Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C1C=CC=CC=1.[S-:10][C:11]#[N:12].[NH4+].[F:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:16]=1[NH2:17].O>CC(C)=O>[F:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:16]=1[NH:17][C:11]([NH2:12])=[S:10]
Reactant: N#C[S-]
Reactant: Nc1c(F)cccc1F
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O=C(Cl)c1ccccc1
Solvent: O
Product: NC(=S)Nc1c(F)cccc1F

Procedure:
Benzoyl chloride (5.44 g, 38 mmol) was added dropwise to a solution of ammonium thiocyanate (2.55 g, 42.6 mmol) in acetone. Solution was refluxed for 10 minutes at which time a solution of 2,6-difluoro-aniline (5.0 g, 38.8 mmol) in acetone was added dropwise and the solution refluxed for approximately 5 minutes. The solution was then poured into 500 mL of water and a resulting solid precipitated out. The separated crystalline solid was collected by filtration and then heated in a NaOH solution (3 g in 50 mL H2O). The solution was acidified with conc. HCl, then made slightly basic using conc. NH4OH. Crystalline solid was seen and collected to obtain (2,6-difluoro-phenyl)-thiourea. A mixture of the thiourea (5.7 g, 30.3 mmol), AcONa (2.43 g) and ClCH2CO2H (2.86 g) in AcOH (20 mL) was heated to reflux at 130 C.° for four hours. The mixture was poured onto water and the formed solid was isolated by filtration. It was washed with water to give the desired thiazolidinone (a compound of formula IV in which R is 2,6-difluorophenyl) (6.75 g, 29.6 mmol). A mixture of the thiazolidinone (200 mg, 0.8 mmol), 6-formyl quinoline (137 mg, 0.8 mmol) and AcONa (211 mg, 2.4 mmol) in AcOH (10 mL) was heated to reflux at 130 C.° for 2 days. Water was added to the solution and generated a solid that was collected by filtration and washed with water, followed by desiccation in vacuo to afford the title compound as a yellow solid. ES (±) MS m/e=368.0 (M+H). HPLC (rt)−4.53 m
Reaction SMILES: [F:1][C:2]1[C:7]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[BrH:12].BrBr>C(O)(=O)C>[Br:12][CH:9]([CH3:10])[C:8]([C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1)=[O:11]
Reactant: Br
Reactant: CCC(=O)c1cccnc1F
Agent: BrBr
Solvent: CC(=O)O
Product: CC(Br)C(=O)c1cccnc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 1-(2-fluoropyridin-3-yl)propan-1-one (12.9 g) and 25% solution (70 mL) of hydrogen bromide in acetic acid was added dropwise bromine (4.4 mL), and the obtained mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure to give the title compound as a red-brown oil (yield 29.6 g, quantitative).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:8].[NH2:15][CH:16]1[C:30](=[O:31])[N:18]2[C:19]([C:27]([OH:29])=[O:28])=[C:20]([CH2:23][S:24][CH2:25][CH3:26])[CH2:21][S:22][C@H:17]12>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:9][CH2:10][CH2:11][C:12]([NH:15][CH:16]1[C:30](=[O:31])[N:18]2[C:19]([C:27]([OH:29])=[O:28])=[C:20]([CH2:23][S:24][CH2:25][CH3:26])[CH2:21][S:22][C@H:17]12)=[O:14])=[O:8]
Reactant: O=C(O)CCCS(=O)c1ccccn1
Reactant: CCSCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: CCSCC1=C(C(=O)O)N2C(=O)C(NC(=O)CCCS(=O)c3ccccn3)[C@H]2SC1

Procedure:
426 mg. of 4-(2-pyridylsulfinyl)butyric acid and 7-amino-3-ethylthiomethyl-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 366 mg. of 7-[4-(2-pyridylsulfinyl)butyramido]-3-ethylthiomethyl-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11]([Zn]CC)[CH3:12].CCCCCC.CN(CCO)C>C1COCC1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:11]([C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[CH3:12]
Reactant: CC[Zn]CC
Reactant: CC(=O)c1ccc(Cl)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CN(C)CCO
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1ccc(C(C)=O)cn1
Temperature: 25 °C
Yield: 20 %

Procedure:
A dry round bottomed flask was charged with 1-(6-chloro-3-pyridinyl)-1-ethanone (IM15) (3.596 g, 23.11 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (1.694 g, 2.315 mmol) in THF (100 mL) under N2. A 1 M solution of diethyl zinc in hexane (35 mL, 35 mmol) was added drop wise to this mixture followed by N,N-dimethylaminoethanol (0.50 mL, 5.0 mmol). The mixture was heated to reflux for 30 minutes. The mixture was cooled to room temperature and then quenched by the addition of saturated aqueous NH4Cl solution (100 mL). The mixture was filtered through a plug of celite. The aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with water, brine and then dried over Mg2SO4. Flash Chromatography (120 g silica, 0-40% EtOAc in heptanes) gave the title compound as a yellow oil (0.699 g, 20%) sufficiently pure for the next step.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(O)(C)C.[CH3:15][CH:16]([NH2:18])[CH3:17]>O>[CH:16]([NH:18][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1)([CH3:17])[CH3:15]
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CC(C)N
Solvent: CC(C)O
Solvent: O
Product: CC(C)Nc1ncnc2[nH]ccc12
Temperature: 120 °C
Yield: 89.5 %

Procedure:
To 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 168 mg, 1.09 mmol), 2.00 mL of isopropyl alcohol is added, followed by 2-propanamine (11, 0.280 mL, 3.28 mmol). The reaction is heated by microwave at 120° C. for 20 minutes, then an additional 40 minutes. Another 0.250 mL of 2-propanamine is added and heated at 120° C. for 60 minutes. The reaction is poured into water and extracted with ethyl acetate. The organic layer is concentrated under vacuum and purified by silica gel column chromatography, eluting with a gradient of 1-5% methanol in dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (12, 172 mg). MS (ESI) [M+H+]+=176.85.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:9]=[C:10]=[O:11])[CH3:8].[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([N+:23]([O-:25])=[O:24])[C:14]=1[O:26][C:27]1[CH:31]=[C:30]([CH3:32])[NH:29][N:28]=1.Cl>C(OCC)(=O)C>[CH2:7]([NH:9][C:10]([N:29]1[C:30]([CH3:32])=[CH:31][C:27]([O:26][C:14]2[C:15]([N+:23]([O-:25])=[O:24])=[CH:16][C:17]([C:19]([F:20])([F:21])[F:22])=[CH:18][C:13]=2[Cl:12])=[N:28]1)=[O:11])[CH3:8]
Reactant: Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2[N+](=O)[O-])n[nH]1
Reactant: CCN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2c(Cl)cc(C(F)(F)F)cc2[N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
Potassium carbonate (0.30 g, 2.2 mmol) and ethyl isocyanate (0.14 g, 2.0 mmol) were added to a solution of 3-(2-chloro-6-nitro-4-trifluoromethylphenyloxy)-5-methylpyrazole (0.64 g, 2.0 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a yellowish solid of N-ethyl-3-(2-chloro-6-nitro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.13 g, yield: 16.6%). mp: 98-99° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.18 (t, J=7.2 Hz, 3H), 2.60 (d, J=0.5 Hz, 3H), 3.32 (dq, J=6.0 and 7.2 Hz, 2H), 5.87 (q, J=0.5 Hz, 1H), 6.40-6.65 (m, 1H), 8.01 (d, J=2.0 Hz, 1H), 8.17 (m, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][NH:11][C:12]=1[NH2:13])=[O:7])[CH3:4].[O:14]1[CH2:19][CH2:18][CH2:17][C:16]([CH:20]=O)=[CH:15]1>CN(C)C=O>[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:20]=[C:16]([CH2:17][CH2:18][CH2:19][OH:14])[CH:15]=[N:13][C:12]=12)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cn[nH]c1N
Reactant: O=CC1=COCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn2cc(CCCO)cnc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
Sodium hydride (60% suspension in mineral oil, 350 mg, 8.78 mmol) was added, at 0° C., to a solution of 5-amino-1H-pyrazole-4-carboxylic acid ethyl ester (1.4 g, 8.9 mmol) and 5,6-dihydro-4H-pyran-3-carbaldehyde (0.5 g, 4.5 mmol) in anhydrous N,N-dimethylformamide (10 mL) and the resulting mixture was stirred, at 0° C., for 30 minutes. The reaction mixture was stirred at room temperature overnight and then heated at 50° C. for 2 hours. The resulting mixture was partitioned between water and ethyl acetate and the organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography to afford 0.24 g of 6-(3-hydroxy-propyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester as a white solid. MS=250 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C@H:8]([NH:19]C(=O)OC(C)(C)C)[CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[O:5][C:6]=1[CH3:7].[ClH:27].CCOC(C)=O>>[ClH:27].[CH3:1][C:2]1[N:3]=[C:4]([C@H:8]([NH2:19])[CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[O:5][C:6]=1[CH3:7]
Reactant: Cc1nc([C@@H](Cc2c[nH]c3ccccc23)NC(=O)OC(C)(C)C)oc1C
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1nc([C@H](N)Cc2c[nH]c3ccccc23)oc1C

Procedure:
A solution of tert-butyl(1R)-1-(4,5-dimethyl-1,3-oxazol-2-yl)-2-(1H-indol-3-yl)ethylcarbamate (3 g, 8.4 mmol) in HCl/AcOEt 1N (80 ml) was stirred at room temperature for about 2.5 hours. The mixture was concentrated under reduced pressure, diethyl ether (100 ml) added, and the white precipitate collected by filtration, and washed with diethyl ether to afford the hydrochloride salt of the desired product (2.4 g). Melting point: 172-174° C.
Reaction SMILES: [CH3:1][S:2]([NH:5][NH2:6])(=[O:4])=[O:3].CCN(C(C)C)C(C)C.C[O:17][C:18](=O)[C:19]1[CH:24]=[C:23]([C:25]2[N:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)[C:22]([C:31]([F:34])([F:33])[F:32])=[CH:21][C:20]=1[NH:35][C:36](OC1C=CC(Cl)=CC=1)=[O:37]>O1CCOCC1>[CH3:30][N:26]1[CH:27]=[CH:28][CH:29]=[C:25]1[C:23]1[CH:24]=[C:19]2[C:20](=[CH:21][C:22]=1[C:31]([F:32])([F:33])[F:34])[NH:35][C:36](=[O:37])[N:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:18]2=[O:17]
Reactant: COC(=O)c1cc(-c2cccn2C)c(C(F)(F)F)cc1NC(=O)Oc1ccc(Cl)cc1
Reactant: CS(=O)(=O)NN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cn1cccc1-c1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F
Temperature: 95 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
CH3SO2NHNH2 (25.5 mg, 1.5 equiv) and i-Pr2NEt (26.5 μL, 1 equiv) were added to a solution of 2-(4-chloro-phenoxycarbonylamino)-5-(1-methyl-1H-pyrrol-2-yl)-4-trifluoromethyl-benzoic acid methyl ester (70 mg, 0.155 mmol) in dioxane (2 mL). The mixture was stirred for 2 h (TLC control) at 95° C. CH3SO2NHNH2 (25.5 mg, 1.5 equiv) and i-Pr2NEt (26.5 μL, 1 equiv) were then added. The mixture was stirred for 48 h at 95° C. The mixture was evaporated to dryness. The crude product was purified by column chromatography (silica gel 60, EtOAc/hexanes 7/3) to give N-[6-(1-methyl-1H-pyrrol-2-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide (50 mg, 80%) as a yellow solid. ESI-MS: m/z 420 [M+NH4]+, rt: 4.83 min. 1H-NMR (DMSO-d6, 400 MHz) 7.91 (s, 2H), 7.57 (s, 1H), 7.54 (s, 1H), 3.88 (s, 3H), 3.14 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[NH:14][CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.Cl.C(O)CC>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[NH:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nccn2Cc2ccc(F)cc2)CC1
Agent: Cl
Solvent: CCCO
Solvent: CO
Product: Fc1ccc(Cn2ccnc2NC2CCNCC2)cc1
Yield: 69.4 %

Procedure:
A mixture of intermediate 29 (0.026 mol) in a solution of HCl in 2 propanol (15 ml) and CH3OH (110 ml) was stirred and refluxed for 1 hour. The solvent was evaporated. The residue was taken up in H2O/CH2Cl2. The mixture was alkalized with NaOH. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 4.95 g (69%) of N-[1-[(4-fluorophenyl)methyl]-1H-imidazol-2-yl]-4-piperidinamine (intermediate 30).
Reaction SMILES: [CH2:1]([NH:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:18]1(=[O:24])[O:23][C:21](=[O:22])[CH:20]=[CH:19]1>C1(C)C=CC=CC=1>[CH2:1]([N:13]([CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])/[CH:19]=[CH:20]\[C:21]([OH:23])=[O:22])[C:18](=[O:24])/[CH:19]=[CH:20]\[C:21]([OH:23])=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCNCCCN
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCN(CCCNC(=O)/C=C\C(=O)O)C(=O)/C=C\C(=O)O
Reaction time: 0.5 h

Procedure:
121 parts of N-dodecylpropanediyl diamine were dissolved in 80 parts of toluene and 98 parts of maleic acid anhydride added at 50° to 60° C. After stirring for 30 minutes at a temperature of 50° to 60° C., the toluene was distilled off under reduced pressure at 50° to 60° C. 221 parts of the crude N-dodecyl-N,N'-propanediyl bis-maleamic acid ##STR9## were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].[OH-].[Na+]>CO.C(O)C>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11](=[O:16])[CH:10]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CC(C)(C)C(=O)C=Cc1ccc(Cl)cc1

Procedure:
evaporation. The yield in that procedure is only 59% of crude product. Apart from the poor yield, the complicated aqueous work up is a disadvantage. In DE-OS (German Published Specification) 2,737,489, a procedure is described, according to which p-chlorobenzaldehyde is reacted with pinacolone in the presence of sodium hydroxide in methanol/ethanol at maximum temperatures of up to 25° C. 4,4-Dimethyl-1-(p-chlorophenyl)-1-penten-3-one is formed as a solid, has to be filtered off with suction and washed with further solvent. The required low temperature results in an inhomogeneous, partially solid reaction mixture, which can only be stirred with difficulty. Furthermore, molar amounts of sodium hydroxide have to be used. A further disadvantage is that the portions of the reaction product which remain in the mother liquor have to be isolated in an additional workup step. To hydrogenate the double bond, the pentenone is dissolved in ethyl acetate and reacted with about 26% by weight of Raney nickel and with hydrogen at atmospheric pressure and a reaction time of about 14 1/2 hours. The very large amount of catalyst and the very long reaction time are the crucial disadvantages of this process. In all known procedures, the condensation product of pinacolone and p-chlorobenzaldehyde has to be isolated and purified as a solid and is only then subjected to hydrogenation in a second separate operation.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11](Cl)(=[O:13])=[O:12])=[CH:6][CH:5]=1.[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11](=[O:13])(=[O:12])[NH:21][CH2:20][C:19]2[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:18]=2[O:17][CH3:16])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CS(=O)(=O)Cl)cc1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: ClCCl
Product: COC(=O)c1ccc(CS(=O)(=O)NCc2ccc(OC)cc2OC)cc1

Procedure:
Under inert gas, 10 g of 4-[(chlorosulfonyl)methyl]benzoic acid methyl ester were initially charged in 100 ml of DCM, then, at a temperature of 0° C., 12.1 ml of 2,4-dimethoxybenzylamine were added dropwise. The reaction mixture was filtered and the filtrate was washed with 1 N HCl. The organic phase was dried over MgSO4 and concentrated by rotary evaporation. This gave the product (14.2 g) with a molecular weight of 379.4 g/mol (C18H21NO6S).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19]Br>CO.O>[C:3]1([CH3:8])[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:1]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: BrCCCCBr
Reactant: Cc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccccc1N1CCCC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
To a solution of o-toluidine (2.0 g; 18.7 mmol) in methanol (62 mL) was added sodium carbonate (4.95 g; 46.75 mmol) followed by 1,4-dibromobutane (4.85 g; 22.4 mmol). The resulting mixture was stirred at 50° C. under a nitrogen atmosphere overnight and then diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 40% v/v over 900 mL gradient elution) to yield the title product as a dark yellow-orange oil (1.24 g).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[C:3]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[C:20]([CH2:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.C(=O)(O)[O-].[Na+]>C(O)C>[C:21]1([C:20]2[CH:28]=[C:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:6]3[N:5]=[C:4]([C:7]4[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=4)[C:3]([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)=[C:2]3[N:1]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Reactant: Nc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Fc1ccc(-c2nn3c(-c4ccccc4)cc(-c4ccccc4)nc3c2-c2ccncc2)cc1
Temperature: 0 °C
Yield: 93.9 %

Procedure:
A mixture of 5-amino-3-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole (153 mg), dibenzoylmethane (162 mg) and conc. hydrochloric acid (0.1 ml) in ethanol (5 ml) was refluxed for 4 hours. The reaction mixture was cooled and poured into ice-water. The mixture was neutralized with an aqueous saturated sodium bicarbonate solution. The separated oil was extracted with dichloromethane and the extract was washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from methanol to give 5,7-diphenyl-2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine (250 mg).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH:13]1([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][C:47]([CH3:57])([S:53]([CH3:56])(=[O:55])=[O:54])[C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:41][CH:40]=1>C1COCC1>[CH:13]1([O:18][C:39]2[CH:40]=[CH:41][C:42]([CH2:45][CH2:46][C:47]([CH3:57])([S:53]([CH3:56])(=[O:55])=[O:54])[C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:43][CH:44]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)C(C)(CCc1ccc(O)cc1)S(C)(=O)=O
Reactant: OC1CCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(CCc1ccc(OC2CCCC2)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
Diethyl azodicarboxylate (40%, 220 uL, 0.48 mmol) was added to a solution of cyclopentanol (30.2 uL, 0.333 mmol), triphenylphosphine (120 mg. 0.456 mmol), and (+/−)-ethyl 4-(4-hydroxyphenyl)-2-methyl-2-(methylsulfonyl)butanoate (120 mg, 0.40 mmol) in THF (3 mL) at 0° C. under nitrogen. The reaction was allowed to warm to rt and was stirred overnight. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (3×30 mL). The combined organics were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified via column chromatography using an Analogiz SF10-8 g using EtOAc in Heptane (10-50%) to afford the title compound as a clear oil (100 mg, 67.8%). LC-MS m/z 369.4 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[F:19][C:20]1[CH:21]=[C:22]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:23][NH:24][C:25](=[O:30])[CH2:26][C:27](O)=[O:28]>>[F:19][C:20]1[CH:21]=[C:22]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:23][NH:24][C:25](=[O:30])[CH2:26][C:27]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:28]
Reactant: O=C(O)CC(=O)NCc1cc(F)cc(F)c1
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Product: CN1C(=O)C(NC(=O)CC(=O)NCc2cc(F)cc(F)c2)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=450.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(3,5-difluoro-benzyl)-malonamic acid.
Reaction SMILES: N1(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)C=CN=C1.[CH3:24][O:25][C:26]([C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][N:29]=1)=[O:27].Cl.Cl[CH2:39][C:40]1[N:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]2=[N:42][C:41]=1[C:49]1[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=1>>[Cl:55][C:52]1[CH:51]=[CH:50][C:49]([C:41]2[N:42]=[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][N:44]3[C:40]=2[CH2:39][N:30]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:28]([C:26]([O:25][CH3:24])=[O:27])=[N:29]2)=[CH:54][CH:53]=1
Reactant: COC(=O)c1n[nH]c2ccccc12
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ccnc2)cc1
Agent: Cl
Product: COC(=O)c1nn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)c2ccccc12

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 1 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride methyl 1H-indazole-3-carboxylate. M/e+ 417 for C23H18ClN4O2 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.22 (d, J=6.9 Hz, 1H), 8.03 (d, J=6.6 Hz, 1H), 7.83 (d, J=8.4 Hz, 2H), 7.68 (dd, J=8.8, 1.8 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 7.30 (m, 2H), 7.24 (m, 1H), 6.81 (t, J=6.2 Hz, 1H), 6.47 (s, 2H), 4.03 (s, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:34]=[CH:33][S:32][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([NH:24]C(=O)OC(C)(C)C)[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[ClH:35]>O1CCOCC1>[ClH:35].[NH2:24][CH:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16]2[N:17]=[C:12]([NH:11][C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:13]3[N:34]=[CH:33][S:32][C:14]=3[N:15]=2)[CH2:19]1
Reactant: COc1ccc(Nc2nc(N3CCCC(NC(=O)OC(C)(C)C)C3)nc3scnc23)cc1OC
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(N3CCCC(N)C3)nc3scnc23)cc1OC

Procedure:
A solution of tert-butyl 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidin-3-ylcarbamate (195 mg, 0.4 mmol) in 85 mL of saturated HCl in dioxane was stirred at room temperature for 24 hours. The solvent was evaporated at 40° C. under reduced pressure to give 5-(3-aminopiperidin-1-yl)-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine hydrochloride (200 mg, crude) as a yellow solid. It was used directly in the next step without further purification. LC-MS: 387.0 [M+H]+, tR=1.19 min.