>[Hg].ClCCCl>[CH2:1]([O:5][C:6]([CH:8]([N:12]1[CH:15]([S:16][N:17]2[C:21](=[O:22])[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:27])[CH:14]([NH:28][C:29](=[O:38])[CH2:30][O:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:13]1=[O:39])[C:9]([CH2:11][Br:40])=[CH2:10])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: C=C(C)C(C(=O)OCCCC)N1C(=O)C(NC(=O)COc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: CC1CO1
Agent: [Hg]
Solvent: ClCCCl
Product: C=C(CBr)C(C(=O)OCCCC)N1C(=O)C(NC(=O)COc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Yield: 10 %

Procedure:
A mixture of 2.7 g (5 mmoles) of 1-(1-n-butyloxycarbonyl-2-methylprop-2-enyl)-3-phenoxyacetamido-4-phthalimidothio-azetidin-2-one, 200 ml of 1,2-dichloroethane, 1,4 g (5 mmoles ) of 1,3-dibromo-5,5-dimethylhydantoin and 3 ml of propylene oxide was irradiated under nitrogen for 3 hours at 14° C with a Hanovia TQ 150 mercury high pressure lamp using a Pyrex filter. After concentrating the reaction mixture, the residue was chromatographed over silica gel [toluene -ethyl acetate 5:1 (v/v)] to obtain 300 mg (0.5 mmole) of 1-(1-n-butyloxycarbonyl-2-bromomethylprop-2-enyl)-3-phenoxyacetamido-4-phthalimidothio-azetidin-2-one.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].[CH2:17]([O:19][C:20](=[O:24])[CH:21](Cl)[CH3:22])[CH3:18]>CN(C=O)C>[F:7][C:8]1[CH:13]=[C:12]([CH:21]([CH3:22])[C:20]([O:19][CH2:17][CH3:18])=[O:24])[CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCOC(=O)C(C)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
To a stirred solution of potassium t-butoxide (20 mmol) in DMF (20 mL) was added a mixture of 2-fluoro-nitrobenzene (10 mmol) and ethyl-2-chloropropionate (10 mmol) at 0° C. dropwise. After being stirred for 10 min at 0° C., the mixture was quenched by 1 N HCl solution, diluted with water and extracted with diethyl ether several times. The combined organic layers were washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:10) as eluant to afford ethyl 2-(3-fluoro-4-nitrophenyl)propionate (1-1, SU-654).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=O)[CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.C(OC([N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]1[CH2:39][NH2:40])=O)(C)(C)C.C(Cl)CCl>CN(C=O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([NH:40][CH2:39][CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38][NH:33]3)=[O:22])[CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NCC1CCCCN1)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 9 (1 mmol) was coupled with 2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (3 mmol) using EDC (2 mmol) in DMF (10 mL). The DMF was removed by rotary evaporation and the residue purified by flash chromatography on silica gel (ethyl acetate as eluent.) The resulting product was deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 432. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.5-8.65 (m, 2H) 8.38 (m, 1H) 8.22 (m, 1H) 7.95 (m, 1H) 7.55 (m, 1H) 7.28 (m, 1H) 7.20 (d, 1H) 7.05 (d, 2H) 6.68 (d, 2H) 3.5 (m, 2H) 3.3 (m, 2H) 2.95 (m, 1H) 2.6-2.85 (m, 3H) 2.48 (m, 1H) 1.0-1.7 (m, 6H).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.[CH:18]1([NH:21][C:22](=[O:36])[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[C:25]([F:35])[CH:24]=2)[CH2:20][CH2:19]1.[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH:18]1([NH:21][C:22](=[O:36])[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([CH2:2][C:3]4[CH:12]=[N:11][C:10]5[N:9]6[CH2:13][CH2:14][CH2:15][C@H:8]6[C:7](=[O:16])[NH:6][C:5]=5[CH:4]=4)[CH2:31][CH2:30]3)=[C:25]([F:35])[CH:24]=2)[CH2:19][CH2:20]1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: O=C(NC1CC1)c1ccc(N2CCNCC2)c(F)c1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: O=C(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)c(F)c1
Temperature: 105 °C
Yield: 40.4 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), N-cyclopropyl-3-fluoro-4-(piperazin-1-yl)benzamide hydrochloride (137 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 45-95% ACN in water, basic). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-MeOH (2:1, 6 mL) and dried in vacuum to afford (S)—N-cyclopropyl-3-fluoro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (85.3 mg, 0.184 mmol, 40.3% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.45-0.61 (m, 2H) 0.61-0.76 (m, 2H) 1.83-2.05 (m, 3H) 2.08-2.25 (m, 1H) 2.44-2.49 (m, 4H) 2.80 (td, J=7.33, 3.79 Hz, 1H) 3.08 (br. s., 4H) 3.54-3.66 (m, 1H) 3.91-4.06 (m, 1H) 6.98 (d, J=1.77 Hz, 1H) 7.02 (t, J=8.84 Hz, 1H) 7.49-7.69 (m, 3H) 8.31 (d, J=4.04 Hz, 1H) 10.44 (s, 1H). [M+H] calc'd for C25H29FN6O2, 465; found, 465.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:16](=[O:18])[CH3:17])=[CH:6][C:7]2[CH:8]=[CH:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)[CH3:2].[CH:19]([N-]C(C)C)(C)C.[Li+].CI>C1COCC1>[CH2:1]([O:3][C:4]1[C:5]([C:16](=[O:18])[CH2:17][CH3:19])=[CH:6][C:7]2[CH:8]=[CH:9][CH2:10][C:11]([CH3:14])([CH3:15])[C:12]=2[CH:13]=1)[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOc1cc2c(cc1C(C)=O)C=CCC2(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOc1cc2c(cc1C(=O)CC)C=CCC2(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(3-ethoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-ethanone (Compound A-25, 0.17 g, 0.68 mmol) in THF (33 mL) at −78° C. was added lithium diisopropylamide (1.5 M in cyclohexane, 0.55 mL 0.82 mmol). The cold bath was removed and the mixture was stirred for 2 h. The mixture was cooled to −78° C. again and methyl iodide (0.13 mL, 2.04 mmol) was added. The mixture was stirred at room temperature for 12 h then quenched with a saturated solution of NH4Cl and extracted with diethyl ether. The combined ethereal layers were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, 2% ethyl acetate in hexane) to give the title compound as a yellow oil.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[C:8]([NH2:9])=[C:7]([Cl:10])[CH:6]=[CH:5][C:4]=1[OH:11].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[ClH:2].[Cl:1][CH:5]1[C:6](=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]([Cl:10])=[C:8]([NH2:9])[CH:3]=[C:4]1[OH:11]
Reactant: Nc1c(Cl)ccc(O)c1Cl
Reactant: O=Cc1ccccc1
Agent: Cl
Product: NC1=C(Cl)C(=Cc2ccccc2)C(Cl)C(O)=C1

Procedure:
Analogously to the procedure and data in Examples 1 and 2, 2,4-dichloro-3-aminophenol hydrochloride was reacted with benzaldehyde. The reaction product of this example of this invention had the following characteristic data: IR-spectrum (Kbr) cm-1 : 1692, 1620, 1598, 1582, 1515, 1480, 1450, 1430, 1310, 1205, 1160, 1075, 1030, 930, 905, 890, 872, 830, 805, 745, 700, 685, 650.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH:18]=[O:19])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.S(=O)(=O)(O)O>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Zn]>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2([CH:18]([OH:19])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:16][CH2:17]2)=[CH:13][CH:14]=1
Reactant: O=CC1(c2ccc(Cl)cc2)CC1
Reactant: CCOC(=O)CBr
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(O)C1(c2ccc(Cl)cc2)CC1
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 75.9 %

Procedure:
A mixture of zinc dust (4.0 g, 61.2 mmol), ethyl bromoacetate (6.5 mL, 58.3 mmol) and 1-(p-chlorophenyl)-cyclopropanecarboxaldehyde (10.0 g, 55.4 mmol) in toluene is stirred at 70° C. for 45 minutes, cooled with an ice-water bath, treated with 100 mL of 10% sulfuric acid, stirred at room temperature for one hour, and diluted with ethyl acetate. The organic phase is separated, washed sequentially with 10% sulfuric acid, water, 10% sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain an oil. Chromatography of the oil using silica gel and a 9:1 to 7:3 hexanes/ethyl acetate gradient gives the title product as a colorless oil (11.3 g, 76%) which is identified by NMR spectral analyses.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:19]=[C:18]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:17]=2)=[CH:12][CH:11]=1.CS(C1C=CC(N2C(C3C=CC(Br)=CC=3)=CC(C(F)(F)F)=N2)=CC=1)(=O)=O>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:19]=[C:18]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:17]=2)=[CH:12][CH:11]=1
Reactant: OB(O)c1ccco1
Reactant: CCOC(=O)c1cc(-c2ccc(Br)cc2)n(-c2ccc(S(C)(=O)=O)cc2)n1
Agent: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)cc2)cc1
Product: CCOC(=O)c1cc(-c2ccc(-c3ccco3)cc2)n(-c2ccc(S(C)(=O)=O)cc2)n1

Procedure:
The title compound was prepared according to the procedure of Example 1 using 2-furanboronic acid instead of 2-thiophenboronic acid and Ethyl 5-(4-bromophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole-3-carboxylate prepared according to the procedure of EXAMPLE 63, step 1) instead of 1-[4-(Methylsulfonyl)phenyl]-5-(4-bromophenyl)-3-trifluoromethyl-1H-pyrazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]=[C:10]=[O:11])[CH:3]=1.[CH3:12][C:13]1[N:14]=[CH:15][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([NH2:23])[C:21]=2[CH:22]=1.BrC1C=CC(CN=C=O)=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][NH:9][C:10]([NH:23][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:21]=1[CH:22]=[C:13]([CH3:12])[N:14]=[CH:15]2)=[O:11]
Reactant: Cc1cc2c(N)cccc2cn1
Reactant: O=C=NCc1cccc(F)c1
Agent: O=C=NCc1ccc(Br)cc1
Product: Cc1cc2c(NC(=O)NCc3cccc(F)c3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 60F using 1-fluoro-3-(isocyanatomethyl)benzene and 3-methyl-5-isoquinolinamine instead of the product from Example 60E and 1-bromo-4-(isocyanatomethyl)benzene. 1H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.69 (bs, 1H), 8.87 (bs, 1H), 8.20 (d, 1H, J=6.9 Hz), 7.76 (s, 1H), 7.70 (d, 1H, J=7.8 Hz), 7.50 (t, 1H, J=7.8 Hz), 7.41 (m, 1H), 7.23-7.05 (m, 3H), 4.39 (d, 2H, J=6 Hz), 2.65 (s, 3H). MS (ESI) 310 (M+H)+. Anal. Calcd for C18H16FN3O: C, 69.89; H, 5.21; N, 13.58. Found: C, 69.86; H, 5.24; N, 13.56.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[NH:8]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9]1.Br[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][CH3:32]>O>[CH2:32]([N:8]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9]1)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: CCOC(=O)c1cc[nH]c1
Reactant: CCCCCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCn1ccc(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.3 %

Procedure:
To dry dimethylformamide (DMF) (15 ml) was added 0.84 g (21 mmol) of sodium hydride (60% oil dispersion), and then 2.78 g (20 mmol) of ethyl pyrrole-3-carboxylate was added portionwise thereto under ice-cooling. After stirring at room temperature for 10 minutes, 6.65 g (24 mmol) of bromotetradecane was added dropwise under ice-cooling. The mixture was stirred for 3.5 hours at room temperature, and then 30 ml of water was added thereto. The resulting mixture was extracted with 70 ml of ethyl acetate, washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After removing the solvent, the remaining oil was purified by subjecting it to column chromatography over silica gel (eluent: ethyl acetate/hexane=1/20-1/10) to obtain 6.33 g (89.0% yield) of ethyl 1-tetradecylpyrrole-3-carboxylate as white crystals, m.p. 32°-33° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Br:12][CH2:13][CH2:14]Br.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[N:7]1[C:8]2[C:3](=[C:2]([O:1][CH2:14][CH2:13][Br:12])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: BrCCBr
Reactant: Oc1cccc2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: BrCCOc1cccc2ncccc12
Temperature: 85 °C
Reaction time: 24 h
Yield: 100.1 %

Procedure:
A mixture of 5-hydroxyquinoline (0.3 g, 2.1 mmol), 1,2-dibromoethane (3.9 g, 21 mmol) and potassium carbonate (1.5 g, 11 mmol) in methyl ethyl ketone (15 mL) was allowed to stir at 85° C. for 24 h. The mixture was evaporated in vacuo and the residue was partitioned between ether (200 mL) and water (200 mL). The organic layer was dried (Na2SO4) and evaporated in vacuo to give the title compound (0.53 g).
Reaction SMILES: C([O:14][C:15](=[O:44])[C@H:16]([CH2:35][S:36][CH2:37][C@H:38]([OH:43])[C@H:39]([OH:42])[CH2:40][OH:41])[NH:17][C:18](=[O:34])[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][CH3:33])(C1C=CC=CC=1)C1C=CC=CC=1>FC(F)(F)C(O)=O.C(Cl)Cl>[C:18]([NH:17][C@H:16]([C:15]([OH:44])=[O:14])[CH2:35][S:36][CH2:37][C@H:38]([OH:43])[C@H:39]([OH:42])[CH2:40][OH:41])(=[O:34])[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][CH3:33]
Reactant: CCCCCCCCCCCCCCCC(=O)N[C@@H](CSC[C@H](O)[C@H](O)CO)C(=O)OC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCC(=O)N[C@@H](CSC[C@H](O)[C@H](O)CO)C(=O)O
Reaction time: 2 h

Procedure:
0.9 g of N-palmitoyl-S-[2(R),3(R),4-trihydroxybutyl]-(L)-cysteine-benzhydryl ester in a mixture of 3 ml of trifluoroacetic acid and 12 ml of methylene chloride is allowed to stand for 2 hours at room temperature. The reaction mixture is then evaporated to dryness; the residue is triturated with ice-water, filtered off with suction and the solid substance is dried. It is then extracted with ligroin, and recrystallised from acetone to yield colourless crystals of N-palmitoyl-S-[2(R),3(R),4-trihydroxy-butyl]-(L)-cysteine, m.p. 76°-76.5°, having the specific rotation [α]D20 =-5° (c=0.819, dioxane).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:36]1[CH:40]=[CH:39][C:38]([CH2:41][C:42](O)=[O:43])=[CH:37]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C1COCC1.C(Cl)Cl>[CH3:34][N:33]([CH3:35])[CH2:32][CH2:31][O:30][C:26]1[CH:25]=[C:24]([NH:23][C:19]2[N:18]=[C:17]([C:16]3[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:42](=[O:43])[CH2:41][C:38]5[CH:39]=[CH:40][S:36][CH:37]=5)[CH:7]=[CH:6][CH:5]=4)=[N:9][N:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=34)[CH:22]=[CH:21][N:20]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CN(C)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(N)c4)nn4ccccc34)n2)c1
Reactant: O=C(O)Cc1ccsc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5ccsc5)c4)nn4ccccc34)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-{[2-(dimethylamino)ethyl]oxy}phenyl)-2-pyrimidinamine (140 mg, 0.3 mmol) in THF were added 3-thienylacetic acid (51 mg, 0.36 mmol), TEA (125 μL, 0.9 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (136 mg, 0.36 mmol). The reaction was stirred overnight at rt, after which the reaction mixture was diluted with DCM, washed with 5% aqueous Na2CO3, dried over Na2SO4, and adsorbed onto silica gel. The crude product was purified by column chromatography and lyophilized to generate the title compound in 72% yield. 1H NMR (400 MHz, d6-DMSO) δ 10.27 (s, 1H), 9.55 (s, 1H), 8.83 (d, J=6.7 Hz, 1H), 8.51 (d, J=8.8 Hz, 1H), 8.26 (d, J=5.1 Hz, 1H), 7.89 (s, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.40-7.53 (m, 4H), 7.26-7.31 (m, 3H), 7.08-7.18 (m, 3H), 6.53 (d, J=8.2 Hz, 1H), 6.48 (d, J=5.3 Hz, 1H), 3.99 (t, J=5.7 Hz, 2H), 3.66 (s, 2H), 2.58 (t, J=5.9 Hz, 2H), 2.18 (s, 6H). ES-LC/MS m/z=588 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Cl[CH2:21][C:22](=[O:24])[CH3:23]>C1COCC1.O>[CH2:1]([N:8]([CH2:21][C:22](=[O:24])[CH3:23])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CCl
Reactant: CCOC(=O)CNCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CN(CC(C)=O)Cc1ccccc1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A solution of ethyl 2-(benzylamino)acetate (40 g, 207 mmol) and NaHCO3 (20.9 g, 248 mmol) in THF (400 mL) and water (30 mL) was heated to 50° C. 1-chloropropan-2-one (23.9 g, 259 mmol) was added and the reaction was stirred at 50° C. for 2 d. Water was added the solution extracted with hexanes. The organic layer was separated, dried, filtered, and concentrated to afford crude ethyl 2-(benzyl(2-oxopropyl)amino)acetate (118) which without further purification
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH3:15])[CH:5]=[CH:4][CH:3]=1.[F:16][C:17]([F:32])([F:31])[C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:21](Cl)=[O:22]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:15])[C:21](=[O:22])[C:20]2[CH:19]=[C:18]([C:17]([F:32])([F:31])[F:16])[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CNc1cnccc1-c1cccc(Cl)n1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1cccc(Cl)n1

Procedure:
The title compound was prepared in analogy to example 55, from (6-chloro-[2,4]bipyridinyl-3′-yl)-methyl-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using preparative HPLC for the purification. Off-white sticky solid (20%). MS (ESI): m/z=460.2 [M+H]+.
Reaction SMILES: [CH:1](=O)[CH3:2].[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[S:13]([NH2:16])(=[O:15])=[O:14]>C(O)C>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]2[NH:4][CH:1]([CH3:2])[NH:16][S:13](=[O:14])(=[O:15])[C:6]=2[CH:7]=1
Reactant: COc1ccc(N)c(S(N)(=O)=O)c1
Reactant: CC=O
Solvent: CCO
Product: COc1ccc2c(c1)S(=O)(=O)NC(C)N2

Procedure:
829 μl of acetaldehyde are added to a suspension of 20 g of 2-amino-5-methoxy-benzenesulphonamide in 20 ml of anhydrous ethanol. The reaction mixture becomes homogeneous and is heated at reflux for 30 min. The ethanol is evaporated off in vacuo. The solid is taken up in ether and filtered off. The solid is taken up in 40 ml of ethanol, refluxed for 15 min. and allowed to return to ambient temperature. The expected product is obtained after filtration.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](F)[C:3]=1[N+:10]([O-:12])=[O:11].[NH3:13]>O1CCCC1.CO>[F:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[NH2:13]
Reactant: N
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(F)cc(F)c1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
A solution of the 1,3,5-trifluoro-2-nitrobenzene (7.08 g, 39.98 mmol) in tetrahydrofuran (50 mL) was stirred at 0 degrees Centigrade while a solution of 7N ammonia in methanol (23 mL) was added. The reaction mixture was stirred overnight in a sealed tube. The mixture was filtered, and the solvent removed to give a red-orange solid which was purified by silica gel column chromatography using 2:1 hexanes/ethyl acetate to give 6.27 g of 3,5-difluoro-2-nitroaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][C:34]1([CH3:40])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)(=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][C:34]3([CH3:40])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: CC1(COS(=O)(=O)C(F)(F)F)CCOCC1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: C1CCOC1
Product: COc1cn(C(CC2(C)CCOCC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
1.91 g (5.08 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate, 2.00 g (7.63 mmol) of (4-methyltetrahydro-2H-pyran-4-yl)methyl trifluoromethanesulphonate and 6.61 ml (6.61 mmol) of bis(trimethylsilyl)lithium amide (1M in THF) in 10 ml of THF were reacted according to General Method 7B. Purification by preparative HPLC (acetonitrile/water gradient) gave the title compound. Yield: 212 mg (8% of theory)